Activated Ester Containing Polymers: Opportunities and Challenges

Review pubs.acs.org/CR

Activated Ester Containing Polymers: Opportunities and Challenges for the Design of Functional Macromolecules Anindita Das and Patrick Theato*

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on August 25, 2015 | http://pubs.acs.org Publication Date (Web): August 25, 2015 | doi: 10.1021/acs.chemrev.5b00291

Institute for Technical and Macromolecular Chemistry, University of Hamburg, D-20146 Hamburg, Germany 5. Orthogonal and Sequence-Controlled Postmodification 6. Functional Materials by Postpolymerization Modification 6.1. Cross-Linked Particles 6.2. Hydrogels 6.3. Bioconjugated Polymers 6.3.1. Lipopolymers 6.3.2. Glycopolymers 6.3.3. DNA-Polymer Conjugates 6.3.4. Peptide/Protein Polymer Conjugates 6.4. Metal Polymer Complexes 6.5. Functionalized Surfaces 7. Concluding Remarks Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Methods of Preparation of Polymers with Pendent Activated Ester Moiety in the Side Chain 2.1. Free Radical Polymerization for Homopolymers and Statistical Polymers 2.1.1. N-Hydroxysuccinimide (NHS) Ester Monomers 2.1.2. Pentafluorophenyl (PFP) Ester Monomers 2.1.3. Other Activated Ester Monomers 2.2. Controlled Radical Polymerization for Homopolymers and Statistical Polymers 2.2.1. Polymerization of NHS Ester Monomers 2.2.2. Polymerization of PFP Ester Monomers 2.2.3. Polymerization of Other Activated Ester Monomers 2.2.4. Amphiphilic and Stimuli-Responsive Statistical Copolymers 2.3. Block Copolymers 2.3.1. Block Copolymerization of Activated Ester Monomers 2.3.2. Amphiphilic and Stimuli-Responsive Block Copolymers 3. Other Macromolecular Designs 3.1. Star Polymers 3.2. Chain-End-Functionalized Polymers 4. Other Methods of Polymerization of Activated Ester Monomers 4.1. Alkyne Metathesis of Acetylenes 4.2. Ring-Opening Metathesis Polymerization (ROMP) of Norbornenes 4.3. Ring-Opening Polymerization (ROP) of Cyclic Carbonates 4.4. Electrochemical Polymerization of Activated Ester Containing Pyrroles and Thiophenes 4.5. Plasma Polymerization © XXXX American Chemical Society

A C D

AC AE AE AF AJ AJ AJ AK AL AN AP AQ AS AS AS AS AS AS

D

1. INTRODUCTION Rapidly growing demand of functional polymers in various interdisciplinary areas of research has accentuated the need for modern synthetic tools to develop advanced polymers featuring a variety of functional groups. Lutz, Sumerlin, and Matyjaszewski stated recently in their editorial to the special issue on precisely controlled polymer architectures “Indeed, controlled polymerization techniques, new routes for post-polymerization functionalization, and the ability to control macromolecular self-assembly have provided access to complex polymer structures that were previously considered inaccessible”,1 thereby highlighting the modern developments in synthesis of functional polymers. While controlled polymerization techniques have found wide acceptance as valuable and sophisticated synthetic tools, the aspect of postpolymerization modification has not been recognized as equally important. Postpolymerization modification (PPM), also referred to as postpolymerization functionalization or simplified postmodification or postfunctionalization, is as old as the discipline of polymer synthesis. However, postpolymerization modification, also known as “polymer analogous reactions”, was first defined by Hermann Staudinger, a pioneer in modern polymer chemistry who consequently was awarded the first Nobel Prize for

E E F F G H I K K N Q R S X X Y

Special Issue: Frontiers in Macromolecular and Supramolecular Science

Y AA AB

Received: May 12, 2015

A

DOI: 10.1021/acs.chemrev.5b00291 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

structures. This marked the need for extremely efficient chemical reactions under mild conditions for PPM. Recent development in chemoselective coupling reactions such as thiol−ene, thiol−yne, Michael addition, nucleophilic activated esters/amine exchange, thiol−disulfide exchange, azide−alkyne cycloaddition, Diels−Alder cycloaddition, and many others have laid the foundation for modern polymer analogous reactions.11−13 In modern days, many of those efficient reactions have been summarized under the umbrella of “click” reactions.11,14,15 In combination with controlled polymerization methods16−20 that show improved functional group tolerance in contrast to conventional polymerization techniques, PPM has led to access to numerous defined functional materials. Among the various examples of chemical reactions under the definition of PPM, activated ester−amine chemistry is a classical one (Scheme 2).21,22 Although activated ester

polymer chemistry. To date, PPM happens to be the most versatile and successful tool for engineering functional polymers. As illustrated in Scheme 1, the PPM technique allows polymerization of monomers with functional moieties that


Scheme 1. Schematic Representation for the Synthesis of Functional Polymer by PPM and Direct Polymerization

Scheme 2. PPM Using Activated Ester Amine Chemistry

remain proactive (often also called reactive groups) under the polymerization condition but can be quantitatively and selectively transformed into other functional groups in subsequent steps. Advantages of such approaches over direct polymerization of the respective functional monomers are manifold. Direct polymerization often suffers from a limited functional group tolerance under the polymerization condition. This can be due to participation of the functional group attached to the monomer in side reactions that often leads to uncontrolled polymerization or suppressing the polymerization process by poisoning the initiator/catalyst or the monomer. Even incompatibility of the functional groups toward the solvent or the reaction conditions can lead to retarded chain growth. Last but not least, the functional group may simply react with the polymerizable group itself, as, for example, seen in amino-containing acrylates.2 Here comes the utility of PPM into the game, where a chemical modification is conducted after the polymerization step, under very mild conditions. Otherwise, this approach is highly attractive for analyzing structure−property relationship behavior as one can think of making a library of functional polymers with identical degree of polymerization and chainlength distributions from a single reactive precursor polymer. Therefore, PPM facilitates diversification in a single polymeric backbone, essential for engineering functional materials which are otherwise not possible by direct polymerization. Ever since its discovery, polymer chemists have tried different chemical reactions for PPMs to fabricate functional materials. These includes hydrogenation of rubber3 and polystyrene,4 modification of polybutadiene backbone via thiol−ene addition,5 chlorination of polystyrene−divinylbenzene used in solid-phase peptide synthesis,6 modification of polymers with pendent epoxide functionalities,7,8 and many more. 9,10 However, many of those earlier examples of PPMs suffered from nonquantitative installation of functional groups due to poor reaction efficiency and required harsh reaction conditions that often lead to potential defects within the polymer

chemistry in polymer synthesis was introduced way before the advent of click chemistry, it was overshadowed by the growing popularity of the 1,3-dipolar cycloaddition reaction, namely, copper(I)-catalyzed alkyne−azide cycloaddition (CuAAC).14,23,24 Without undermining the triumph achieved in PPM utilizing click reactions, it is still believed that activated ester amine exchange has some advantages over other reactions. Primarily, activated esters are useful derivatives for covalent attachment of functional amines based on a stable amide bond formation that is the basis of most biological systems. It is presumed that judicial application of this chemistry can potentially mimic the synthesis of many biostructures and help to comprehend their functions. It comes as no surprise that activated ester chemistry has drawn tremendous interest in synthetic peptide chemistry.25−29 Even from the synthetic standpoint, activated ester amine chemistry is advantageous owing to the abundant availability of most amines from natural or commercial sources when compared with other abiotic synthons (e.g., azides and alkynes) commonly employed in alkyne−azide click reactions. Additionally, the auxiliary use of toxic metal catalysts in 1,3-dipolar cycloaddition reactions during PPM limits the practical application of those polymers in biomedical research. On the down side, activated ester amine chemistry is a substitution reaction, which requires the removal of the released alcohol afterward. However, the removal of small molecular compounds from polymers is a routine procedure that is conducted anyways and allows recycling of the activating alcohol. The objective of this review is to provide the readers with an extensive overview of the advancement made in the area of polymeric activated ester chemistry in designing precisely defined functionally diverse polymer structures, starting from utilizing classical polymerization techniques to state-of-the-art controlled polymerization methods and to highlight their potential applications in various interdisciplinary research areas. This review is divided into two parts. The first part will B


Chemical Reviews

Review


Table 1. Structures of Various Activated Ester-Containing Monomers

emphasize the development of activated ester chemistry in constructing different reactive polymer structures where detailed information will be provided on various activated ester monomers being used under different polymerization techniques, and their advantages and drawbacks will be discussed explicitly. In the second part, focus will be on the versatility and fidelity of this chemistry in fabricating numerous functional materials and their possible opportunities in different areas of application ranging from biomedical sciences to materials chemistry. Considering the vast literature available

in this area, only selected examples will be presented in each subsection to make the review comprehensible while citing many similar studies in the corresponding references.

2. METHODS OF PREPARATION OF POLYMERS WITH PENDENT ACTIVATED ESTER MOIETY IN THE SIDE CHAIN Ringsdorf21 and Ferruti22 introduced the concept of activated ester chemistry for preparing reactive polymers. Soon after, polymer chemists started developing numerous activated esterC



Chemical Reviews

Review

aminolysis of polyNHSA with allylamine, which could not be prepared by direct polymerization of the corresponding monomer. However, the major drawback of polyNHSA or polyNHSMA is their poor solubility in most organic solvents (except DMF and DMSO) that accounts for their limited use as homopolymers. Thus, NHSA and NHSMA are most often copolymerized with other monomers (Scheme 3b) to enhance the solubility of the resulting copolymers in a wide range of solvents. This extends their scope for aminolysis with different amines of varying polarity. To gain insight into the distribution profile of the activated ester group along the polymer backbone during copolymerization, it is important to have an idea of the reaction kinetics and/ or the reactivity ratio between the reactive and the nonreactive monomer during copolymerization. The reaction kinetics for the copolymerization of NHSMA31 with other commonly used (meth)acrylate monomers such as butyl acrylate (BA) and methyl methacrylate (MMA) during free radical copolymerization have been studied by automatic continuous online monitoring of the polymerization technique (ACOMP).32 The results revealed a similar reactivity ratio (r) between the MMA/NHSMA pair in contrast with the BA/NHSMA pair, providing useful information on copolymerizations of NHSMA. Copolymerization of NHSA with hydrophilic monomers can lead to water-soluble reactive polymers that can be functionalized, for example, with various biomolecules. Therefore, the kinetic behavior of NHSA with aqueous soluble N-acryloylmorpholine (NAM) during radical-initiated copolymerization has been investigated in 1,4-dioxane at 60 °C in the presence of AIBN.33 The reactivity ratios of two monomers were determined to be rNHSA = 0.63 ± 0.03 and rNAM = 0.75 ± 0.01, illustrating an almost perfectly random copolymerization behavior of the binary comonomer mixture, leading to the synthesis of macromolecules with homogeneous composition. The average copolymer composition and sequence of monomeric distribution within the linear chain was also determined by 1H NMR and 13C NMR spectroscopies. Similarly, kinetic studies for copolymerization of NHSA and N-vinylpyrrolidone (NVP) were investigated in DMF using 4,4′-azobis(4-cyanopentanoic acid) as an initiator.34 The reactivity ratios of the two monomers were determined to be rNHSA = 0.27 ± 0.04 and rNVP = 0.01 ± 0.01, which seemed to have a strong impact on the overall rate of copolymerization. Unlike the previous example, it indicates a strong alternating tendency during copolymerization.35 During copolymerization of N-isopropylacrylamide (NIPAM) with NHSA in THF/toluene mixture and AIBN as initiator, the molecular weight of the copolymer, poly(NIPAMco-NHSA), was found to depend heavily on the solvent composition and showed a rise in molecular weight with increasing ratio of toluene to THF. Even by adjusting the comonomer feed ratio, it was possible to control the activated ester content per polymer chain, determined from the UV absorption band (259 nm) of the N-hydroxysuccinimide anion generated during aminolysis of the copolymer with isopropylamine.36 Even photopolymerization of NIPAM with NHSA was conducted in the presence of the photoinitiator 2,2-dimethoxy2-phenyl-acetophenone using a UV source, resulting in random copolymers poly(NIPAM-co-NHSA) with molecular weights varying between 10 and 20 kD.37 The reactive prepolymer was conjugated with different proteins (α-lactalbumin, albumin, and IgG) via their amine binding sites. The surface-initiated polymerization of N-methacryloyl-β-alanine N′-oxysuccinimide

based monomers that could be easily polymerized under mild conditions to generate reactive precursor polymers. Table 1 provides a glimpse of various types of monomers featuring different activated ester moieties that have been used as a reactive entity for postpolymerization modification. This section has been categorized into different subsections to allow the readers to have clear insight into how this area of reactive polymer synthesis utilizing different activated ester monomers has advanced from an era of conventional free radical polymerization to modern controlled chain polymerization and in present day created a facile route for highly functional block copolymers. Particular emphasis is given to the synthesis of reactive homopolymers and statistical copolymers utilizing both free and controlled chain polymerization methods followed by synthesis of reactive functional block copolymers. Focus will be on the synthetic aspects, the reaction kinetics, and the advantages and drawbacks of using one reactive monomer over the other. In addition, utilizing this chemistry, synthesis of numerous amphiphilic and stimuli-responsive polymers will be discussed in detail in separate subsections. Reactive polymers based on azlactone have been excluded in this review as their chemistry of PPM is the addition reaction of nucleophiles with no release of a leaving group unlike in the case of conventional activated ester amine substitution reactions. 2.1. Free Radical Polymerization for Homopolymers and Statistical Polymers

Following are lists of different activated ester monomers that have been used for the synthesis of homopolymers and statistical copolymers by free radical polymerization. 2.1.1. N-Hydroxysuccinimide (NHS) Ester Monomers. Among several activated ester monomers, N-hydroxysuccinimide (NHS) ester-containing monomers are the oldest and most popular ones and have attracted a lot of attention in making different functional polymers. The earliest examples of free radical polymerization of N-hydroxysuccinimide acrylate (NHSA) and N-hydroxysuccinimide methacrylate (NHSMA) (also sometimes named as N-acryloxysuccinimide, NAS, or Nmethacryloxysuccinimide, NMAS) were described by Ringsdorf and Ferruti with azobis(isobutyronitrile) (AIBN) (Scheme 3a).21,22 NHS-ester-based reactive polymers are quite (yet not fully) resistant to hydrolysis30 and subjected to nucleophilic aminolysis with primary and secondary amines under mild reaction conditions to generate functionalized polyacrylamide derivatives. Under identical reaction conditions, polyNHSA was found to be more reactive than polyNHSMA.21 Ferruti et al.22 illustrated the synthesis of linear poly(N-allylacrylamide) by Scheme 3. Free Radical (a) Homopolymerization and (b) Copolymerization of NHSA/NHSMA

D


Chemical Reviews

Review

amines as well as with alcohols. In general, PFP-ester polymers were found to be slightly more reactive than the NHS-ester polymers, while their acrylate backbones show extremely high reactivity compared to their own methacrylate analogue. Although the reactivity of polyPFPA toward primary and secondary amines was investigated to be satisfactory, low conversion was observed for aromatic amines and alcohols (Scheme 5). The physical properties (such as glass transition temperature) of MMA are often improved by randomly copolymerizing it with PFPMA via free radical polymerization.44,45 However, the refractive index and the light transmittance properties of these copolymers remained close to that of PMMA. Nilles and Theato46 demonstrated free radical polymerization of different activated ester monomers based on 4-vinyl benzoic acid and compared their reactivity toward series of functional amines. Most interestingly, among all tested activated ester polymers of 4-vinyl benzoate, pentafluorophenyl 4-vinyl benzoate (PFP4VB) (Table 1) exhibited the highest reactivity. Its reactivity was even much higher compared to its own polymethacrylate or polyacrylate analogues as demonstrated by its quantitative reaction with even less nucleophilic aromatic or secondary amines such as aniline and morpholine or N-propylpiperazine, respectively. Conversions with aliphatic amines proceeded within less than 5 min at 0 °C and practically immediately at room temperature. The same group later described free radical polymerization of novel PFP-functionalized 1,1-disubstituted-2-vinylcyclopropane (PFP2VCP) with AIBN to produce polyPFP2VCP (Scheme 6), which could also be easily modified with amines.47 Noteworthy, many of the resulting polymers featured an upper critical solution temperature (UCST) in ethanol/water mixtures, with the npropylamide derivative showing additionally a large UCST hysteresis and gelation behavior. 2.1.3. Other Activated Ester Monomers. Compared to the vast literature available on NHSA/NHSMA or PFPA/ PFPMA polymers, examples of polymers featuring other activated ester groups are very limited. Although some of them have few advantages they could not show up to the standard of the two earlier mentioned classes of activated ester polymers. Ringsdorf and co-workers48 reported free radical polymerization of acrylates and methacrylates of trichlorophenol (TCP) or N-hydroxy benzotriazol (NHB) derivatives. On one hand, the toxicity of trichlorophenol limited the use of TCP-based polymers, while on the other hand, the hydrolytic susceptibility of NHB-based polyesters raised the question of their long lasting stability. Rejmanova and Kopecek 49 copolymerized a new class of methacrylate monomer, p-nitro phenyl methacrylate (PNPMA) (Table 1), with N-(2hydroxypropyl)-methacrylamide (HPMA) under free radical


ester (MAC2AE) using a self-assembled monolayer of an azo initiator was achieved on silicon oxide substrates with very high grafting density.38 Aminolysis of NHS-ester groups within the brush with various n-alkylamines were studied by infrared and surface plasmon spectroscopy. Using inverse microemulsion/ free radical polymerization,39 reactive microparticles of copolymer, poly(NHSA-co-NVP), were prepared in one pot that could be coupled with amine-functionalized dye to generate fluorescent particles. Although NHS-ester-based polymers are the most commonly used reactive polymers, they have some limitations. There is proof of unexpected side reactions taking place during the aminolysis step such as ring opening of the succinimide functionality and formation of N-substituted glutarimides by attack of amides on neighboring activated esters (Scheme 4).40 Scheme 4. Side Reactions during Aminolysis of polyNHSA/ polyNHSMA

Even methods to combat those side reactions have been achieved by carrying out the substitution at high temperature and using an excess of amine or proton scavengers such as triethyl amine or 4-dimethylaminopyridine.41 2.1.2. Pentafluorophenyl (PFP) Ester Monomers. After NHS-ester monomers, pentafluorophenyl (PFP) ester-based acrylates (PFPA), methacrylate (PFPMA), and vinylbenzoates (PFP4VP) stand as the second most explicitly explored activated ester monomers that can be subjected to free radical polymerization.42 The first paper on the synthesis of PFPA and its polymerization in bulk was reported by Blazejewski and coworkers.43 However, the insolubility of the polymeric material did not allow further characterization by size exclusion chromatography or other analytical techniques available. Eberhardt and Theato42 illustrated homopolymerization of PFPA and PFPMA using AIBN as a thermal initiator. Unlike polyNHSA/polyNHSMA, whose solubility is limited to DMSO and DMF, polyPFPA and polyPFPMA were found to be soluble in a wide range of organic solvents and thus considered superior for PPMs from a solubility aspect. A comparative study between the reactivities of polymethacrylates and polyacrylates of both PFP-ester and NHS-ester as well as between these two different classes of activated ester polymers were conducted by treating all four of them with primary, secondary, and aromatic

Scheme 5. Comparative Study of the Reactivity of polyPFPA with Various Nucleophiles

E


Chemical Reviews

Review


Scheme 6. Synthesis of polyPFP2VCP and Its PPM with Primary Amines

polymerization.50−53 However, incorporation of PNPMA within the copolymer resulted in a low polymerization yield as also observed by Okawara et al. for poly(styrene-coPNPA).54 For a series of copolymers of p-nitrophenyl acrylate (PNPA) with styrene, methyl acrylate, and N,N-dimethylacrylamide (DMA), the rate of aminolysis was studied in dioxane and chlorobenzene.55 The reactivity of the pendent PNP-ester was found to be dependent on the nature of the polymer backbone, highest for poly(DMA) due to the activating effect of the dimethylamide groups. Photosensitive polymers containing pendent chalcone moieties were prepared by free radical homopolymerization and copolymerization of PNPMA with vinyl-chalcone monomers that acted as a photosensitizer. Photochemical cross-linking by UV irradiation was found to be faster for the copolymer when compared to chalcone homopolymer.56,57 Agosto and Pichot58 introduced a new class of bifunctional activated ester monomer, named di-NHSA, obtained as a byproduct during NHSA synthesis. Under free radical polymerization, homopolymerization reached only 5% conversion, probably due to cross-propagation to minimize steric hindrance from homopropagation. However, high molecular weight poly(NAM-co-di-NHSA) could be obtained with 92% conversion using NAM as a comonomer (Scheme 7). This new

As alternative activated esters that can be used in aqueous conditions, sulfonated NHS-esters were proposed.60−63 4Sulfotetrafluorophenyl (STP) esters were also proposed as an alternative activated ester to be used under aqueous conditions but have not found broad application.64,65 Metz and Theato66 reported free radical polymerization of acetone oxime acrylate (AOA) to develop a new class of activated ester polymer that exhibits solubility in various organic solvents (Table 1). The same group later introduced salicylic-acid-derivatized acrylates (SAA)67 as novel reactive monomers for free radical polymerization. The resulting polymers could be subjected to facile postfunctionalization with both primary and secondary amines (Scheme 8). Although

Scheme 7. Free Radical Copolymerization of di-NHSA

kinetic studies revealed a lower reactivity toward amines when compared with polyPFP(M)A, salicylate ester polymers showed a far less in vitro cytotoxicity as expected from the released salicylic acid derivates in contrast with toxic pentafluorophenols during aminolysis of polyPFP(M)A. Consequently, such reactive precursor polymers look very promising for in vivo synthesis of biologically relevant functional polyacrylamides.

Scheme 8. Synthesis of Polymers from Salicylic-AcidDerivatized Acrylates (SAA) and Their PPM with Primary and Secondary Amines

2.2. Controlled Radical Polymerization for Homopolymers and Statistical Polymers

The advent of modern polymerization techniques such as atom transfer radical polymerization (ATRP), reversible addition− fragmentation chain transfer (RAFT), and nitroxide-mediated polymerization (NMP) has embarked on a new era of advance polymer synthesis. Combining PPMs with controlled polymerization techniques has created new possibilities to realize highly functionalized and complex polymeric scaffolds that were never achieved before by free radical pathways. This section will highlight synthesis of a variety of reactive polymers using stateof-the-art polymerization techniques and their contribution in tailoring amphiphilic and stimuli-responsive polymers utilizing activated ester amine chemistry, while complex poly(meth)acrylamides designed for targeting specific applications will be discussed in the respective subsections (see section 6). 2.2.1. Polymerization of NHS Ester Monomers. Müller and Brocchini68 described ATRP polymerization of NHSMA with controlled molecular weight and narrow molecular weight distribution using 2-bromo-2-methyl(2-hydroxyethyl)propanoate, CuBr, and 2,2′-bipyridine as initiator, catalyst,

reactive polymer displayed two reactive sites per incorporated di-NHSA monomer and is therefore capable of exhibiting a multivalent effect upon PPM, compared to copolymers with a single activated ester as side groups. An interesting class of activated ester polymers that can potentially replace polyNHS(M)A is thiazolidine-2-thione (TT)-based polymers. Ulrich and co-workers59 copolymerized TT-based methacrylate monomer (MAPTT) (Table 1) with HPMA to prepare water-soluble reactive polymers with controlled molecular weight and narrow dispersity. Unlike NHS- or PFP-ester polymers, these reactive polymers displayed rapid aminolysis in aqueous medium with a negligible rate of hydrolysis when the solution pH was maintained within 7.4− 8.0. Although TT-based reactive polymers appear promising for aminolysis in aqueous medium, they exhibit poor selectivity between amines and thiols under identical reaction conditions. F


Chemical Reviews

Review


Scheme 9. Graft-Copolymer Synthesis by a “Grafting-from” Approach by Immobilizing a RAFT Agent on an NHSA Copolymer by PPM

and ligand, respectively. Pan et al.69 later improved the initiator efficiency using NHSA monomer. Haddleton et al.70 subsequently optimized the polymerization conditions for polyNHSMA with CuBr, N-(n-propyl)-2-pyridylmethanimine, and ethyl-2-bromoisobutyrate in DMSO and successfully achieved conversion up to 70%. While a plethora of welldefined homopolymers and statistical copolymers of NHSA/ NHSMA71 have been achieved by ATRP, their homopolymerization by RAFT often led to polymers with broad molecular weight distributions. However, their copolymerization with other acrylamide monomers by RAFT have been successfully achieved with good control of molecular weight and polydispersity.72−75 Thayumanavan and co-workers74 standardized conditions for copolymerization of NHSMA with NIPAM under most commonly used ATRP, RAFT, and NMP methods to obtain control over the molecular weight distribution. Among all three controlled CRP methods, RAFT was able to afford copolymers with the lowest molecular weight distribution (Mw/Mn = 1.1−1.2). Gilbert and co-workers76 described RAFT copolymerization of NHSA and n-butyl methacrylate (BMA) to produce linear poly(BMA-co-NHSA) chains. The statistical copolymer was later immobilized with primary hydroxyl-functionalized RAFT agents through nucleophilic substitution at the activated ester sites (Scheme 9). Immobilized RAFT agents along the side chains were further used to polymerize BMA to synthesize linear-graft copolymer, poly(BMA-co-NHSA-graf t-BMA). Möller and et al.77 synthesized α,ω-isocyanate-telechelic poly(MMA-co-NHSA) and poly(MMA-co-acrylamidohexanoic succinimide) using carboxylic-acid-functionalized RAFT agent followed by two-step PPM of end functional groups to generate isocyanate-immobilized homotelechelic copolymers. Obtained polymers featuring isocyanate groups at the chain ends produced reactive polyurethanes by condensation polymerization with diols. Recent interest is developed in activated ester polymers based on 4-vinyl benzoate for their greater reactivity compared to the (meth)acrylate analogues. For instance, Tew et al.78 reported RAFT polymerization of NHS-ester of 4-vinyl benzoic acid (NHS4VB) (Table 1) with controlled molecular weights (44−61 kDa) and a narrow molecular weight distribution (Mw/ Mn < 1.07). Hawker and co-workers79 described nitroxidemediated copolymerization of NHS4VB and NHSA with styrene in the presence of 2,2,6,6-tetramethylpiperidinoxy (TEMPO) as a stable radical. Quantitative amidation with amine-based polyether dendrons resulted in dendritic-linear graft copolymer. Using surface-initiated atom transfer radical polymerization (SI-ATRP), polymer brushes with high grafting density were

prepared from NHSMA80 and NHS4VB.81 The feasibility and versatility of these reactive polymer thin films toward nucleophilic substitution with a variety of n-alkylamines were investigated. Even reactive polyNHS4VP brushes were effectively used as macroinitiators for block copolymerization of styrene.82 2.2.2. Polymerization of PFP Ester Monomers. As mentioned earlier, PFPA/PFPMA has emerged as an attractive alternate to NHSA/NHSMA polymers for their better hydrolytic stability, higher reactivity, and good solubility in a wide range of organic solvents. However, homopolymerization of PFP(M)A via ATRP does not proceed efficiently, owing to the interference of copper(I) catalyst with the monomer, which may potentially lead to hydrolysis of the ester and protonation of the metal ion and the ligand.83 As a result, only lower molecular weights have been reported.84 Recent careful investigation also led to some success in the polymerization.85 On the contrary, RAFT polymerization of these activated ester monomers has been very successful. For example, homopolymerization of PFP(M)A by RAFT can be controlled. Theato et al.86 described polymerization of PFPA with a precisely controlled molecular weight and narrow molecular weight distributions (Mw/Mn ≤ 1.2) using cumyl dithiobenzoate or 4cyano-4-((thiobenzoyl)sulfanyl)-pentanoic acid. Under similar conditions, linear diblock copolymers consisting of a reactive PFP-ester block were achieved. Employing this monomer, Klok and co-workers87 created diverse libraries of functional watersoluble polymers, demonstrating the potential of PFP-ester monomers for designing functional polyacrylamides. Barz and Zentel88 described the synthesis of water-soluble HPMA-based homopolymers89 and copolymers,90 one of the most investigated polymers in biomedical research, by PPM of PFPMA with 2-hydroxypropyl amine. Interestingly, the aminolysis step does not contribute to additional cytotoxicity87 after intensive dialysis when compared with direct polymerization of HPMA.91,92 This makes the PPM approach effective for structure−property relationship studies of those biologically active polymers under physiological conditions. Frey et al.93 reported the synthesis of linear-hyperbranched graft-copolymers of polyHPMA via “grafting-to” approach by sequential modification of polyPFPMA backbone with a dendritic amine followed by 2-hydroxypropylamine. In a slightly different strategy, they synthesized polyHPMA with pendent β-cyclodextrin via triple PPM of polyPFPMA obtained by RAFT. The water-soluble copolymer was used to fabricate reversible linear-graf t-(linear-hyperbranched) supramolecular graft terpolymers by complexation with monoadamantylfunctionalized linear polyglycerols.94 G


Chemical Reviews

Review


Scheme 10. Schematic Representation of Sequence-Controlled Installation of PFP4MB to the Polystyrene Chains Prepared by NMP

Scheme 11. Synthesis of polyPFPMA Brushes by SI-RAFT and PPM with Amines

Nilles and Theato reported RAFT polymerization of PFP4VB with extreme precision and further displayed it as potential macrochain transfer agent (CTA) for diblock copolymerization of styrene derivatives.95 Remarkably increased reactivity of PFP4VP has been taken advantage of in creating dual-reactive statistical copolymers poly(PFPMA-coPFP4VP) that offered selective modification with amines of varying reactivity.96 In a joint work, the groups of Lutz and Theato97 showed sequence-controlled installation of pentafluorophenyl 4-maleimidobenzoate (PFP4MB) within a polystyrene backbone by kinetically installing it at different stages of a nitroxide-mediated polymerization (Scheme 10), followed by postpolymerization functionalization with polar and nonpolar amines. Apart from polymerization in solution, Klok and coworkers98 reported surface-initiated RAFT polymerization (SIRAFT) of PFPMA. The resulting reactive brushes could be postmodified in quantitative yields with various amines (Scheme 11). That conversion of the PFP-ester groups can be conducted in bulk has been reported by the group of Theato, who synthesized polyPFPMA-containing photocleavable block copolymers for the preparation of functional nanoporous thin films.83,99 PPM modification of a nanoporous polyPFPMA with amines could be achieved without destroying the nanoporous character of the film. Also, photo-cross-linking of reactive films obtained from a copolymer of PFPA and an onitrobenzyl-protected amine-based monomer using a photomask created pattern surfaces (Scheme 12).100 2.2.3. Polymerization of Other Activated Ester Monomers. Besides polymerization of NHS- and PFP(meth)acrylates, various other activated ester monomers have been subjected to controlled radical polymerization. Kim and Theato101 showed ATRP polymerization of 2,4,5-trichloro-

Scheme 12. Schematic Representation for the Preparation of Photo-Cross-Linked Films Obtained from polyPFPA Containing o-Nitrobenzyl Protected Aminesa

a

Redrawn after ref 100. Copyright 2013 Royal Society of Chemistry.

phenyl acrylate (TCPA)102 and endo-N-hydroxy-5-norbornene2,3-dicarboxyimide acrylate (NHNorbDA) (Table 1) in bulk and DMSO, respectively, using 2-bromoisobutyric ethyl ester, CuBr, and 2,2′-bipyridine. Both polymers showed improved solubility compared to polyNHSA/polyNHSMA in a wide spectrum of solvents. Even polyNHNorbDA was obtained with quantitative initiator efficiency and could be used for a block copolymer synthesis with MMA. Liu and Pan103 described polymerization of PNPMA in bulk by ATRP. Accumulation of Cu2+ ions within the polymer resulted in poor conversion and H



Chemical Reviews

Review

higher than that of polyPFP(M)A, although their aminolysis followed an opposite trend.112 2.2.4. Amphiphilic and Stimuli-Responsive Statistical Copolymers. Well-defined amphiphilic polymers find tremendous applications in biology and medical sciences. Examples comprise the use of polymeric materials in drug delivery,113 gene delivery,114 tissue engineering,115 antibiotic agents,116 and so forth. The high fidelity in functionalization of polymeric activated ester with variety of functional amines has been greatly taken advantage of in amphiphilic polymer synthesis. Utilizing polymeric activated esters, amphiphilic statistical copolymers are commonly prepared via two synthetic approaches: (1) Sequential conversion of a reactive precursor homopolymer with different functional amines of varying polarity117−121 (often the minor component or the most precious amine (based on availability) is incorporated in the first step to ensure quantitative consumption of the amine, followed by aminolysis of the remaining activated ester units with the amine that makes up the majority of the copolymer composition); (2) Copolymerization of an activated ester monomer with another nonreactive polar/apolar monomer, followed by aminolysis with hydrophobic or hydrophilic amines.122−125 Amphiphilic polymers with stimuli-responsive functional groups are subjected to conformational changes upon exposure to external stimuli (pH, temperature, light, etc.) and therefore are highly interesting for various biomedical applications. Widespread synthetic strategy for stimuli-responsive polymersalso called “smart polymers”mostly takes advantage of PPM via aminolysis of an activated ester (meth)acrylate.30 In this regard, polyacrylamides, more precisely polyNIPAM, have attracted great interest as thermoresponsive polymers in aqueous medium owing to its lower critical solution temperature (LCST) in water at 32 °C, being very close to the human body temperature.126 LCST of functional polyNIPAM can be shifted to higher or lower values by copolymerizing NIPAM with an activated ester monomer and subsequent modification with functional amines.127−129 A library of structurally isomeric copolymers of poly(N-npropylacrylamide) and polyNIPAM was prepared from a single reactive polyNHSA by aminolysis with varying fractions of 1propyl- and 2-propyl-amines.130 The LCST of all copolymers, featuring identical moleculat weight, degree of polymerization, and polydispersity, was found to be linearly dependent on the feed ratio of the more hydrophobic poly(N-n-propylacrylamide). A series of dye-labeled polar polyNIPAM and nonpolar poly(N-octadecylacrylamide) was generated from a precursor polyNHSA by double PPM. Their phase-selective solubilities were measured in a mixture of polar (90% EtOH−H2O mixture) and nonpolar (hexane) thermomorphic solvents at 25 °C.131 Starting from polyPFPA, temperature-responsive polyNIPAM132 or poly(N-cyclopropylacrylamide)133 copolymers containing 1.0 or 3−5 mol % of pyrene side chains, respectively, were prepared. The LCSTs of the copolymers were governed by the amount of hydrophobic pyrene moiety incorporated. Those copolymers were employed to disperse single-walled carbon nanotubes (SWNT) in water. They triggered temperature-responsive dispersion behavior of SWNT and controlled the extent of exfoliation or bundle formation of the nanotubes. In recent years, polymers that respond to multiple stimuli have attracted more attention. Utilizing activated ester chemistry, numerous multiresponsive polymers have been generated from polyNHSA37,134,135 or polyPFPA136,125 by

broad molecular weight distribution. However, block copolymerization of PNPMA with styrene by ATRP proceeded with controlled molecular weight and low dispersity. Under RAFT conditions, homopolymerization104 and block copolymerization105,106 of PNPA resulted in better yield and control. Gan and co-workers107 described controlled ATRP of 2,3,5,6tetrafluorophenyl methacrylate (TFPMA) (Table 1) using CuBr2 deactivator. Although being less reactive than polyPFPA, quantitative reaction with unhindered primary amines was successfully achieved at elevated temperature for the obtained polyTFPMA. Notably, the possibility to characterize polyTFPMA by 1H NMR makes it advantageous over polyPFP(M)A. Metz and Theato66 conducted polymerization of AOA by both RAFT and NMP. Partial modification with isopropylamine imparted a reactive copolymer of poly(NIPAM-co-AOA) featuring LCST at 61 °C that disappeared on complete substitution with ammonia. Godula and Bertozzi108 treated polyAOA with hydrazides to obtain poly(acryloyl hydrazide) (PAH) with pendent free amines that was later used to immobilize glycans to form glycopolymers. Kakuchi and Theato109 described RAFT polymerization of a novel monomer, 4-acryloxyphenyldimethylsulfonium triflate (APDMST), that offered an external stimuli-triggered reactivity switch for activated ester amine click reaction. The reactive form poly(APDMST), which readily reacts with amines as expected for an activated ester, could be converted to a nonreactive form by thermo-triggered demethylation to yield poly(4-acryloxyphenyl methylsulfide) (polyAPMS). The nonreactive polymer could not afford a conversion with amines, hence featuring a “switched off” reactivity (Scheme 13). Scheme 13. Temperature-Induced Switch in the Reactivity of polyAPDMST

Nuhn and Zentel110 developed a series of novel activated ester polymers with adjustable molecular weights (16−30K) and a narrow molecular weight distribution (PDI = 1.15−1.3) from 1,1,1,3,3,3-hexafluoroisopropyl methacrylate (HFIPMA) (Table 1) via RAFT polymerization, providing a versatile tool for multifunctional water-soluble polymers. These activated ester polymers showed potential for block copolymerization. Formation of a volatile byproduct 1,1,1,3,3,3-hexafluoroisopropanol during aminolysis makes the purification step easier but limits a potential recycling. Studer et al.111 described nitroxidemediated homopolymerization and alternating copolymerization of HFIPA with n-butyl vinyl ether (Scheme 14) with sterically hindered alkoxyamine initiator followed by quantitative amidation with primary amines. Percec et al. even showed that polyHFIPA and polyHFIPMA can be subjected to quantitative transesterification using DBU as catalyst. The rate of alcoholysis of polyHFIP(M)A was found to be even I


Chemical Reviews

Review


Scheme 14. Nitroxide-Mediated (a) Homopolymerization and PPM (b) Alternate Copolymerization of HFIPA with n-Butyl Vinyl Ether

reacting with functional amines containing stimuli-responsive groups. Temperature-responsive polyNIPAM featuring photoresponsive azobenzene137−139 side groups were prepared by copolymerizing NIPAM with different NHS-ester monomers followed by aminolysis with light-responsive (3aminopropyloxy)azobenzene.140 Photoirradiation of azobenzene from a more hydrophobic trans to cis isomer contributed to a change in the phase transition temperature of polyNIPAM. Besides azobenzene, copolymers of NIPAM with other photochromic moieties in the side chains such as fulgimide141 and salicylideneaniline142 groups have been synthesized via a double PPM of polyPFPA. Light-induced changes in the LCST behavior of these polymers could be observed. Besides polyNIPAM displaying photoresponsive groups, polyNIPAM copolymers that exhibit both temperature and pH sensitivity were fabricated from precursor poly(NIPAM-co-NHSA) by installation of pH-sensitive m-aminophenylboronic acid at the NHS-ester site.143 Dual temperature- and pH-responsivefunctionalized polyNIPAM 144,145 and poly(methacrylamide)146−148 microgels have been prepared using PNPA as a reactive copolymer for installation of pH-responsive 4methylpyridine and folic acid as a targeting ligand. Collagenase-sensitive peptide-based polyNIPAM copolymers, poly(NIPAM-co-GAPGL-NH 2 ) and poly(NIPAM-coGAPGLF-NH2), have been constructed by derivatization of poly(NIPAM-co-NHSA) with the corresponding peptides. Both copolymers revealed an increase in LCST when subjected to enzymatic degradation in the presence of collagenase.149 Starting from polyPFPA, a thermo-sensitive polyNIPAM featuring both light-responsive (azobenzene) and redoxresponsive (TEMPO)150 side groups was fabricated by sequential substitution of the PFP-ester with N-(2-aminoethyl)-4-(2-phenyldiazenyl) benzamide (amino-azobenzene) and 4-amino-2,2,6,6-tetramethyl-1-oxyl-piperidine (aminoTEMPO). Remaining PFP-esters were treated with an excess amount of isopropylamine to generate a triple-responsive copolymer (Scheme 15).151 Besides polyNIPAM, poly/oligo(ethylene glycols) (PEG/ OEG) are another class of thermoresponsive polymers that have attracted significant attention due to their well-established biocompatibility. Ethylene glycol chains can be easily incorporated within the polymer scaffold by PPM. Davis and

Scheme 15. Synthesis of a Triple Responsive NIPAM-Based Copolymer by PPM of polyPFPA

Lowe117 obtained a library of thermoresponsive poly(meth)acrylamides with ethylene glycol side chains of varying lengths by treating polyPFPA or polyPFPMA with different PEG-based amines. Similarly, Ghosh et al.122 created a series of amphiphilic random copolymers from a single reactive prepolymer made by RAFT copolymerization of NHSMA with a hydrophobic methacrylate monomer with octyl chains, followed by substitution of pendent NHS-ester groups with different hydrophilic OEG-amines. All polymers obtained showed an identical degree of polymerization and equal extent of randomness. The aggregation behavior123 and thermoresponsive phase transition of these polymers could be adjusted by incorporating OEG-amines of different chain lengths. Noteworthy, the reactive precursor-based synthetic approach provides the opportunity for structure−property relationship studies that are otherwise difficult to achieve by employing direct polymerization. In an alternate approach, Lowe, Davis, and Boyer152 copolymerized PFPA with oligoethylene glycol acrylates (OEGA) or diethylene glycol acrylate followed by quantitative amidation with hydrophobic amines to tailor the thermoresponsive behavior of the resulting amphiphilic copolymers. Ion-sensitive polymers, those with the ability to undergo conformational changes in solution, have also been designed and constructed utilizing activated ester amine chemistry. Fluorogenic ion sensors were developed from ion-responsive copolymers. They were prepared by statistical copolymerization of NHSA with a polarity-sensitive fluorophore-based monomer followed by substitution of the NHS-ester groups with SO42− J


Chemical Reviews

Review

Scheme 16. Synthesis of Polyacrylamide-Based Fluorogenic Ion Sensor by PPM of polyNHSA Copolymer


Scheme 17. Synthesis of Sulfobetaine Copolymer from polyPFPA

Scheme 18. Synthesis of PNPMA-Based Block Copolymer (a) by ATRP Using PNPMA as the Second Monomer and (b) by RAFT Using PNPMA as the First Monomer

ion-selective tris(3-amino-propyl) amino ligand153 (Scheme 16). Conformational change of the copolymer upon binding with SO4 2− ions in aqueous solution caused a decrease in the local polarity across the fluorophore that significantly enhanced the observable fluorescence signal. Zwitterionic polymers such as polysulfobetaines have received great attention as a very promising class of materials.154−156 They exhibit dual responsiveness toward temperature and salts. Roth et al.157 described a facile synthetic route for hydrophobically modified sulfobetaine-based zwitterionic copolymers. In a single step, polyPFPA was derivatized with a mixture of 3-((3-aminopropyl) dimethylammonio)propane-1-sulfonate (ADPS) and different hydrophobic amines in propylene carbonate solvent (Scheme 17), creating those

polymers. Notably, it is very difficult to prepare those zwitterionic copolymers by direct polymerization techniques.158 2.3. Block Copolymers

2.3.1. Block Copolymerization of Activated Ester Monomers. The ability of block copolymers159−161 to undergo phase separation and nanostructure formation has initiated research on developing new synthetic strategies to design complex block copolymers for targeting various applications in both biomedical162,163 and materials science.164,165 Controlled chain polymerization in combination with PPM166 continues to be the most efficient tool to access well-defined and chemically diverse block copolymers. Along this line, activated ester chemistry has been extensively employed in engineering multifunctional block copolymers. K


Chemical Reviews

Review


Scheme 19. Convergent Approach for Synthesis of Cleavable Block Copolymer from Two Separate Homopolymers with Complementary Reactive Handles at the Chain End

The diversity in block copolymer architectures can be enhanced many fold if one of the blocks features an activated ester group that performs as a functional handle for PPMs. Additionally, this approach allows synthesis of block copolymers with blocks that cannot be generated by direct block copolymerization of certain monomers owing to their incompatibility toward the polymerization conditions or methods. Currently, activated ester monomers can be directly involved in structuring one of the blocks or an additional precursor for postincorporation of target functionalities within the preformed blocks. The choice of monomers and their sequence of addition during the course of block copolymerization are highly crucial. During sequential copolymerization, the activated ester monomer can be either the part of the macroinitiator or macro-CTA that mediates the polymerization of the second monomer or itself polymerized in the second step from a macroinitiator or macro-CTA developed from a nonreactive block. Most activated ester monomers subjected to controlled chain polymerizations can be used in designing functional block copolymers (see also section 2.2).82,107,110,167 However, their sequence of addition sometimes has an influence on the rate and quality of polymerization that depends on the efficiency and living character of the first block. For example, Pan et al.103 synthesized well-defined block copolymer polySt-b-polyPNPMA by ATRP in bulk using CuBr/bpy as catalyst and polystyrene as a macroinitiator (Scheme 18a). Poorly controlled homopolymerization of PNPMA under similar ATRP conditions restricted their use as a reactive macroinitiator for polymerization of styrene in the second step. Hydrolysis or aminolysis of the polyNPMA segment with n-butylamine resulted in two new block copolymers, polySt-block-poly(methacrylic acid) and polyStblock-poly(N-butyl methacrylamide), respectively, both difficult to prepare directly from their corresponding monomers. Interestingly, the same group later described controlled homopolymerization of PNPMA under RAFT conditions using cumyl dithiobenzoate as the CTA and AIBN as the initiator with 90% monomer conversion. Also, the living character of the reaction was illustrated by controlled chain

extension of polyPNPMA when used as a macro-CTA for the RAFT polymerization of diethoxypropyl methacrylate (DEPMA)105 (Scheme 18b). The resulting block copolymer polyPNPMA-b-polyDEPMA prepared in 86% yield revealed an orthogonal reactivity of the two different blocks, featuring activated esters and protected aldehydes. Similar to PNPMA, homopolymerization of PNPA by ATRP proceeded with low yield and did not show a living character. However, their RAFT polymerization afforded controlled polyPNPA chains with an intact terminal dithioester groups that could reinitiate the polymerization of styrene as the second block.104 Therefore, it is evident that the method of polymerization often determines the sequence of addition of the activated ester monomer during block copolymer synthesis. When it comes to NHS-ester monomers, reports on their use both as first or as second block by ATRP polymerization is well known. Haddleton and co-workers70 demonstrated controlled chain extension of MMA from a polyNHSMA macroinitiator. PolyNHSMA was prepared by ATRP using Cu(I)Br and N-(npropyl)-2-pyridylmethanimine catalyst and ethyl-2-bromoisobutyrate as the initiator. Transformation of the reactive block to poly(N-benzyl methacrylamide) by reaction with benzyl amine offered an indirect route for polyacrylamide synthesis which usually does not proceed well by ATRP with Cu(I) catalysts.168 Tew et al. followed an inverse pathway to generate poly(NHSMA-b-MMA) or poly(NHSMA-b-St) by using PMMA or polystyrene macroinitiators for polymerization of NHSMA using a Cu(I)Br/PMDTA catalyst.169,170 The reverse strategy produced better results compared to when polyNHSMA was used as a macroinitiator. This was due to the fact that under identical conditions, polyNHSMA induced less effective initiation for polymerization owing to their significant chain termination. Following a similar strategy, Segalman et al.171 prepared poly(NHSMA-b-St) from a polystyrene macroinitiator. The precursor block copolymer was developed into a polymeric ionic liquid by PPM of polyNHSMA block with histamine and subsequent treatment with trifluoroacidic acid to synthesize an imidazole pendent block copolymer. In contrast, synthesis of diblock copolymers using polyNHNorbDA (Table L


Chemical Reviews

Review


Scheme 20. Synthesis of Thiol-Functionalized (top) and Fluorophore-Functionalized (bottom) Block Copolymers from Reactive PFPMA

Scheme 21. Synthesis of Functional Block Copolymer Featuring Donor−Chromophore−Acceptor Segments Using PFPA

1) as macroinitiator and MMA as the second block has been successfully achieved with CuBr and 2,2′-bipyridine catalyst using ethyl-2-bromoisobutyrate as the starting initiator.101 Unlike polyNHSMA, the initiation with polyNorbNHSA was quantitative as no homopolymer peak could be detected from GPC after polymerization of MMA. However, Thayumanavan and co-worker172 depicted a novel convergent approach for a cleavable reactive block copolymer, polyNHSMA-b-PMMA, utilizing a pyridyldisulfide-functionalized ATRP initiator. In this method, they separately prepared pyridyldisulfide chain-endfunctionalized polyNHSMA and PMMA from the corresponding initiator. Selective reduction of the disulfide linkage at the chain end of PMMA with dithiothreitol (DTT) generated terminal free thiol. The thiol-terminated PMMA was reacted with the second pyridyldisulfide-terminated polyNHSMA homopolymer to synthesize disulfide linked redox-sensitive polyNHSMA-b-PMMA. Again, the block copolymer could be cleaved into its constituent homopolymers under mild exposure to DTT (Scheme 19). As homopolymerization of NHS(M)A under RAFT conditions does not go well, they are usually employed in

constructing the second block, during their block copolymerization by RAFT. Usually, the first block is constructed from a nonreactive monomer that mediates the polymerization of NHSA/NHSMA to construct the second block.75,72 In this regard, using PFPA/PFPMA is more advantageous, as they can be used in building of either the first or the second block. Theato et al.86 used polyPFPMA as a macro-RAFT agent for block copolymerization of MMA, NAM, or N,N-diethylacrylamide. In all these cases, controlled chain extension occurred and the resulting diblock copolymers had a molecular weight distribution Mw/Mn close to 1.3. Comparing the GPC profile of the resulting block copolymers with polyPFPMA, less than 5% fraction of the homopolymer was detected in the diblocks, possibility due to naturally occurring chain termination. This fraction is less when compared with macroinitiation from polyNHSA or polyNHSMA, prepared by ATRP. Thus, synthesis of block copolymers by RAFT using PFP-ester monomers offers better access to reactive copolymers of diverse attributes. Yet, Sohn et al.173 successfully showed the synthesis of diblock copolymer, PMMA-b-polyPFPMA, from a polymeric macro-CTA of PMMA, with both blocks of equal degree of M



Chemical Reviews

Review

ester amine chemistry is highly celebrated in making functionalized stimuli-responsive amphiphilic block copolymers.182,183 Precise functional group incorporation requires installation of the activated ester monomers selectively within the hydrophobic or hydrophilic segment during the course of block copolymer synthesis, which provides a synthetic handle for postintroduction of target functionality. Now, the hydrophilic and hydrophobic blocks either can be generated by polymerizing two nonreactive monomers of varying polarity or can be engendered by treating activated ester-containing blocks with polar or apolar amines. Categorically, functionalized ABCs can be synthesized by two pathways: (1) By homo- or copolymerization of activated ester monomers from either a hydrophilic or a hydrophobic nonreactive macroinitiator or macro-CTA and (2) growing a hydrophobic or hydrophilic chain from an activated ester-containing macroinitiator or macro-CTA. Now, depending on whether the macroinitiator is hydrophilic or hydrophobic, core or shell modifications are further possible. 2.3.2.1. Block Copolymerization from a Nonreactive Macroinitiator/Chain Transfer Agent. PEO-based functional block copolymers have drawn considerable interest in pharmaceutical applications. They are often prepared by conjugating PEO with reactive polymers that facilitate chemical modification of the hydrophobic block.184,185 Brocchini et al.30 prepared a library of pH-responsive cationic block copolymers, all with an identical degree of polymerization from a single precursor block copolymer, made by ATRP polymerization of NHSMA with PEG-macroinitiator. Sequential conjugation with a different amount of secondary, tertiary, or quaternary amines introduced a varying density of positive charges within the polymer backbone that determined their ability to bind with plasmid-DNA. From a PEG-macroinitiator, Ghosh and coworkers186 copolymerized MMA and NHSMA to prepare a precursor block copolymer, PEO-b-P(MMA-co-NHSMA). The activated ester groups distributed within the hydrophobic segment were chemically modified with β-alanine to yield pHsensitive amphiphilic block copolymers. Those polymers selfassembled into micelles in water, featuring a carboxylic-acidfunctionalized hydrophobic core that endowed it with swelling/ deswelling properties upon pH regulation. To this end, Bong et al.187 synthesized PEG−polyacrylamide diblock copolymers comprised of a melamine-rich hydrophobic segment by treating a reactive PEG-b-PNHSA with aminoethylmelamine. Installation of melamine functionality within the block copolymer helped in structure formation in the presence of a complementary hydrogen-bonding small molecule such as 5fluorouracil (5-FU) or cyanuric acid (CA). Under similar conditions, a control polymer bearing acyl-protected melamine failed to complex with 5-FU or CA due to a lack of hydrogen bonding. Prefunctionalization of NHSA with amidine-based amines and subsequent polymerization of the resulting monomer (Namidino)dodecyl acrylamide with PEG initiator lead to CO2responsive block copolymers endowed with gas-sensitive properties, conferred by the amidine functionality.188 Starting from a PEO-based macro-CTA, Theato et al. prepared photocleavable amphiphilic block copolymers comprised of a hydrophobic block of polyPFP(M)A and a hydrophilic block of PEO connected together with a photoresponsive o-nitrobenzyl ester group. Phase separation of the two incompatible blocks followed by selective degradation of the PEO segment resulted in nanoporous thin films of polyPFP(M)A that could be

polymerization. From this single reactive lamellar diblock copolymer precursor, two individually functionalized daughter block copolymers featuring a fluorophore and a quantum dot (QD) binding thiol-based ligand were developed (Scheme 20). Blending of those two sibling polymers together employed dual-functionalized lamellar nanostructures, incorporated with both QD and organic fluorophore. Similarly, Zentel and coworkers prepared a series of block copolymers featuring a reactive polyPFPA block for covalent anchoring of inorganic nanoparticles or quantum dots to realize their application as optoelectronic materials.174−178 A donor−chromophore−acceptor-type system was fabricated from a block copolymer synthesized by chain extending a p-type semiconducting block of poly(vinyltriphenylamine) PVTPA with an anchoring block of polyPFPA179,180 (Scheme 21). The polyPFPA block was modified with amine-functionalized perylene bisimide dye and dopamine that acted as a ligand for ZnO nanoparticle acceptors to create polymeric dye-sensitized organic solar cells.179 Theato et al.95 exploited the potential of PFP4VB as an extremely important activated ester monomer in constructing functional polymers under RAFT conditions, especially for their exceptionally high reactivity toward amines.96 They standardized the conditions for polymerizing PFP4VB by RAFT to obtain polymers with good control over molecular weight and narrow molecular weight distributions and further investigated their behavior in diblock copolymer synthesis. The reactive monomer was tested as either the first or the second block. However, when used as a first block, the polymerization with nonreactive styrene derivatives such as 4-octylstyrene or 4acetoxystyrene gave better control over the molecular weight distribution compared to when they were polymerized from macro-CTA of styrene or its derivatives. Unlike PFP4VB, other activated ester monomers of vinylbenzoate, namely, poly(2,4,5trichlorophenyl 4-vinylbenzoate), poly(pentachlorophenyl 4vinylbenzoate), poly(benzotriazole 4-vinylbenzoate), poly(Nhydroxy-5-norbonene-2,3-dicarboximide 4-vinylbenzoate), and poly(imino-2-phenylacetonitrile 4-vinylbenzoate), did not produce satisfactory results and could not match up to the standard of their PFP-ester analogue. Considering the importance of sulphonamides as biologically active drugs, polymeric activated esters of sulfonic acid such as poly(pentafluorophenyl 4-vinylbenzenesulfonate) [poly(PFP4VBS)] were successfully prepared by both RAFT and NMP, and their reactivity toward amines was tested.181 Unlike polyPFP4VB, structurally similar polyPFP4VBS revealed a lower reactivity for amines and more susceptibility toward hydrolysis. Further, investigating PFP4VBS monomer for block copolymer synthesis, either as the first or as the second block did not work out as effectively as PFP4VB monomer. 2.3.2. Amphiphilic and Stimuli-Responsive Block Copolymers. Amphiphilic block copolymers (ABCs) are widely used in a variety of biomedical and pharmaceutical applications owing to their ability to assemble into discrete core−shell nanostructures in aqueous medium, where the core is comprised of the hydrophobic block, while the shell consists of a hydrophilic segment. Introducing responsive receptors within amphiphilic polymers offers the additional advantage of stimuli-responsive morphology transitions that make such polymers extremely important for triggered drug delivery applications. Targeting specific functions requires precise positioning of the functional groups within the tailormade polymeric structures that contribute significantly to the selfassembly behavior and the properties of the ABCs. Activated N


Chemical Reviews

Review


Scheme 22. AFM Images of (a) Phase-Separated Structures of PEG-b-polyPFPMA and (b) Cysteamine-Functionalized Nanoporous Filmsa

a

Rearranged after ref 83. Copyright 2013 American Chemical Society.

Scheme 23. Synthetic Strategy for PLA-b-poly(NHSA-co-NVP) Starting from a Macroalkoxyamine Initiator

postmodified with functional amines (Scheme 22).83,99 Bolamphiphilic multiblock copolymers comprised of a hydrophilic polynorbornene shell made from a diblock of PEG- and NHS-ester-based norbornenes and a hydrophobic inner core of fluorescent conjugated polymers were prepared by ROMP.189,190 These amphiphilic polymers produced fluorescent nanoparticles in water that were surface functionalized with folic acids at the NHS-ester sites to target and image tumor cells. Besides PEO, polyHPMA has shown significant pharmaceutical importance. Zetterlund and Stenzel191 prepared an ABC comprised of a hydrophobic polyPFPMA block generated from a hydrophilic PHPMA macro-CTA. The resulting polymer was used as an amphiphilic macro-RAFT stabilizer to generated pH-responsive polymeric nanocapsules following an inverse miniemulsion periphery RAFT polymerization technique. When a hydrophobic macroinitiator is used to polymerize activated ester monomers alone or in conjunction with a hydrophilic monomer, amphiphilic block copolymers are obtained that integrate activated ester groups within the polar domain. Polymeric micelles produced from such polymers offer scope for shell modification.192 Pichot and co-workers193 used

dithioester-functionalized poly(tert-butylacrylamide) as a macro-CTA to copolymerize NAM and NHSA. The obtained amphiphilic block copolymer, featuring a hydrophobic block of poly(tert-butylacrylamide) and a hydrophilic block of a copolymer of NHSA and NAM. Polymer−oligonucleotide conjugates were obtained by partially reacting an amine-based starter of oligonucleotide (OND) with the activated ester groups of the polymer. Taking advantage of the remaining activated ester groups, the polymer was grafted onto hydroxylated controlled pore glass (CPG) support for OND synthesis. Nitroxide-mediated copolymerization of NHSA and Nvinylpyrrolidone (NVP) by SG1-functionalized poly(D,L-lactide) macro-alkoxyamine (PLA-SG1) resulted in the amphiphilic block copolymer PLA-b-poly(NHSA-co-NVP) (Scheme 23). The block copolymer was used for surface modification, diafiltration, and nanoprecipitation of PLA.194 Dual pH- and temperature-responsive block copolymer featuring a poly(εcaprolactone) (PCL) hydrophobic block and a hydrophilic poly(triethylene glycol) block copolymerized with an aminoacid-functionalized monomer was produced by combining ROP with ATRP.195 In the first step, a bromide-terminated alcohol O


Chemical Reviews

Review


Scheme 24. Synthesis of P2 by ATRP of NHSMA with a Supramolecularly Engineered Hydrophobic Initiator Followed by PPM with Water-Soluble Amine and Its Self-Assembly in Water and Benzenea

a

Reprinted from ref 200. Copyright 2013 American Chemical Society.

was used to catalyze the ROP of ε-caprolactone. In the second step, the obtained macroinitiator (PCL) with the terminal bromide functionality catalyzed the ATRP of a mixture of methoxytri(ethylene glycol) methacrylate and NHSA to prepare an amphiphilic block. pH-responsive amino acids were then installed within the polymeric micelles at the activated ester sites by PPM. Zhang and co-workers196 followed a reverse sequence of RAFT and ROP to obtain a thermoresponsive amphiphilic triblock copolymer, poly(NHSA-b-NIPAM-b-CL). A terminal carboxylic acid group of the diblock copolymer poly(NHSA-b-NIPAM) prepared by RAFT was sequentially modified for the initiation of ROP of εcaprolactone. The reactive terminal polyNHSA block was modified with biotin-NH2 to enhance the tumor cell permeability of the resulting polymeric micelles. In a two-step RAFT polymerization process, Uhlmann and co-workers197 prepared two different amphiphilic triblock copolymers that comprised of a hydrophobic block of randomly copolymerized tert-butylstyrene and n-hexyl acrylate and a hydrophilic blocks derived from polyDMA. An additional anchor block of polyNHSA was introduced either in the middle between the hydrophobic and hydrophilic segments or at the hydrophilic terminus of the polymer chain by varying the sequence of addition of the monomers. They enabled attachment of these polymers onto textile surfaces to facilitate their cleaning process. Reactive diblock copolymers prepared by ROMP of NHSNorb from a hydrophobic benzylic macroinitiator were modified into an amphiphilic peptide−polymer conjugate that self-assembled into micelles in water and showed an enzymetriggered reversible morphology transition.198,199 Special types of ABCs with engineered hydrophobic blocks were demonstrated by Ghosh and et al. (Scheme 24).200 Apart from using a linear nonpolar block, a supramolecularly engineered wedge-shaped hydrophobic macroinitiator was used to polymerize NHSMA. After substitution with water-

soluble amines, the resulting polymer (P2) showed interesting self-assembly properties, not in water alone but in nonpolar solvent such as benzene. Similarly, Lowe and Davis201 copolymerized DMA and NHSA from bis-pyrene- or bischolesterol-functionalized CTA to generate hydrophobically modified end-functionalized amphiphilic polymers that displayed bis-ω-cholesteryl or bis-pyrene as the hydrophobic chain-end segments. These examples illustrate that instead of extended hydrophobic blocks even a small segment can induce self-assembled structures in water if properly designed. The smaller segment can be cholesterol, which has a definite hydrophobic packing mode, or pyrene for π-stacking or a NDIbased wedge-shaped group for synergistic hydrogen bonding and π-stacking. 2.3.2.2. Block Copolymerization from an Activated Ester Containing Macroinitiator/Chain Transfer Agent. The alternative approach for ABC synthesis starts with an initial controlled chain polymerization of an activated ester monomer to produce a reactive macroinitiator or CTA that upon chain extension with a hydrophobic or hydrophilic monomer leads to a precursor diblock copolymer. When a hydrophilic monomer is used, the method directly leads to ABC where the reactive block also represents the hydrophobic block. For a hydrophobic monomer, the precursor diblock copolymer is postfunctionalized with polar amines to generate ABCs. However, an important parameter that needs to be considered in this method of polymerization is the solubility compatibility of the reactive macroinitiator/CTA and the second monomer during the chain extension step. When used as macroinitiator/CTA, polyNHS(M)A are copolymerized with other monomers to improve their solubility. For example, Tribet and co-workers202 made a hydrophilic macro-CTA containing two randomly distributed monomers, oligo(ethylene oxide) methacrylate (OEGMA) and NHSA, which was then used to polymerize a cholesterol-derivatized acrylate monomer (Scheme 25). CoP


Chemical Reviews

Review


Scheme 25. Synthesis of Light-Responsive Amphiphilic Block Copolymer Featuring Cholesterol-Derivatized Polyacrylate as the Hydrophobic Block

Scheme 26. Synthesis of Phosphonic-Acid-Terminated Amphiphilic Block Copolymer

valent attachment of azobenzene functionalities at the NHSester site within the amphiphilic polymer produced lightresponsive rod-like micelles in water with a photoisomerizable corona. Unlike polyNHSMA/polyNHSA, polyNHSNorb can be used as a reactive macroinitiator for ROMP of (PEG-Norb). Following ROMP, Zang et al.203 synthesized PEG-based amphiphilic triblock copolymer brushes by sequential block copolymerization of NHSNorb and PEGNorb. PPM with nucleic acid sequences allowed polycondensation of the polymer chains by DNA hybridization of the terminal brushes. Roth and Lowe204 polymerized DMA from dithioesterterminated polyPFPA to prepare a reactive parent diblock copolymer. PPM with histamine resulted in CO2-responsive amphiphilic copolymers that revealed a reversible assembly− disassembly switching by a change of polarity of the histamine block as a function of CO2 bubbling.205 The synthesis of other CO2-responsive polymers and hydrogels via activated ester amine-based PPM has also be explored.206,207 Reactive polyPFPA generated from terminal phosphoric acid bearing RAFT agent was chain extended with a hydrophilic block, polyOEGA, to synthesize a reactive amphiphilic block

copolymer (Scheme 26) that could adhere to the surface of magnetic iron oxide nanoparticles (IONPs) through its terminal phosphoric acid group.208 Those surface-functionalized nanoparticles featuring a reactive inner core of polyPFPA could be postmodified with various functional amines to fabricate different multifunctional NPs. Zentel and co-workers engineered a library of amphiphilic diblock copolymers featuring poly(HPMA) as the hydrophilic block and poly(laurate methacrylate) as the permanent hydrophobic block from a polyPFPA macro-CTA.90,209−214 Coderivatization of the PFP-ester residues with 2-hydroxypropylamine and/or a dye or radioactive or other bioconjugated amines resulted in highly functionalized amphiphilic polymers of pharmaceutical importance.

3. OTHER MACROMOLECULAR DESIGNS Significant advances in controlled radical polymerization (CRP) techniques have simplified the synthesis of macromolecules with complex architectures and programmed chemical composition. Availability of exceptional variety of functional monomers and initiators or chain transfer agents and their wide Q


Chemical Reviews

Review


Scheme 27. Synthesis of Amphiphilic Star Block Copolymers with (a) PNIPAM Arms and (b) Miktoarms Comprised of P(NIPAM-co-HMAA)

Scheme 28. Synthesis of Star Block Copolymer by (a) ATRP from Triphenylene Core and (b) RAFT from Dendrimer Core

central core. Star polymers form compact nanostructures and, therefore, find application in drug delivery, catalysis, photonics, etc.217 They can be further classified depending on the chemical composition of the arm segments: (1) homoarmed stars in which all radiating arms have identical structures and chemical compositions; (2) heteroarmed stars, commonly known as miktoarm star polymers, are comprised of more than one arm segment with different structure or chemical compositions. They can be further categorized based on the methods of their preparation as core-first or arm-first routes, which differ from one another by the sequence of formation of the core and the arms. The core-first route is a divergent approach where the core is prepared first, followed by propagation of the polymer arms from the core. In the arm-first approach, star polymers are usually synthesized via a convergent method by covalent attachment of preformed linear arm precursors to a core or with polymerization of divinyl monomers forming a cross-

tolerance limit to various controlled polymerization techniques have opened doors for new polymeric structures with a vision to mimic the elegance and complexity of Mother Nature. Simple synthetic strategies that enable control over both structure and function of polymers are in high demand. High fidelity of activated ester chemistry makes it a versatile choice for polymer chemists to design novel polymeric architectures. Inevitably, well-defined block copolymers are one of the best designs achieved until today, both in terms of structure and function. This section will showcase the achievements and future scope of PPM via activated ester amine chemistry in combination with CRP in engineering other structurally different polymers215 with distinct configuration following a modular approach. 3.1. Star Polymers

Star polymers216 are one of the simplest forms of branched polymers in which all chains of a polymer are connected to a R



Chemical Reviews

Review

linked core. Both methods have been realized in the synthesis of star polymers utilizing activated ester chemistry.218−220 Zhuo and co-workers221 described the synthesis of a thermosensitive seven-arm star block copolymer (PLLA-sbPNIPAM) comprised of a hydrophobic poly(L-lactide) (PLLA) arm and six average hydrophilic polyNIPAM arms following a convergent method in three steps (Scheme 27a). In the first step, amino-terminated polyNIPAM (PNIPAM−NH2) was prepared by radical polymerization using 2-amino ethanethiol hydrochloride as a CTA. In the second step, resulting PNIPAM−NH2 was transformed into a PNIPAM macromonomer by reacting the terminal amino group of PNIPAM with NHSA. Radical polymerization of the resulting PNIPAM macromonomer using AET_HCl resulted in PNIPAM brush with average degree of polymerization (DP) = 6. Those brushes were finally connected to a PLLA block by coupling reaction to produce an amphiphilic seven-arm miktostar polymer. In a similar approach, a four-arm star block copolymer, comprised of a hydrophobic PMMA core and an average of three hydrophilic PNIPAM arms, was synthesized by reducing the DP of PNIPAM to 3 and connecting it to a PMMA core.222 Copolymerization of PNIPAM and N-hydroxymethylacrylamide (HMAA) with different feed ratios resulted in series of amphiphilic star polymers, PLLA-sb-P(NIPAM-co-HMAA), whose LCST behavior could be tuned by varying the feed ratio of the two monomers (Scheme 27b).223 Starting from a hexahydroxy triphenylene core, Pan and co-worker224 synthesized six-armed star polymer comprised of a triphenylene core and PLLA-b-poly(St-co-NHSA) arms. Hydroxy-terminated polylactide chains obtained by ROP from the tripheylene core were reacted with 2-bromoisobutyryl chloride to generate bromine-terminated stars that acted as macroinitiators for copolymerization of styrene and NHSA (Scheme 28a). The star polymer was obtained, comprised of PLLA as the inner layer and poly(St-co-NHSA) as the shell. Shell cross-linking utilizing the NHS-ester groups followed by hydrolysis of the PLLA block produced hollow nanospheres. The same group also reported the synthesis of dendrimer-star polymers by RAFT polymerization of styrene from a multifunctional dithiobenzoate-terminated poly(propyleneimine) dendrimer. The dendritic-CTA was prepared by coupling an NHS-ester-functionalized CTA with amine-functionalized dendrimer, DAB-Am-8 (Scheme 28b). This star macro-CTA comprised of polySt arms was then employed for block copolymerization of MMA to generate a dendrimer-star block copolymer, Den(PSt-bPMMA)8.225,226 To this end, Guan et al.227 constructed amphiphilic dendritic nanoparticles featuring a hydrophobic dendritic core and reactive hydrophilic arms of a diblock copolymer, poly(OEGMA-b-NHSA), by combining chain walking polymerization (CWP) of ethylene with ATRP of OEGMA (Scheme 29). The dendritic macroinitiator was prepared by copolymerizing ethylene with a monomer bearing a radical initiating site using chain walking palladium−αdiimine catalyst. ATRP of OEGMA from the core created a discrete core−shell structure. Futher, end capping of hydrophilic poly(OEGMA) arms with polyNHSA enabled bioconjugation of the resulting nanoparticles with protein ovalbumin. Combining the arm-first approach with active ester chemistry, David et al.228 synthesized a series of well-defined star polymers via RAFT polymerization of PFPA. Initially prepared linear precursor polyPFPA arms were chain extended with PFPA and bis-acrylamide or bis-acrylate cross-linker to generate a reactive star copolymer (Scheme 30a). PFP-ester

Scheme 29. Synthesis of Star Polymer Combining CWP with ATRP

groups were later exploited to attach multiple amino functionalites to the polymer arms to create functional stars. For example, star glycopolymers could be fabricated using an amino sugar, e.g., glucosamine, illustrating the versatility of this method. During aminolysis, the CTA end group is cleaved as well, generating free thiols within the core. A second modification via thiol−ene click allowed incorporation of a fluorescent dye inside the core, eventually creating luminescent star polymers. Following a similar convergent strategy, Hawker et al.229 synthesized core−shell PEGylated star polymers185 from diblock copolymer arms comprised of reactive NHS-ester groups. A PEG-based macro-CTA that formed part of the outer arm was used to copolymerize DMA and NHSA. Further chain extension with divinylbenzene or ethylene glycol diacrylate cross-linkers created the core of the star (Scheme 30b). The reactive inner arms featuring NHS-ester groups allowed covalent attachment of amine-functionalized tris(tert-butyl)protected 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (TB-DOTA) for immobilization of 64Cu nuclei to create radiolabeling polymers used in positron emission tomography (PET). Similarly, RAFT cross-linking polymerization of styrene and divinylbenzene with an azide end-functionalized polyNIPAM macro-CTA resulted in thermoresponsive core crosslinked star polymer.230 Postfunctionalization of the azideterminated surface with biotin was achieved following an azide−alkyne click reaction. 3.2. Chain-End-Functionalized Polymers

Functionalization of macromolecules at the α- or ω-chain ends allows installation of a single functional entity per polymer chain that finds increasing use in creating biomolecule− polymer conjugates, telechelic polymers, and precursor for diblock copolymer synthesis or in surface modification by a grafting-to approach. Terminal derivatization of polymers is a synthetic challenge for free radical polymerization and is most cases achieved by controlled chain polymerization techniques using functional initiator or chain transfer agents.231−233 Use of initiators or CTAs equipped with a reactive group offers possibilities for multiple variations by PPM at the chain terminus of the polymer without changing its degree of polymerization, which is nearly impossible in a direct polymerization with initiator or CTA featuring a particular functional entity. Polymerization with activated ester-based S


Chemical Reviews

Review


Scheme 30. Synthesis of Star Polymer with (a) polyPFPA Arm and (b) PEG-b-P(DMA-co-NHSA) Arm Following “Arm-First” Approach

Table 2. Structures of Various Activated Ester Containing Initiators and CTAs

Scheme 31. Synthesis of (a) Lysozyme-Conjugated Homopolymer and (b) Trypsin-Conjugated Copolymer Using NHSI-1 Initiator

Haddleton and co-workers234 described a generalized method for protein−polymer conjugation from NHS-ester αend-functionalized polyPEGMA obtained by ATRP of PEGMA with NHS-2-bromopropionate (NHSI-1) and NHS-2-bromoisobutyrate (NHSI-2) (Table 2). Polymer conjugation with model protein lysozyme through its amine function (Scheme 31a) was found to be dependent on the reactivity of the initiator used. The less reactive NHSI-2 failed to instigate

initiator or CTA happens to be one of the most versatile approaches for chain-end modification that can generate polymers with active sites on α-chain ends. These precursor polymers can potentially react with different classes of aminecontaining species (biomolecules, surfaces, polymers, etc.) to generate functionalized bioconjugates, surfaces, block copolymers, or other complex polymeric architectures. T


Chemical Reviews

Review


Scheme 32. Synthesis of Maleimide Chain-End-Functionalized Polymer and PPM by Photoinduced Cycloaddition

Scheme 33. Synthesis of Amphiphilic Block Copolymer Connecting Polypeptide with Polyamide Backbone by ROP Followed by RAFT

poly(butyl acrylate) from NHSI-1 by PPM with an amino maleimide linker (Scheme 32).241 When exposed to a UV-flow reactor, the single maleimide unit at the polymer terminus could efficiently take part in alkene−enone [2 + 2] photocycloaddition reaction with functional alkenes, leading to complex polymers with different cycloadducts at the chain end. RAFT polymerization with activated ester-functionalized CTAs provide an alternative pathway toward chain-endmodified polymers. Besides ATRP, bioconjugation via RAFT polymerization has also been successfully achieved using activated ester-based CTAs.242,243 From a single NHS-ester containing RAFT agent, structurally diverse CTAs were generated by conjugation with various biotic and nonbiotic functional amines.244,245 Biotin- and galactose-functionalized CTAs generated from NHSCTA-1 (Table2) were used for polymerization of NAM. The reaction proceeded with high conversion, leading to biomolecule−polyNAM conjugates.244 Additionally, NHSCTA1 was employed in the synthesis of fluorescently tagged thermosensitive block copolymer whose critical micellar concentration (CMC) was determined from Förster resonance energy transfer (FRET) between loaded anthracene and endcapped phenanthrene dye.246 A PEG macro-CTA247,248 was prepared in high yield by coupling of NHSCTA-2 with PEG-amine. It was used for RAFT aqueous dispersion block copolymerization of HPMA.249 From a single macro-CTA, a family of amphiphilic

lysozyme−polymer complexation. Protein conjugation with glycopolymers can be achieved if protected glucose- or galactose-based monomers are used.235 Emissive bioconjugates prepared from fluorescently tagged Rhodamine B or Hostasol containing PEGylated polymers allowed in situ monitoring of products using a fluorescent detector equipped SECHPLC.236,237 In a similar approach, thermosensitive protein conjugates have been prepared by covalent attachment of bovine pancreas trypsin with thermoresponsive copolymer P(MEO2MA-co-OEGMA475) starting from an activate ester containing initiator (Scheme 31b).238 As an alternative to PEGylated proteins, biocompatible zwitterionic methacryloyloxyethyl phosphorylcholine (MPC) polymers were prepared and their conjugates with lysozyme and two therapeutic proteins, granulocyte colony stimulating factor (G-CSF), and erythropoietin (EPO) were studied.239,240 Besides bioconjugation, end group modification via an activated ester approach allows incorporation of complex functionalities at the chain end, which are difficult to achieve by direct polymerization. Maleimide-functionalized polymers are generally prepared from furan-protected maleimide initiators or monomers to avoid copolymerization. Deprotection by retro-Diels−Alder reaction after the polymerization step generates free maleimide-containing polymers. However, direct installation of maleimide units can be achieved by PPM. High fidelity and versatility of activated ester chemistry have been illustrated in preparing a maleimide end-functionalized U


Chemical Reviews

Review


Scheme 34. Different Strategy for Grafting Polymers to Silica Nanoparticles

Scheme 35. (a) Synthetic Scheme for Heterotelechelic Water-Soluble Polymers Featuring (b) Thyroxin and Biotin and (c) Oregon Green Cadaverine and Texas Red Dye at the α- and ω-Chain End, Respectively

block copolymers was obtained whose morphology (worms, vesicles, or spheres) could be tuned by varying the degree of polymerization of the hydrophobic polyHPMA block. Similarly, polyethylene (PE) containing RAFT agent, made by amidation of NHSCTA-2 with PE-NH2, was used as a macro-CTA for block copolymerization of n-butyl acrylate.250 In a different strategy, amine-functionalized RAFT agent was prepared from reactive NHSCTA-3 and used for sequential ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydride (NCA) monomer from the amine terminal and RAFT polymerization of NIPAM from the trithiocarbonate end group to generate an amphiphilic block copolymer connecting

a polypeptide backbone with pendent polyamide chain (Scheme 33).251,252 Polymer chains with an activated ester end group also offer a versatile and efficient approach for surface modification.253 NHS-ester-functionalized alkoxyamine initiator, nitroxide SG1 (NHS-SG1) (Table 2), was used in NMP of styrene, n-butyl acrylate, or MMA. Those polymer chains with high chain-end functionality were grafted on amino-coated silica particles (Scheme 34) and revealed a grafting density of 0.1−0.2 chains nm−2. In contrast, following a one-pot grafting strategy, where polymerization and graft on worked simultaneously, much higher grafting density (0.9 chains nm−2) could be obtained using amino-coated silica, NHS-SG1 initiator, and the V


Chemical Reviews

Review


Scheme 36. Synthesis of (a) Telechelic Polymer with Azobenzene Chain End and (b) High Molecular Weight Condensation Polymer

respective monomer in one pot.254 Combining NMP with ROP, polystyrene-block-poly(D,L-lactide) or polystyrene-blockpoly(propylene oxide) was synthesized from NHS-SG1 following a pre- or postfunctionalization approach with ethanolamine that catalyzed the ROP from its hydroxyl end.255 Comparable results obtained following the two different pathways illustrated the efficiency of the activated ester amine chemistry. Polymer−silica hybrid composites256 were fabricated by end group modification of a thermoresponsive statistical copolymer poly(MEO2MA-co-OEGMA) with amino-functionalized silica monoliths. Those composites acted as a potential stationary phase in chromatographic separation of steroid and protein mixtures in aqueous phase under isocratic highperformance liquid chromatographic elution.257 Activated ester-containing CTAs allow a flexible functionalization of the CTA either prior to or after the polymerization.258 Phosphine-based CTAs were synthesized from a PFP-ester-based RAFT agent, PFPCTA-1 (Table 2), by thioesterification with P-borane-(diphenylphosphanyl)-methanethiol. The phosphine−thioester CTA was not only found to be suitable for polymerization of styrene but also showed facile polymer chain-end modification by Staudinger ligation with a variety of azide-functionalized molecules.259 PFPCTA-2 (Table 2) has been thoroughly investigated by Theato and co-workers in the synthesis of stimuli-responsive PEGMA with reactive chain ends. PPM with different amines created a library of α-chain-end-modified polymers with identical degree of polymerization. The self-assembly behavior and LCST/UCST properties of those polymers could be precisely altered by installation of functional groups at the chain end (Scheme 35a).260,261 Additionally, aminolysis of ωdithioester in the presence of an excess of amine and functional methane thiosulfonate (MTS) allowed one-pot modification of both the α- and the ω-chain ends, leading to heterotelechelic polymers. Following this protocol, a biotargeted heterotelechelic polymer, polyDEGMA featuring thyroxin and biotin at the α- and ω-chain ends, respectively, was prepared (Scheme

35b). Orthogonal complexation with site-specific thyroxin transport protein prealbumin and biotin-specific streptavidin was studied.262 Using a similar approach, incorporation of a FRET pair, Oregon Green Cadaverine and Texas Red dye at the α- and ω-chain end, respectively, was also achieved (Scheme 35c). Temperature-induced chain collapse or extension was studied from the intensity of FRET emission during phase transition.263 Heterotelechelic PMMA, tagged with fluorescent Texas dye at the α-chain ends, enabled ligand exchange on both gold nanoparticles (AuNP) and CdSe/ZnS quantum dots (QD) through its ω-end-modified methyl disulfide group, leading to polymer/NP or polymer/QD composites. Binding efficiency of those composites was determined from energy transfer between the dye and the NP/QD.264 Subsequently, a slightly modified route conferred dual (thermo and light)-responsive telechelic polyOEGMA with azobenzene functionality at both ends. PPM of the ωdithioester group with an azo initiator (PFP-ACV) containing PFP-ester moieties resulted in incorporation of PFP-ester at both ends of the polymer chain. Subsequent modification with amino-functionalized azobenzene employed stimuli-responsive telechelic polymers (Scheme 36a); the LCST of those could be tuned by conformational changes of the two azobenzene groups during photoisomerization.265 Simple replacement of the terminal photoresponsive dye with ethylenediamine produced very high molecular weight polymers by polycondensation reaction between the reactive telechelic PFP-ester polymer and the diamine (Scheme 36b).266 In a completely different pathway, heterotelechelic poly(β-amino ester) (PAE) featuring a fluorescent dye and a cell-targeting protein at the two extreme chain terminals was obtained by sequential ring-opening polymerization of ε-caprolactone with a functionalized initiator. Condensation polymerization of the macroinitiator with a diamine, 4,4′-trimethylene dipiperidine, and a diacrylate, hexane-1,6-dioldiacrylate, generated free amine at the ωterminal that was subjected to Michael addition reaction with NHSA to incorporate cell-targeting ligand c(RGDfK).267 W


Chemical Reviews

Review


Scheme 37. Synthesis of Poly(t-BuMA-b-DEGMA) from Two Homopolymers Containing Complementary Chemical Handles at the Chain End by Convergent Approach

acid. The reactive monomer was subjected to polymerization using metathesis catalyst tungsten hexachloride (WCl6) in the presence of cocatalyst tetraphenyltin (SnPh4) in dry toluene at 80 °C (Scheme 38a). The broad molecular weight distribution

Apart from chain-end modification with different abiotic small molecules and biomolecules, the versatility of reactiveCTAs for the synthesis of block copolymers was also demonstrated.268 Stimuli-responsive polyDEGMA was covalently attached on both ends of a diamine-functionalized bocprotected collagen−peptide through its terminal PFP-ester groups. The resulting polyDEGMA-b-collagen-b-polyDEGMA triblock copolymer formed a temperature-dependent triplehelical structure.269,270 Using a convergent strategy, poly(tBuMA-block-DEGMA) was synthesized by click coupling between azide- and alkyne-end-functionalized poly(t-BuMA) and polyDEGMA, respectively.258 The chain-end-functionalized homopolymers were obtained by PPM of PFP-ester of the respective block ends with complementary amines (Scheme 37). An alternative strategy using alkyne- or azide-functionalized CTA obtained from PFPCTA-2 prior to polymerization revealed similar efficiency.

Scheme 38. (a) Synthetic Scheme for polyPFPEB and PPM with Amines, (b) Structures of Ortho-, Meta-, and ParaSubstituted polyPFPEB, (c) Structures of polyPFPEB with Varying Spacer between the PFP-Ester and the Polymer Backbone

4. OTHER METHODS OF POLYMERIZATION OF ACTIVATED ESTER MONOMERS Besides polymerization of acrylate-, methacrylate-, and styrenebased activated ester monomers in solution phase, on surface, or from surfaces by free and controlled radical polymerizations, various other types of activated ester monomers are known that can be polymerized in solution and/or on surfaces by other advanced polymerization techniques. 4.1. Alkyne Metathesis of Acetylenes

Ever since the invention of conjugated polyacetylenes (PAs),271 winning the Nobel prize, conducting polymers272,273 have received immense attention from various interdisciplinary sciences. It is due to their rich electronic and optical properties that find potential applications in conducting materials, organic photovoltaics, sensors, and biomedical sciences. Despite being known for their metallic conductivity in the doped form, difficulty with processing due to insolubility and instability to air are the major downside of polyacetylenes that often put into question their practical applicability. This demanded the need for functionalized polyacetylenes274 that could be produced by formally replacing the hydrogen atoms in each repeat unit either by one or by two substituents to yield monosubstituted or disubstituted PAs, respectively. Functional tolerance of several novel metathesis catalysts based on Mo-, W-, Ta-, or Rhbased insertion catalysts enabled easy design and synthesis of functional PAs. Activated ester chemistry has been employed to create widely functional mono- as well as disubstituted polyacetylenes. Theato et al.275 synthesized an activated estercontaining acetylene monomer, pentafluorophenyl 2-ethynylbenzoate (PFPEB), in few steps starting from 4-bromobenzoic

(Mw/Mn < 2.1) obtained for the homopolymer polyPFPEB could be improved by copolymerization with phenylacetylene or methyl 4-ethynylbenzoate. Functional polyacetylenes were obtained by PPM of polyPFPEB with various amines. Significant reactivity was exemplified from quantitative reaction of polyPFPEB with aromatic amines. The same group later prepared three constitutional isomers of PFPEB by changing the activated ester site at the ortho, meta, and para positions of the phenyl ring (Scheme 38b).276 The polymerization conditions, configuration of the monosubstituted polyacetylenes, as well as their reactivity toward different amines were found to be dependent on the position of the activated ester moiety in the phenyl ring. Although rhodium-based catalyst failed to initiate polymerization of ortho-substituted monomer, polymerization with tungsten catalyst was successful for all isomers. Interestingly, rhodium catalyst-mediated PAs featured X


Chemical Reviews

Review


Scheme 39. Synthesis of polyNHSNorb by ROMP and Their PPM with Amine Containing Sugar Moieties

a cis−transoid configuration, while polymers synthesized using tungsten catalysts revealed a trans−transoid structure. In addition, the reactivity of these polymers toward functional amines could be tailored by varying the location of the PFPester within the monomers. A reduced reactivity of the orthosubstituted polyPFPEB compared to its meta and para analogues was observed. The group of Sun and Tang277 prepared series of monosubstituted polyacetylenes with pendent PFP-ester groups by varying the number of methylene spacers between the PA backbone and the PFP-ester moiety (Scheme 38c). Derivatization of the precursor polyphenyl acetylenes (PPAs) with either or both chiral and achiral alkyl amines resulted in multiple functionalized PPAs with different properties. For more rigid polymers, directed helicity could be induced within the polymer backbone from the pendent asymmetric carbon centers, while polymers with more flexible spacers failed to generate helical bias from the chiral centers. Modifying reactive PPAs with amine-functionalized PEGs led to water-soluble polyacetylenes with tunable LCST behavior governed by the length of the hydrophobic alkyl spacer and/or the incorporated amount of the alkyl amine. Following a similar synthetic strategy to that of Theato et al., this group prepared PFP-esterbased disubstituted PPAs from PFPPEB (Table 2) using WCl6−SnPh4 catalyst.278 PPM of the precursor polymer with chiral amine featuring a polar hydroxyl or carboxylic group offered a very convenient strategy for designing functional disubstituted polyacetylenes. This is hard to achieve by direct polymerization of monomers containing polar functional groups as they are inclined to poison the catalyst.

Figure 1. Structure of two random copolymers (left) featuring complementary H-bonding groups introduced by PPM and their mode of self-assembly (right).

Vogel and Theato286 described ROMP of bicycle[2.2.1]hept5-ene-exo-2-carboxylic acid pentafluorophenyl ester (PFPNorb) (Table 1) using Grubbs first-generation catalyst, producing polymers with molecular weights up to 75,400 g/ mol. Molecular weights of the polymers could be controlled by varying the monomer/initiator ratio, thereby illustrating the controlled nature of the polymerization. PFP-ester containing polynorbornenes could be successfully postmodified with functional amines without affecting the polymer backbone. Both NHSNorb287,288 and PFPNorb289 have been employed in constructing reactive diblock copolymers. Kane and coworkers287 described the synthesis of reactive block copolymer with NHSNorb monomers. Grafting with amine-functionalized hexaethylene glycol generated amphiphilic block copolymers. Orthogonally clickable statistical terpolymers and diblock copolymers featuring PFP-ester and protected alkyne side groups were obtained using PFPNorb as one of the monomers.289

4.2. Ring-Opening Metathesis Polymerization (ROMP) of Norbornenes

Ring-opening methathesis polymerization (ROMP) of activated ester containing norbornenes has been another successful method for creating functional polymers. Following this approach, Kiessling and co-workers 279,280 polymerized bicyclo[2.2.1]hept-5-ene-exo-2-carboxylic acid N-hydroxysuccinimide ester (NHSNorb) (Table 1) using first-generation Grubbs catalyst. The degrees of polymerization (DP) could be reached between 21 and 150. The obtained reactive polynorbornenes were modified with different amine-based sugar moieties to develop cellular binding assay for Lselectin280,281 (Scheme 39). On modification with guanidinium-substituted amines, cell-penetrating polymers were produced, whose cell permeability could be monitored by fluorescence microscopy, when tagged with a fluorophore.282−284 Polynorbornene bearing complementary diamidopyridine and uracil recognition elements were prepared following the precursor polymer approach.285 The random copolymer self-assembled into spherical polymersomes by H bonding between the complementary functional groups and slowly fused together to form larger structures (Figure 1).

4.3. Ring-Opening Polymerization (ROP) of Cyclic Carbonates

Aliphatic polycarbonates are among the most extensively investigated classes of polymers in biomedical sciences for their biodegradability, biocompatibility, and nontoxicity. However, their hydrophilicity, biodegradability, and mechanical properties can be improved many fold by incorporating pendent hydrophilic functional moieties within the polymer chain. Zhuo and co-workers290 copolymerized a novel sixmembered cyclic carbonate monomer 5-methyl-5-(succinimideN-oxycarbonyl)-1,3-dioxan-2-one (MSTC) (Table 2) containing an NHS-ester group with caprolactone (CL) in bulk at 140 °C by organocatalytic ring opening. Aminolysis of poly(MSTCco-CL) with ethylenediamine produced poly(MATC-co-CL) (Scheme 40). The obtained poly(carbonate-ester) with pendent free amine groups showed enhanced hydrophilicity and hydrolytic degradability. In order to expand their scope and versatility, a highly efficient one-pot synthetic route to PFPester-containing cyclic carbonate monomer MTC-OPhF5 was Y


Chemical Reviews

Review


Scheme 40. Synthesis and Amidation of poly(MSTC-co-CL)

CsF291 or tetra-n-butylammonium fluoride (TBAF).293 Hydrophobically modified polyethylenimines (PEIs) were prepared by covalent attachment of low molecular weight PEI to functionalized polycarbonates (MTC) generated from a single reactive poly(MTC-OPhF5) by nucleophilic substitution with different hydrophobic amines. The polymer obtained showed improved gene transfection efficiency as probed by their DNA binding studies.294 Hydrophilic polycarbonates prepared by the acid-catalyzed ring-opening polymerization of MTC-OC6F5 and consequent reaction with various amino alcohols were developed as a better alternative for PEG for their added advantage of being hydrolytically and enzymatically degradable.295 To expand the future possibilities of this monomer, Hedrich et al.167 synthesized diblock copolymers either using poly(ethylene glycol) monomethyl ether as a macroinitiator or by sequential addition of two MTC monomers, MTC-OC6F5 and MTC-OEthyl, in one pot. Polycarbonate copolymers bearing pendent hydroxyl groups with disulfide linkage were used for ROP of lactide or trimethylene carbonate. The two graft polymers polycarbonate-graf t-polylactide and polycarbonategraf t-poly(trimethylenecarbonate) obtained following a graft-

developed by Sanders and Hedrick.291 MCT-OPhF5 synthesis was carried out by reacting two equivalents of commercially available bis(pentafluorophenyl)carbonate (PFPC) with 2,2bis(hydroxymethyl)-propionic acid (bis-MPA) resulting in concomitant transformation of acid into PFP-ester and ring closure of the 1,3-diol to cyclic carbonate, unlike its NHS-ester analogue made earlier in multiple steps (Scheme 41). Taking Scheme 41. Synthesis of MTC-OPhF5 and Its Derivatives by Aminolysis

advantage of the activated PFP-ester moiety, a library of functional monomers was generated by aminolysis with various amines, which on organocatalytic ROP resulted in highly functionalized polycarbonates.292 Transesterification with primary alcohols proceeded in near quantitative yields using

Scheme 42. Synthetic Scheme for Cleavable Brush Copolymer from Polycarbonate Backbone Following Grafting-from Approach

Z



Chemical Reviews

Review

ing-from approach carried redox-responsive detachable brushes.296 The polycarbonate backbone was generated from a single reactive MTC-OPhF5 monomer in few steps. The precursor MTC-OPhF5 was modified with 2-(tritylthio)ethanol and benzyl alcohol to generate two daughter monomers; those were later copolymerized to produce the polymer backbone (Scheme 42). Deprotection of the thiol group within the copolymer and its further treatment with 2-(2-pyridyldithio)ethanol produced the pendent OH group attached with a dithiol linkage that further mediated the ROP. This method demonstrates the versatility of the approach for generating functionalized tailormade cleavable graft copolymers.

polymer deposition. Solvent permeability could be enhanced by increasing the amount of unsubstituted pyrroles within copolymer films.309 This improved the hydrophilicity and thus its reactivity toward water-soluble amines.310 Besides pyrrole, electrochemical polymerization of activated ester-based thiophenes has also been reported.311,312 Similar to pyrroles, reactive polythiophene films of varying compositions were obtained by copolymerization of either pentafluorophenyl thiophene-3-acetate (PFPT1) or N-hydroxy succinimidyl thiophene-3-acetate (NHST1) with 3-methylthiophene in different ratios (Scheme 44).313 The conducting properties of

4.4. Electrochemical Polymerization of Activated Ester Containing Pyrroles and Thiophenes

Scheme 44. Electrocopolymerization of NHST1 or PFPT1 with 3-Methylthiophene

Electrochemical polymerization297 of pyrroles298 and thiophenes299 happens to be a standard protocol for making smooth and robust conducting polymer films that find widespread use in bioelectrocatalysis, sensors, or even diagnostics by acting as templates for biomolecular immobilization. Activated ester-containing pyrroles and thiophenes offer additional possibilities for surface modification in tailormade electropolymers, whose properties can be manipulated by incorporating different functional motifs during aminolysis of the activated ester groups. Cooper and co-workers300 illustrated the electrochemical polymerization of PFP-ester-containing βsubstituted pyrroles (PFPPy-1) (Table 1) into reactive polypyrrole films. Multiple functional polypyrroles were obtained on treatment with a variety of different nucleophiles, including amine-based sugar moieties. Even electropolymerization of various activated ester-containing N-substituted pyrroles are well known. They have been modified with amino acid, dopamine, and chiral sugar derivatives to generate highly functionalized conducting films.301 Cystine-based polypyrroles act as a novel surface for binding redox-active cofactors such as iron−sulfur clusters to create ferredoxin electrodes.302,303 Immobilization of diiron complex into the electropolymer is achieved by a postpolymerization technique. As the diiron unit is sensitive to oxidative degradation during electrochemical polymerization of pyrrole, it can be immobilized into the electropolymer only by PPM.304 Chemical modification of a reactive film derived from Nderivatized pyrrole305 (PFPPy-2) with a solution-phase model nucleophile, ferrocene ethylamine (Scheme 43), was analyzed

these reactive films were similar to that of unsubstituted polythiophene and also unaffected by surface modification with different amines. Systematic variations in the monomer structures by incorporating a different number of methylene spacers between the activated ester and the thiophene center seemed to have no effect on both electrochemical polymerization or postfunctionalization of the surface.314 Conducting polymer films obtained by copolymerizing a binary mixture of activated ester-based pyrrole and thiophene revealed lower incorporation of thiophene monomers within the polymer chain compared to the respective pyrroles as described by Ryder et al.315 Polythiophene has been successfully used as an electrically conducting material for covalent immobilization of biochemically interesting molecules.316 A simple and straightforward two-step procedure for amperometric polythiophenebased enzyme electrodes was presented by Schuhmann et al.317 This was achieved by electrochemical deposition of polythiophenes comprising NHS-ester groups on an electrode surface and subsequent covalent binding of enzyme glucose oxidase onto the electroactive surface via its amine functionality. Following a similar strategy, oligonucleotides were immobilized on conducting polythiophene surfaces that acted as electrochemical biosensors for detecting the sequence of short DNA oligomers.318−320 Besides bioconjugation, electrooxidation polymerization of terthiophenes has been advantageously used for reduction of HAuCl4 to gold nanoparticles (AuNPs). Polyamidoamine (PAMAM) dendrimer-encapsulated AuNPs decorated with a polythiophene outer shell were synthesized from a PAMAM-terthiophene precursor that worked as a reducing agent for simultaneous formation of AuNPs and electro-oxidative polymerization of terthiophene (Scheme 45).321 Besides electrochemical polymerization, electrografting of acrylates and methacrylates featuring activated ester moieties was developed as another powerful technique for surface modification of conducting substrates.322−324 Jerome et al.325 showed electrografting of NHSA onto a conducting substrate by voltammetry in the presence of a conducting salt, tetraethylammonium perchlorate. Surface modification with electroactive ferrocene or bioactive proteins or enzymes by

Scheme 43. Modification of polyPFPPy-2 Film with Ferrocene Ethylamine

by in situ neutron reflectivity.306,307 The rate of modification was not uniform throughout the entire film thickness and proceeded faster at the polymer−solution interface and much slower in the dense inner part of the film. It was due to limited diffusion of the amines into the inner parts of the film.308 Other parameters that influence the chemical reactivity of the conducting films include identity of solvents, its adsorbed amount within the films due to swelling, and the rate of AA


Chemical Reviews

Review


Scheme 45. Formation of Polyterthiophene Dendrimer-Coated AuNP by Simultaneous Electropolymerization and Reduction

SWNTs aggregates could be derivatized with glucose oxidase to investigate electrocatalytic oxidation of glucose within those SWNTs assemblies. Following scanning electrochemical microscopy (SECM),331 patterned microelectrografting of reactive spots of NHSA on an electrode surface was achieved. Subsequent derivatization of the electrografted reactive polymer coating with a fluorescent probe highlighted those micropatterened surfaces, a technique that is being used in biomolecular electronic devices or in multisensory arrays.

nucleophilic substitution provided an easy method to fabricate electrochemical sensors or biosensors. Duwez et al.326 electrografted polyNHSA brushes from silicon surface of an atom force microscopy (AFM) tip. They further described singlemolecule delivery and immobilization of polyNHSA electrografted from a gold-coated AFM tip on amine-functionalized surfaces (Scheme 46).327,328 This was achieved by simply Scheme 46. (a) Schematic Representation for the Transfer of Polymer Chain Grafted to an AFM Tip to a Reactive Surface; (b) Chemical Bonding of a polyNHSA graft to an Amine-Functionalized Surfacea

a

4.5. Plasma Polymerization

Plasma polymerization,332 also named glow discharge polymerization, is an efficient technique to fabricate polymer films from acrylate and methacrylate monomers. This method of polymerization leads to extremely branched and cross-linked insoluble polymer films that can strongly adhere to a variety of solid substrates such as metals or glass or even other polymer supports. These excellent properties of this technique contribute to their growing application in the field of protective coatings, adhesion promoters, selective membranes, biomedical materials, diagnostic biosensors, etc. Plasma polymerization of activated ester monomers is a widely established strategy for immobilization of biomolecules on reactive surfaces that forms the basis for biological assays333 and microfluidic biosystems.334 Förch et al. demonstrated pulsed plasma polymerization of PFPMA.335,336 The reactive films obtained revealed very high retention of activated ester groups that provided a reactive site for conjugation of various amines. As a proof of demonstration, surface reactivity toward diaminohexane and protein immunoglobin was studied in aqueous buffer solution using FTIR spectroscopy, X-ray photoelectron spectroscopy, and real-time surface plasmon resonance spectroscopy. Following same technique, Gleason and co-workers337 achieved cross-linked polyPFPMA films by copolymerizing PFPMA with ethylene glycol diacrylate. Surface modification with fluorescently labeled amines could even produce patterned films through microcontact printing. The versatility of plasma polymerization method was further illustrated by achieving layer-by-layer polymer deposition. PFPMA was vapor deposited on silicon wafers in the presence of a divinyl cross-linker. The reactive films were quantitatively reacted with amine-functionalized biotin that conferred layer-by-layer self-assembly via biotin− streptavidin interactions.338,339 Langer and co-workers340 reported chemical vapor deposition of PFP-ester-functionalized [2.2]paracyclophanes (Scheme 47). The reactive poly[pxylylene carboxylic acid pentafluorophenol ester-co-p-xylylene] template was patterned by microcontact printing with biotinNH2 and used as template for specific protein and cell binding.334 Following this technique, surfaces with high amine density can be developed by grafting poly(L-lysine) dendrigrafts

Reprinted from ref 327. Copyright 2006 Nature Publishing Group.

pulling away the AFM tip from the surface that broke the weaker chemical bond between the polymer and the AFM tip. In an alternative approach, an amino thiol-functionalized AFM tip was covalently connected with polyNHSA chains electrografted onto gold substrates.329 Amidation resulted in a strong bonding between the polymer chain and the AFM tip. Also, single-wall carbon nanotubes (SWCTs) untangled in room-temperature ionic liquids (RTILs) provided large surface area for electrografting of NHSA.330 Reactive polymer-coated AB


Chemical Reviews

Review


Scheme 47. Chemical Vapor Deposition of PFP-Ester-Functionalized [2.2]Paracyclophanes

Scheme 48. Schematic Representation of the Orthogonal and Reversible Functionalization of a Random Copolymer Featuring NHS-Ester and Pyridyl-Disulfide Groups

onto plasma-activated polymers.341 Chemical modification of the dendrigraft was achieved by partially treating the amine residues on its surfaces with NHSA or other NHS derivatives.

a bifunctional polymer precursor with two orthogonal reactive handles by copolymerizing NHSMA and pyridine disulfidefunctionalized methacrylate monomer by ATRP. The copolymer offers two functionalities, complementary to amine and thiol (Scheme 48).343 Quantitative modifications in either one pot or by sequential addition resulted in the same complex functional polymer with interesting properties. Using polyNHSNorb, Kiessling and co-workers344 polymerized maleimide-substituted norbornene to obtain a diblock copolymer featuring two orthogonally reactive pendent functionalities, NHS-ester and maleimide. Dual-reactive precursor polymer was subjected to reversible Diels−Alder reaction with a furan-based resin. This provided a means for solid-phase polymer synthesis by derivatization of the immobilized polymer with various amine functionalities of interest. To this end, Sanyal et al.345 described copolymerization of NHS4VB with a furan-protected maleimide-based styrene monomer to generate orthogonally functionalizable random copolymers, reactive toward thiols and amines. Studer et al.111 described a nitroxide-mediated alternating copolymerization of HFIPMA with 7-octenylvinylether. Sequential chemical modification of the resulting copolymer was achieved by thiol−ene and amidation reactions. Novel pentafluorophenyl-based (meth)acrylate monomers obtained by Passerini multicomponent reactions revealed selective para-fluoro substitution with thiols. Copolymerizing those monomers with PFPA produced orthogonally reactive precursor copolymers where the reactivity of the two functional groups was specific to thiols and amines.346 A statistical terpolymer, with three orthogonally functionalizable groups comprising of PFP-ester, maleimide, and silyl-protected alkyne was successfully prepared by ROMP. A three-step PPM with benzyl mercaptan, hexylamines, and piperonyl azide, respectively, led to multifunctional polymer (Scheme 49).289

5. ORTHOGONAL AND SEQUENCE-CONTROLLED POSTMODIFICATION Rapidly growing demand of polymeric materials in various interdisciplinary applications has created the need to construct multifunctional macromolecules with precisely controlled architectures following simple but efficient chemical transformations. Polymers bearing “clickable” moieties generate scope for multiple functionalizations from presynthesized macromolecular scaffolds by PPM. Near quantitative yields, mild reaction conditions, and tolerance toward a wide range of functional groups have led to the utmost use of click reactions as synthetic tools for PPM that includes azide−alkyne cycloaddition, Diels−Alder, thiol−ene and −yne, thiol− maleimide, and activated ester amine reactions.11,14 Most of these reactions under the broad umbrella of click chemistry are orthogonal in nature and perform with tremendous fidelity and selectivity in the presence of other reactive groups that form the basis of most biochemical pathways.342 Combined click reactions can facilitate synthesis of even more complex macromolecules. Inspired by Mother Nature, several research groups have developed orthogonally functionalizable polymers featuring two or more chemoselective handles that can react specifically with functionally diverse complementary reactive tools either simultaneous in one pot or in stepwise/sequential fashion. By combining activated ester amine chemistry with other click reactions, extremely versatile and efficient multifunctional polymers have been prepared.105 Thayumanavan et al. designed AC


Chemical Reviews

Review


Scheme 49. Sequential Modification of a Statistical Copolymer into Multifunctional Polymer by Triple Click Reaction

Scheme 50. Cascade Strategy for Multifunctionalization of NHS-Ester-Containing Copolymer

Precise positioning of functional groups within a polymer chain during PPM is another challenging task. The group of Theato developed a new synthetic strategy for difunctional polymers with precise functional group display from a single PFP2VCP monomer (Table 1).47 PolyPFP2VCP featured two sequentially accessible reactive side groups, such as ketone and PFP-ester, for stepwise multifunctionalization with amines and other ketone reactive moieties such as alkoxyamines or hydrazides.352 In contrast with orthogonally functionalizable copolymers obtained from acrylate/methacrylate monomers, where the two chemoselective groups are either randomly distribution within the polymer chain or in two specific blocks, ROP of disubstituted vinylcyclopropane confers allocation of two functional groups per repeat unit at a precise position with respect to each other along the entire polymer chain. This was also realized by stepwise PPM of poly(pentafluorophenyl 4vinylbenzenesulfonate) by aminolysis followed by a Mitsunobu reaction with alcohols.353 Nitroxide-mediated sequence-controlled copolymerization of styrene and its derivatives with pentafluorophenyl 4-maleimidobenzoate (PFP4MB) allowed precise positioning of single reactive groups along a polymer chain.97,354,355 Those polymers were used for specific allocation of functional moieties by PPM.356 Incorporation of an

Even incorporating two different activated ester monomers within a polymer chain with disparate reactivities allows for selective aminolysis by sequential addition of amines. Exploring the reactivity difference of PFP4VB and PFPMA, Theato et al. sequentially modified individual repeat units of statistical and block copolymers of PFP4VP and PFPMA with aromatic and aliphatic amines selectively.96,347 As an alternative, the difference in reactivity of azlactone and PFP-ester toward various amines was explored in selective amidation of a copolymer featuring these two activated esters. Sequential aminolysis led to amphiphilic block copolymer.348 Similarly, selective reactivity of PFPA ester and methyl salicylate acrylate (MSA) ester toward isopropylamine/cyclopropylamine and N,N-diethylethylenediamine, respectively, was utilized in generating dual temperature- and pH-responsive block copolymers.349 For a copolymer featuring NHS-carbonate and NHS-ester, stepwise conjugation with two different amines was achieved utilizing greater reactivity of NHS-carbonate for carbamate formation.350 Following a one-pot cascade strategy, Hawker et al.351 prepared complex macromolecular architectures from a single reactive NHS-ester-functionalized copolymer by simultaneously utilizing amidation and CuAAC reactions with an amine and azide moiety in the same reaction medium (Scheme 50). AD


Chemical Reviews

Review


Scheme 51. Intramolecular Chain Folding by Two Orthogonal Click Reactions

additional monomer such as N-propargyl maleimide along with PFP4MB within the polymer backbone enabled chain folding by sequential conjugation of the two orthogonally reactive alkyne and activated ester groups with one equivalent of a bifunctional linker featuring both an azide and an amine functionality (Scheme 51).357,358

Graft copolymers comprised of acrylic acid and 2methacryloylethyl acrylate (MEA) backbone with polyNIPAM or polyNIPAM-co-PEG grafts were synthesized by partial esterification of polyNHSA with 2-hydroxyethyl methacrylate (HEMA) and subsequent amidation with polyNIPAM-NH2 and PEG-NH2.368−370 Free radical polymerization of MEA within thermally-induced micellar assemblies produced dual pH- and temperature-responsive cross-linked particles. Morphology of those could be tailored by the presence or absence of grafted PEG chains.368 Starting from reactive poly(PFPMAb-MEO3MA), cationic core cross-linked (CCL) nanoparticles were developed by covalently linking the hydrophobic PFPester core with an amine-containing spermine cross-linker. Those cross-linked particles offered promising ability to complex and deliver siRNA into cells.371,372 Additionally, the presence of activated esters within the core enabled installation of fluorescent dyes that allowed tracking of siRNA−particle complexes inside the cells. Temperature-induced phase transition of thermoresponsive block copolymer, PEO-bpoly(NIPAM-co-NHSA), produced micellar aggregates featuring well-solvated PEO coronas and reactive P(NIPAM-coNHSA) cores that could be cross-linked by cystamine and later cleaved by DDT (Scheme 52).373 Those particles revealed opposite thermoresponsive phase behavior in ionic liquids.374 When a disulfide-based cross-linker373,375,376 was used, nanoparticles showed reversible disruption−reformation abilities in the presence or absence of DTT. Such particles can be transformed into ratiometric Hg2+ ion sensors by installing additional naphthalimide-based Hg2+-reactive moieties within the thermoresponsive block.377 Li et al.378 decorated the outer surface of single-walled carbon nanotubes (SWCNs) with CCL micelles by covalently attaching a polyDMA-b-poly(NIPAM-coNHSA) on the surface of the nanotube. The polymer was attached by its azide functionality at the polyDMA chain end that could adhere to the nanotube by a nitrene addition reaction upon decomposition of the azide. Thermoresponsive nanoparticles obtained along the walls of the nanotubes were stabilized by core cross-linking with diamines. Shell cross-linked (SCL) nanoparticles can be constructed from both reactive di- or triblock copolymers. In a diblock copolymer, the activated ester unit is incorporated within the

6. FUNCTIONAL MATERIALS BY POSTPOLYMERIZATION MODIFICATION The easy and mild reaction conditions of converting an activated ester with amines into the respective amide has led to the utilization of activated ester chemistry in various areas of functional materials. Examples include particles, hydrogels, numerous bioconjugation ligations, metal polymer complexes, and functional surfaces. 6.1. Cross-Linked Particles

Stimuli-responsive polymeric nanoparticles show great promise as therapeutic materials.163,359−361 However, for delivery applications an important consideration is to overcome invariable disassembly/dissociation of these polymeric nanostructures into single chains once their concentration is diluted under physiological conditions, a cause for premature drug release.362 An approach to address this problem is the use of cross-linked particles, reported as early as 1996.363 A general method for tailoring such cross-linked nanoparticles146,364,365 is by supramolecular assembly of amphiphilic block copolymers into core−shell micelles, followed by covalent cross-linking within the core or shell to ensure particle stability.366,367 Tailormade polymeric approaches have enabled engineering of advanced multifunctional cross-linked nanoparticles with precisely controlled architecture, shape, size, and functional group display. In this context, activated ester-based chemistry has been utilized for designing such polymeric nanostructures, where the role of the activated ester group is either to install the cross-linker or immobilization of functional/stimuli-sensitive molecules within the particle. In addition, rationally designed selective core or shell cross-linked particles can be fabricated by judicial placement of the activated ester moiety within the hydrophobic or the hydrophilic domain of the respective block copolymer. AE


Chemical Reviews

Review

polyNHSA-b-polySt, with a pH-sensitive fluorescent pyrazine cross-linker.386,387 SCL polymeric micelles obtained from the triblock copolymer, poly(OEGMA-b-NHSMA-b-MAETC), by covalent attachment of an acid labile ketal-based diamino crosslinker enabled a selective binding and pH-dependent release of anticancer drug cisplatin (Scheme 54).388 Highly emissive nanoparticles prepared from ABA type bolamaphiphilic triblock copolymers were used as photonic nanoprobes for protease sensing. 389 The polymer core featured rigidly packed conjugated chromophores, while the shell was comprised of polynorbornenes with pendent NHS-esters groups. Crosslinking of the shell by a protein linker caused luminescence quenching due to aggregation-induced quenching phenomenon. The fluorescence turned on again by enzymatic cleavage of the cross-linkers with protease.


Scheme 52. Schematic Representation for TemperatureResponsive Core Cross-Linked Micelle Formation and Its Disassembly in the Presence of DTTa

6.2. Hydrogels

a

Hydrogels are 3-dimensionally cross-linked polymer networks that can retain a substantial amount of water by maintaining their overall chemical structure. Such soft materials have been extensively explored in biomedical applications390−393 as a delivery vehicle and for tissue engineering, biosensors, medical devices, and other applications as they can sequester watersoluble drugs, proteins, or other biomaterials for targeted release. The most common method for preparation of robust and mechanically strong hydrogels involves the polymerization of water-soluble monomers in the presence of divinyl crosslinkers. Alternatively, physically cross-linked hydrogels utilize noncovalent interactions such as ionic, hydrogen-bonding, hydrophobic, or host−guest interactions to form the polymeric networks. However, these hydrogels tend to have weaker mechanical strength compared to hydrogels obtained from chemically cross-linked polymers. Environmental-sensitive hydrogels394,395 can alter their shapes and volumes when exposed to external stimuli such as pH, temperature, light, or certain chemicals and therefore hold great promise for triggered drug release when responding to physiological stimuli. In this regard, injectable hydrogels396 that can be generated in situ under physiological conditions by virtue of physical or chemical cross-linking are potential drug reservoirs that offer a convenient method for administration of bioactive materials. Considering these application aspects of hydrogels, new


hydrophilic block,379 while for triblock copolymers,380it forms a separate segment that tethers the hydrophobic and hydrophilic chains. Wooley and co-workers381 prepared SCL micelles from amphiphilic diblock copolymer, polyMA-b-poly(NHSA-coNAM), by cross-linking the hydrophilic segment with diamino linkers. Replacing hydrophobic poly(methyl acrylate) core with hydrolytically degradable poly(lactic acid) (PLLA) triggered enzymatic hydrolysis of the PLLA core without degrading the overall nanostructure assembly (Scheme 53).382 Reversible SCL micelles were prepared from amphiphilic triblock copolymers, PEO-b-poly(DMA-co-NHSA)-b-polyNIPAM obtained from a PEO-based macro-CTA.383 Thermoresponsive phase transition produced micelles with polyNIPAM core, a PEO corona and reactive shell featuring NHS-ester groups. Particles were stabilized by covalent cross-linking with cleavable cystamine-based difunctional primary amines for controlled drug release study.384 A ratiometric pH sensor was developed from fluorescent SCL nanoparticles,385 prepared by covalently cross-linking an amphiphilic triblock copolymer, PEO-b-

Scheme 53. Pictorial Representation of the Shell Cross-Linked Micelles Containing Polylactide Core Showing Enzymatic Degradationa

a

Reprinted from ref 382. Copyright 2012 American Chemical Society. The structure is redrawn for clarity. AF


Chemical Reviews

Review


Scheme 54. Synthetic Scheme for Acid-Degradable SCL-Particles Bound to Cisplatin Drug

Scheme 55. Synthetic Scheme for Preparation of (a) Pamidronate and (b) Phospholipid Conjugated Hydrogels

cross-linked enzyme degradable hydrogel.398 An antigensensitive hydrogel403,404 has been prepared by chemical grafting of antigen (Rabbit IgG) and its corresponding antibody to NHSA and subsequent copolymerization of the resulting monomers with acrylamide.405 Noncovalent cross-linking was introduced within the copolymer by specific complementary interaction between the antigen and the antibody, which could be cleaved by competitive binding with free antigens. DNAimmobilized divinyl cross-linkers have been prepared by reacting PFPMA with 5′-amino-modified nucleotide. Copolymerization of acrylamide with such DNA-cross-linker in the presence of an additional divinyl monomer containing disulfide bonds resulted in a dual-responsive hydrogel that could respond to specific DNA sequences or be cleaved under reducing conditions.406,407 Reactive polyNIPAM obtained by copolymerizing NIPAM with NHSA happens to be the most popular constituent for creating thermoresponsive hydrogels.408,409 Such systems render double-network structures where the physical crosslinking occurs due to hydrophobic collapse of polyNIPAM above LCST, while the method for chemical cross-linking varies from system to system. In some cases, the polymer chains are cross-linked by conjugating the reactive NHS-ester sites with polymeric diamines such as diamino PEGs.21 A trithiol-based

synthetic techniques have been employed to generate biologically active hydrogels. Along this line, activated ester chemistry has been utilized in constructing pharmaceutically important hydrogels. The most commonly used method for preparing polymeric hydrogels involves copolymerization of activated ester monomers with water-soluble, biocompatible monomers, where the role of the activated ester is specific. Either it can be used to introduce a cross-linker subsequent to the polymerization step or it can act as an anchor for covalent attachment of biologically active ingredients within the preformed gel network. There are also examples where reactive monomers have been pretransformed into biologically significant new monomers that upon polymerization create polymeric hydrogels.397−400 For example, therapeutic hydrogels comprised of pamidronate drugs have been prepared by copolymerizing pamidronate acrylate developed from NHSA with NIPAM using a bis(acrylamide) cross-linker (Scheme 55a).401 Molecules containing bisphosphonate groups can effectively chelate calcium ions and thus can be used as active drugs for curing several bone diseases. Similarly, phospholipid−hydrogel conjugates have been prepared from acrylate-based lipid anchors obtained from NHSA (Scheme 55b).402 Free radical copolymerization of methacryloylated polyamino acids with HEMA resulted in a covalently AG


Chemical Reviews

Review


Scheme 56. Synthesis Scheme for siRNA-Loaded Nanoparticle Hydrogel from polyPFPA Block Copolymer

Scheme 57. Synthetic Scheme for Peptide Conjugation and Hydrogel Formation from a DMA Copolymer Featuring Coumarin Side Chains

polyNIPAM offers easy access to hydrogels by thiol−ene click coupling (Scheme 58).423−425 While incorporating two

cross-linker has been reported to be very robust due to its high reactivity toward NHS-esters.411 Examples where the crosslinker itself is a targeted protein for delivery such as polylysine,412 collagens,413 elastins,414 or microtubule415 are also known. Amphiphilic block copolymer poly(PFPMA-bMEO 3 MA) was chemically cross-linked with spermine produced cationic hydrogel particles that revealed efficient electrostatic complexation with siRNA for gene delivery (Scheme 56).371,372,416 In some cases, the polymerization and cross-linking takes place simultaneously when a divinyl monomer is employed, while the role of the activated ester is to immobilize biologically active molecules within the gel matrix.417−420 Polymeric hydrogels comprised of hydroxamic acid groups were prepared from a cross-linked precursor polyNHSA that showed high affinity for iron binding under acidic pH. These hydrogels can be potentially exploited as a polymeric drug for overloading of gastrointestinal iron.421 Other biologically relevant hydrogels were prepared by copolymerizing NHSA and DMA with a coumarin-based monomer (Scheme 57).422 The linear polymer obtained in the first step was photo-cross-linked through coumarin moieties, while the reactive NHS-ester sites were available for modification with a cell adhesive peptidyl ligand Arg-Gly-AspSer (RGDS). Another strategy includes preparation of hydrogels by twostep PPM in which the reactive site initially allows incorporation of two amine-based complementary chemical handles that can react with each other in the following step to form the chemical network. Thiol−ene coupling is one such reaction that operates under very mild physiological conditions. Incorporation of thiol and vinyl groups at the reactive sites in

Scheme 58. PolyNIPAM Hydrogel Preparation by Networking through Thiol−Ene Click Reacton

complementary supramolecular handles such as cholic acid and β-cyclodextrin at the reactive sites can lead to noncovalently cross-linked, self-healing supramolecular hydrogels occurs through inclusion complex formation.426 Naturally occurring hyaluronic acid (HA)-based glycopolymers are often used as raw materials for hydrogelation. They are an interesting biomimetic scaffold for delivery of stem cells and or other morphogenic proteins for tissue engineering.427 The common approach involves stepwise treatment of HA with dihydrazides and subsequent treatment with NHSA to obtain acrylated hyaluronic acid. It is then connected with a dithiol- or tetrathiol-based cross-linker to generate a network structure for aqueous imbibition under physiological conditions (Scheme 59).428−435 Functionalized injectable thermoresponsive hydrogels414,436 have been prepared by copolymerizing NIPAM, acrylic acid, and NHSA with macromer polylactide−hydroxyethyl methacrylate437 or hydroxyethyl methacrylate−polyAH


Chemical Reviews

Review

Scheme 59. Synthesis of Hydrogel from Hyaluronic Acid Acrylates by Thiol−Ene Click Reaction


Scheme 60. Synthesis of Boronic-Acid-Based Gluocose-Responsive Hydrogels from PFPA Copolymer

(trimethylene carbonate)438 by free radical polymerization. Gelation takes place under physiological temperature due to a change in hydrophilic/hydrophobic balance inside the body as a result of hydrophobic collapse of the NIPAM segment. For those systems, the activated ester moiety offers chemical tool for immobilization of collagen peptides of varying concentration to improve the cytocompatibility of those bioactive gels. Such degradable hydrogels have been successfully used as a biomimetic scaffolds for coencapsulation and release of growth factors (bFGF) and mesenchymal stem cells (MSCs) for regeneration of heart cells.438,439 Besides temperature, other environmental-sensitive hydrogels were prepared by introducing new reactive functional groups within the polymer chain by PPM. Such examples include glucose-responsive boronic-acidbased hydrogels, obtained by physical cross-linking of two DMA copolymers featuring boronic acid and dopamine, introduced via PPM. Those gels revealed self-healable properties at neutral and acidic pH (Scheme 60).440 Dual pH- and temperature-sensitive microgel particles were fabricated from poly(PNPA-co-NIPAM) by precipitation copolymerization.441,442 The activated ester site allowed covalent conjugation of pyridine and folic-acid-functionalized amines for anticancer drug delivery.443 In the recent past, reactive surface- immobilized hydrogels have attracted significant interest as biomimetic matrices to study the influence of different physiological signals (both chemical and mechanical) on the cell behavior.444,445 These artificial matrices frequently rely on hydrogel films; their tunable swelling properties depend upon the extent of crosslinking. Cross-linked density happens to be an essential parameter that controls the stiffness of these materials, providing opportunities to study cellular response as a function of tailored mechanical signals, while the activated ester sites allow covalent bonding of biologically active molecules that

release chemical signals for cells. Also, surface-attached hydrogels featuring activated ester motifs have been effectively used as tools for microarray446−448 or electrical microswitches.449 Usually, those systems were prepared by copolymerizing an activated ester monomer with a watersoluble monomer in the presence of a cross-linker on a solid surface. PEG-based 3D hydrogels containing activated ester groups coated on glass surfaces showed high efficiency as small molecule microarrays over conventional 2D hydrogels.450 Biotin-functionalized amines were immobilized at the activated ester sites on the hydrogel surface and probed with a fluorescent dye, avidin. Those surface-immobilized hydrogel materials revealed stronger fluorescence signal and prominent spot morphology, illustrating their potential for protein microarray experiments. However, following this technique, ligand proteins bound to the hydrogel are not quantitatively available for binding with the analyte protein. To address this issue, loosely bound protein−polymer hybrid hydrogels have been fabricated. The technique required spotting a mixture of protein IgG and a copolymer of poly(NAM-co-NHSA) on a Au surface functionalized with NHS-ester motifs. Covalent binding of the amine functionality of the protein with NHS-ester of the polymer and/or substrate resulted in highly porous cross-linked networks.451 Photopolymerization of NHSA, acrylamide, and a cross-linker on top of 2D polystyrene particle array followed by selective removal of PS beads resulted in 2D hole array on hydrogels.452 Such reactive 2D array hydrogels were used as photonic crystal sensors for sensing avidin when functionalized with biotin ligands. Enzyme-immobilized composite hydrogel membranes can be used in biocatalytic reactions.453,454 To this end, enzymetically triggered injectable hydrogels are particularly attractive. Horseradish peroxidase (HRP)-mediated radical polymerization has been exploited in formulating tough nanocomposite hydrogels AI


Chemical Reviews

Review


Scheme 61. Schematic Representation of Synthesized Lipopolymers Starting from Lipophilic ATRP Initiators and the PolymerSupported Bilayers Made There From

monomers, such as n-octadecylacrylamide as a lipophilic unit. The lipopolymers insert via their lipophilic group into giant liposomes and allow temperature-induced shape changes of these self-assembled aggregates.461 Besides stabilizing liposomes, lipopolymers can induce a pH-triggered transmembrane release, as described by Chiu and co-workers. They partially converted polyNHSA with mPEG-NH2 followed by hydrolysis of remaining NHS-esters to produce anionic polymers that assembled with cationic lipids.120,462,463 Stabilizing lipid membranes on surfaces by polymersupported lipid bilayers has been investigated over several decades. Such supported lipid bilayers are suited for biophysical investigations.464 Essentially, activated ester chemistry has been utilized for the synthesis of thin polymerized hydrogel layers or hydrophilic polymeric monolayers equipped with lipid-anchor groups. Again, NHSA has been employed for the synthesis of monomeric lipids457 to be included in hydrogels. However, also PFPA when copolymerized with 4-benzoylphenyl methacrylate was used to prepare reactive thin film networks. Subsequently, those films were efficiently modified to result in proteintethered bilayer lipid membranes via functionalization with nickel chelating nitrilotriacetic acid (NTA) groups to which cytochrome c oxidase (CcO) was bound via a his-tag.456 Synthesis of statistical copolymers featuring a hydrophilic polymer backbone while being equipped with a lipophilic group and a surface anchor (e.g., disulfide for Au surfaces) has been a common approach that utilized PPM of polyNHSA.459,465−467 In combination with controlled radical polymerization techniques, this concept was expanded to the synthesis of end-functionalized lipopolymers by utilizing NHSA for synthesis of a short end block that allowed for immobilization of the lipolymers on surfaces (Scheme 61).458 Those lipopolymer supports were used for fixing lipid vesicles to form polymersupported bilayers. 6.3.2. Glycopolymers. Glyocolated structures play an important role in biology in specific recognition events. Therefore, as a possibility to mimic natural oligosaccharides, glycoproteins, or glycolipids, carbohydrate-containing polymers, so-called glycopolymers, have attracted increased attention. The actual binding affinities are a common example of polyvalency, which require multiple copies of the same or different carbohydrates. Even though the direct polymerization of glycomonomers is convenient, there have been numerous

from a mixture of silica nanoparticles, acryloylated human serum albumin, and DMA that displayed high enzyme activity and catalytic performance in organic medium.455 Stable, longlived bilayered lipid membranes (BLMs) can be engineered by covalent attachment of lipid bilayers to reactive hydrogel supports that offer the possibility for investigating functional membrane proteins.456 Those artificial cytoskeletons were also prepared by copolymerizing an acrylate-modified lipid with a PEG-based dimethacrylate that led to concomitant formation of gel and conjugation of lipid to the gel matrix.457 The acrylated lipid membrane was obtained by treating diphytanoylphosphatidylethanolamine (DPhPE) with NHSA. This complements work on polymer-supported lipid membranes that utilized lipo-polymers, often prepared from reactive polyNHSA.458−460 6.3. Bioconjugated Polymers

Activated ester polymers have been employed as synthetic handles in the preparation of bioconjugated polymers. These include areas of (i) lipopolymers, (ii) DNA-polymer conjugates, (iii) glycopolymers, and (iv) protein−polymer conjugates. It is noteworthy to state that early studies almost exclusively utilized NHS-ester containing polymers, while in recent years the exploitation of PFP-ester derivatives has become increasingly popular. However, also other activated esters have found accepted use in the synthesis of numerous bioconjugates. The following paragraphs are not intended to provide the reader with a full and exhaustive overview of the applications but rather focus on synthetic possibilities of activated ester polymers and their valuable contribution to the synthesis of bioconjugated polymers. In many aspects, the discussed solutions are complementary to other efficient ligation chemistries. 6.3.1. Lipopolymers. Lipopolymers have been explored in stabilizing liposomes that can be used for self-assembling surrogates. Early approaches followed copolymerization of water-soluble monomers with polymerizable lipids. Often such monomeric lipids were synthesized by reacting amino-lipids, such as 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) or fluorescence-labeled derivatives 1-myristoyl-2-[6[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]caproyl]-sn-glycero3-phosphoethanolamine (PE-NBD), with NHSA.402 Alternatively, for the synthesis of stimuli-responsive lipopolymers, NHSA was copolymerized with NIPAM and hydrophobic AJ



Chemical Reviews

Review

followed by a CuAAC with, for example, 1-azido-β-Dgalactose.488 The group of Kiessling could also demonstrate that numerous glycopolymers can also be synthesized by ROMP of norbornene monomers featuring an activated ester.489−491 Again, this approach can also be utilized in a sequential PPM, by reacting the activated ester first with an amino−azide linker, followed by a CuAAC with propargyl β-D-galactoside.492 6.3.3. DNA-Polymer Conjugates. Nucleic acid detection has become very important in recent years, and hence, it comes as no surprise that numerous routes have been developed to conjugate oligonucleotides (ODNs) to polymers. In order to enable a conjugation of ODNs via activated ester chemistries, a terminal amino group at the ODNs is required. In most studies, ODNs are synthesized by β-cyanoethyl phosphoramidite chemistry using modern synthesizers and an accessible amino group is introduced via a 5′-aminohexyl modification using the phosphoramidite derivative of trifluoracetylaminohexanol, which after deprotection yielded a primary amino group. This allowed the conjugation to various NHSA-derived copolymers493−495and NHSMA copolymers.496 When densely grafting oligo-DNA on a polymer backbone, cylindrical brushes can be obtained.497 The group of Ke Zhang could show that triblock copolymer brushes with functionalized ODN sequences at the ends allowed for polycondensation via a head-to-tail connection by DNA hybridization forming supramolecular nanostructures (Scheme 63).203 Another important area of nucleic acid conjugation is found for RNA delivery. Here, often amphiphilic block copolymers featuring a hydrophobic activated ester block are utilized to prepare core−shell structures with a cationic charged core that can complex siRNA and a hydrophilic shell.182,498,499 However, microcapsules have also been obtained from DNA-grafted polyNIPAM micelles, where NHSA copolymers were used as reactive intermediates.500 Further, RNA-functionalized γ-Fe2O3 nanoparticles have been prepared by coating the inorganic nanoparticles with multifunctional polymers, which were synthesized via sequential aminolysis of activated ester polymers.501 Similarly, DNAcoated MnO nanoparticles have been prepared and utilized as specific cellular cargos.502,503 Those selected examples nicely document the versatility of preparing highly specific and multifunctional polymers by a simple series of aminolysis steps using an activated ester precursor polymer. In efforts to detect specific DNAs, various sensing approaches have been presented. Among those, DNAresponsive hydrogels that show a distinct swelling in response to specific DNAs have been reported.406 Here, NHSMA has been utilized as a reactive monomer for the synthesis of ssDNA cross-linked hydrogels. This approach has been taken further for the synthesis of polymer−DNA hydrogels that respond to a specific ODN and a nonspecific trigger, enabling dual-input and mutiscale responses.504 The most common route to DNA detection is the preparation of microarray chips. For this amphiphilic block copolymers featuring reactive NHSA and surface anchor units are used for polymer supports.193,448 On these supports ODN polymer conjugates are prepared. Planar supports as well cellulose-derived fibers have been used in such a functionalization scheme.505 Alternatively, electrochemical DNA biosensors have been prepared using activated ester chemistry. For example, poly(MMA-co-PEGMA-co-NHSMA) has been synthesized to noncovalently bind to CNTs.506 Attachment of

examples of employing PPM for the synthesis of glycopolymers.468 A recent review on this account summarizes nicely various approaches in this respect but leaves out the utilization of activated ester chemistries. Most commonly, acrylic or metharylic derivatives have been used as monomers, but also norbornene derivatives have been reported. NHS-ester-based chemistry is still dominating the area of glycopolymer synthesis. For example, NHSA and NHSMA monomers have been utilized in the synthesis of complex (meth)acrylamide monomers and their direct polymerization for the synthesis of Fucoidan-mimetic glyopolymers469 or mannan trisaccharide hapten gyclopolymers.470 Early studies utilized polyNHSA for the synthesis of monosaccharide-derived glycopolymers by attachment of ω-aminoalkylglycosides471,472 or amino-diethylene glycolglycosides.473 Later, attachment of monosaccharides was conducted with reaction of polyNHSA, for example, with galactosamine,69 glucosamine,474 or sialic acid.475 However, pepitdoglycans have been attached via this route to polymers for the synthesis of polyacrylamide copolymers.476 As glycopolymers that are suited for specific binding or recognition events are mostly copolymers, the attachment of larger units, such as specific disaccharides477,478 or trisaccharides479 for the synthesis of copolymers has been described. The group of Brocchini even reported the attachment of larger complexes, such as Amphotericin B.480 The group of Bovin very early on focused on the use of polyPNPA as an activated ester platform for the attachment of ω-aminoalkylglycosides.481,482 However, also disaccharides483 and trisaccharides484 have been attached following this approach. In recent years, the use of PFP-esters became very popular as well. Similar to polyNHSA, glycopolymers can be prepared by simple aminolysis of polyPFPA with, for example, glucosamine, resulting in poly(glucose acrylamide).485 It had been shown that PFPA-containing polymers can also be used for an efficient surface modification of porous polymers486 and polymer fibers,487 allowing modification with galactose and mannose derivatives. Via an arm-first method, star glycopolymers have been prepared by aminolysis of polyPFPA arms with galactose amine and glucose amine (Scheme 62).228 If azido-functionalized saccharides are only available, a sequential PPM can be conducted by aminolysis of the activated ester polymer with propargyl amine or 2-[2-(prop-2-ynyloxy)ethoxy]ethanamine, Scheme 62. Synthesis of PFPA-Derived Star Polymer Using an Arm-First Approach

AK


Chemical Reviews

Review


Scheme 63. Synthesis of the Hairpin DNA−Polymer Brush Conjugates and Their Polycondensation into Wormlike Nanostructures via DNA Hybridizationa

a


enzyme surfaces enabled a labeling of enzymes with different polymers by taking advantage of triple bioorthogonal ligation chemistries, while activated ester chemistry520 was heavily used for the monomer synthesis. To graft polymers precisely onto enzymes requires often polymers that feature an activated ester at one chain end.242 Alternatively, initiators or chain transfer agents for ATRP or RAFT polymerization can be conjugated onto the enzyme surface that enable grafting-from polymerization.243 For further details, the reader is referred to recent reviews of such protein−polymer conjugates.521,522 Utilizing a PPM approach, polyPFPMA has been functionalized with numerous moieties that even allow the formation of antibody− polymer conjugates.523 Conjugation of peptides onto polymer chains follows very much the same route as for proteins. Activated esters can be easily prepared by activation from poly(acrylic acid) units within polymers with DCC coupling of NHS524 or by direct polymerization of the respective activated ester monomers (see section 2) and subsequent PPM with peptide fragments. Because of the possibility for altering LCST of thermoresponsive polymers upon recognition events or the elegant thermoprecipitation of peptide−polymer conjugates, many polyNIPAM copolymers have been investigated. Commonly starting from a copolymer of NIPAM and NHSA, peptide attachment was straightforward, following established PPM protocols. The thermoresponsive behavior has then been utilized for purification or recognition events.149,525−528 However, also copolymers of NHSMA and HPMA have been utilized for the synthesis of biocompatible peptide−polymer conjugates.73 More recent studies take advantage of the activated ester polymers based on PFPMA529 in a sequential postmodification by first reaction with allylamine and then attachment of cysteine thiol side group (Scheme 64). The synthetic protocols to attach peptide segments onto polymer chains via activated ester chemistries enabled an efficient synthesis of polyvalent conjugates.288 Such polyvalent peptide−polymer conjugates found application in areas such as enhancing inhibitors,530,531 HIV-1 entry inhibitors,532 promo-

ssDNA allowed the electrochemical sensing of complementary DNA strands due to the charge-trapping nature of base pairs in hybridized DNA. Another electrochemical sensing utilized hydrophobic poly(nBA-co-NHSA) microspheres, which were functionalized with ssDNA, during differential pulse voltametry using anthraquninone-2-sulfonic acid monohydrate sodium salt (AQMS) as the electroactive hybridization label.507 6.3.4. Peptide/Protein Polymer Conjugates. Proteins or peptides are ideal candidates that can be linked via activated esters to form protein− or peptide−polymer conjugates. The inherent amino group at the N-terminus of a polypeptide chain allows conjugation to activated ester polymers. While this essentially allows synthesis of a practically infinite number of conjugates, it is the intention in the following section to highlight a number of selected examples to provide the reader with a categorization of areas that heavily utilize activated ester polymers. These areas include (a) grafting-from/to enzymes, (b) peptide conjugates, (c) incorporation of peptide recognition sites, (d) peptide-coated particles, and (e) peptidecoated surfaces. The group of Hoffman intensively studied protein−polymer conjugates, often conjugated to PNIPAM, to take advantage of the varying LCST properties of the protein−polymer conjugates.508−511 For this they mostly used copolymers derived from NHSA and NIPAM. Their work has inspired numerous other scientists to study similar PNIPAM conjugates that all were prepared using NHSA-derived copolymers.512−514 Alternatively, enzymes have also been immobilized within a polymer gel,515−517 which find application either as catalysts or as responsive sensors. To be reasonably applicable, such a covalent enzyme immobilization has been performed on highly porous monoliths that were prepared from a polymerized high internal phase emulsion.518 In ways to stabilize enzymes, they have been covered by a polymer network around them.519 For this NHSA has been reacted with lysine groups exposed at the enzyme surface, and subsequent polymerization led to a thin permeable shell around the enzyme. Taking advantage of different functionalities on AL


Chemical Reviews

Review

copolymerization of NHSA with NIPAM, a thermoreversible cell attachment could be observed.540 The cell adhesive RGD peptide could also be used to deliver a drug cargo that can be released upon thermal stimulation of polyNIPAM copolymer to induce cell death.541 Polymers displaying the desintegrin domain of fertilin β, Glu-Cys-Asp (ECD), mediate inhibition of mammalian fertilization.542,543 Functionalization of particles has been conducted in order to immobilize enzymes. Commonly, emulsion polymerization was used to prepare latex (nano)particles that contain NHSesters.544 After successful immobilization of various enzymes, the particles have been used as catalysts.545,546 Utilizing conducting polymer nanoparticles that have been functionalized with collagen mimetic peptides enabled the sensitive fluorescence imaging of collagen strands.547 Equipping polymer opals that were assembled from reaction colloids featuring activated esters on their surface enabled immobilization of Histagged silicatein.548 Such reactive photonic crystals provide a versatile platform as sensors. A route to detect proteases has been reported by the group of Swager. They prepared luminescence-quenched shell cross-linked nanoparticles utilizing peptide strands as cross-linkers.549 Upon exposure to protease, these cross-links are cleaved and luminescence is recovered. Micellar nanoparticles have been prepared from polymer−peptide block copolymer amphiphiles, which had been synthesized by attachment of peptide sequences on activated ester polymer chains.550 Through a phosphorylation− dephosphorylation cycle, the morphology changes in response to proteolysis. Lastly, activated ester polymers have been investigated as linkers to conjugate enzymes onto inorganic nanoparticles, which have been used for bioseparation or catalysis.551−553 Similar to the enzyme immobilization on nanoparticle surfaces, proteins and peptides have been linked to planar surfaces. Most commonly the terpolymer derived from NHSA, DMA, and 3-(trimethoxysilyl)propyl methacrylate has been utilized to coat glass slides with a reactive polymer layer that enables covalent attachment of proteins and peptides within microarrays.554−557 As an alternative route, the plasma surface modification via plasma polymerization of PFPMA generates a reactive surface that has been used to covalently immobilize protein layers, as shown for bovine serum albumin (BSA).558 Last but not least, also other functional groups have been conjugated to polymers via activated ester chemistries. As long


Scheme 64. Synthesis of Peptide−Polymer Conjugates by Sequential Postpolymerization Modificationa

a

Reprinted with permission from ref 529. Copyright 2011 American Chemical Society.

tors for cellular internalization,533 directing fibrillar assembly,534 or activation of cell signaling.535 Polymer−glycopeptides conjugates have been suggested as potential antitumor vaccines.209 Alternatively, polymer−drug conjugates have been described taking advantage of an enzymatically cleavable peptide linker.68 In combination with the formation of disulfide cyclic bridges via cysteine linkages within peptide sequences, complex single polymer chain topologies have been reported.536 Polymer−peptide conjugates have also been found to feature interesting self-assembly properties. pHresponsive coil to α-helix transitions of topological differences in grafted ABA peptide−PEO conjugates showed a clear influence on the transitions.219 Also, collagen-like peptidecontaining block copolymer conjugates have been prepared utilizing activated ester end group modifications of linear polymer chains.269 The obtained structures showed an interesting temperature-dependent self-assembly of nanostructures (Scheme 65).270,537 Probably the most commonly attached peptide sequence is the arginine-glycine-aspartic acid (RGD) peptide, which is a common element in cellular recognition and involved in cellular attachment via integrins. Polymer thin films expressing the RGD sequence after attachment via activated esters support strongly cell attachment.538,539 When combined with the thermoresponsive properties of PNIPAM films, prepared by

Scheme 65. Conjugation Scheme Showing the Synthesis of the Triblock Hybrid via the Reaction of the Activated EsterTerminated PDEGMEMA with Telechelic Amine-Functionalized Collagen Peptide and Their Proposed Self-Assemblya

a

Reprinted from ref 270. Copyright 2012 Royal Society of Chemistry. AM


Chemical Reviews

Review

Scheme 66. Synthesis of Lanthanide Ion Binding Terpyridine Polymers


Scheme 67. Synthesis of Novel DOTA(Gd3+)−Polymer Conjugates

directly copolymerized to achieve similar targets.566,565 The ability of the terpyridine motifs to complex with lanthanide ions such as Eu3+ and Tb3+ produced metal-functionalized polymers that exhibit strong emission of pink and green light for Eu3+ and Tb3+ ions, respectively.567 The color of the emissive light could be tailored by incorporating a mixture of these two ions within the polymer backbone. Heating the polymer above 50 °C also conferred thermochromic properties to those materials. Multichromophoric metallopolymers obtained by anchoring ruthenium(II) polypyridine complexes to polyNHS4VB side chains grafted from reduced graphene oxide (RGO) sheets revealed enhanced photovoltaic performance.568 Gadolinium (Gd), an important element in the lanthanide series, has been used as a contrasting agent in magnetic resonance imaging (MRI) application. The contrasting efficiency of Gd3+ ions can be improved significantly by immobilizing them with high molecular weight compounds that enhance the relaxivity of the macrocontrasting agents. For this purpose, various Gd3+ chelating ligands such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DTPA (diethylenetriaminepentaacetic acid) have been covalently attached to activated ester-containing water-soluble copolymers through their amine functionality (Scheme 67).569 Lowe, Davis, and Boyer570 developed gadoliniumfunctionalized gold nanoparticles as bimodal contrasting agent for computed X-ray tomography (CT) and magnetic resonance imaging (MRI). The hybrid nanoparticles were prepared by covalently attaching the Gd3+ ligands, DO3A-tBu-Et-NH2, to the PFP-ester sites of reactive oligoethylene glycol-based statistical copolymers, synthesized by RAFT. Grafting of the Gd3+-chelated polymer onto gold nanoparticles was achieved through its free thiol residue obtained by reducing the dithiocarbonate unit at the ω-chain end of the polymer. A single nanoscale theragnostic device was developed from polymer−Gd metal organic framework (MOF) nanoparticles

as the functional group of choice is equipped with an accessible amine (best primary amine) group, attachment is very straightforward. Examples include tamoxifen-conjugated polymers,559,560 folate−polymer conjugates,441,443,561 biotinylated polymers,196,562,563 or simply fluorogenic polymers.288 6.4. Metal Polymer Complexes

Metal-based polymers564,565,3 have for long been a topic of interest especially in the area of bioanalytical chemistry, sensors, wastewater treatment, catalysis, and photovoltaics. Integrating metal chelating ligands into macromolecules has bestowed a variety of advanced polymeric materials with unique properties, depending upon the sequestered metal ions. However, the synthetic challenges in carrying out polymerization reactions with monomers featuring metal complex comes from their bad solubility, undesired side reactions, poor yield, and so forth. As a result, the field of metallopolymers was comparatively much less developed until the advent of postpolymerization functionalization. It turned out to be one of the most versatile approaches in the context of metal chelating polymer synthesis, offering the easiest way to introduce a library of different metal complexing ligands into the side chains of polymer backbones. With this advancement, lanthanide-containing polymers as luminescent probes, biosensors, and contrasting agents for magnetic resonance imaging (MRI) have become available. For a long time, terpyridine−lanthanide complexes have been known to impart strong luminescence properties along with other features such magnetism and thermochromism. Nevertheless, to utilize these complexes as an active component in materials applications, they are required to be embedded within a polymer matrix to make them soluble and processable for device fabrication. Tew et.al developed polymers with terpyridine-functionalized side groups by reacting NHS-ester containing homo- or copolymers with amine-based terpyridine ligands (Scheme 66).169,78 Also, monomers featuring terpyridine residues were AN



Chemical Reviews

Review

polymer side chain. Hydrogels prepared by chelating Fe3+ ions with polymers containing pendent hydroxamic acid groups could act as potential chelators for excess iron in the gastrointestinal tract.421 This approach was extended to polymers containing other metal binding ligands introduced by PPM. Terpyridine functional polyNIPAMs, obtained from precursor poly(NIPAM-co-NHSMA), was cross-linked with Mn2+ or Co2+ to produce supramolecular metal gels.170,582,583 Gelation properties of those gels were dependent on the strength of metal−ligand interactions, which were found to be greater than hydrogen-bonding interactions-based supramolecular cross-linking. Cu 2+ or Fe 3+ served as potentially biodegradable cross-linkers for polymeric nanoparticles comprised of poly(N-methyl methacryloyl hydroxamic acid) with PEO-grafts prepared from a polyNHSMA precursor.584 Internalization of those metal ions within the polymer core through the hydroxamic acid chelates could be expressed inside the cells by a transchelation mechanism happening due to intracellular bioreduction of the metal ions. This resulted in degradation of the nanoparticles under physiological conditions, prerequisite for drug delivery. Fe3+ binding catechol ligands introduced at the chain end of thermoresponsive polyNIPAM resulted in Fe3+-ion-induced solubility switch of polyNIPAM. This is essentially an alternative to a temperature stimulus that has tremendous significance in treatment of neurodegenerative disorders.585 Besides various aforementioned biomedical applications, water-soluble metal binding polymers that can selectively chelate toxic and heavy transition metal ions are effective in ultrafiltration and wastewater treatments. Reactive PolyNIPAM displaying NHS-ester groups were utilized for covalent attachment of 3-hydroxy-2-pyridinone or hydroxamic-acidfunctionalized ligands that complexed with a trace amount of Fe3+ ions in aqueous solution. Metal ions were removed by thermal precipitation of the polymer that could be regenerated by treatment with ethylenediaminetetraacetate (EDTA).586 For removal of Fe3+ from the organic phase, hydroxamicacid-based fluorinated polymers were employed that could be removed from organic layers by liquid/liquid phase separation following fluorous biphasic conditions.586,587 There has been a major impetus toward detection and removal of toxic Hg2+ ions, whose presence in the environment can cause severe cellular dysfunction. Therefore, Hg2+-responsive solid-state probes were developed by covalent attachment of aminocontaining spirolactam rhodamine derivatives on polyPFPMA, grafted on cellulose filter papers by surface-initiated ATRP (SIATRP).588 The response of the functionalized filter papers to Hg2+ was analyzed by the change in color and fluorescence of the filter paper that operated as a disposable solid-state sensor for detection of Hg2+ ions. Aluminum-ion-sensitive optical imaging fibers were developed to investigate in situ localized corrosion of galvanic aluminum−copper couple.589 The optical sensor was created by immobilizing pH-sensitive fluorescent dye, SNAFL-SE, and Al3+ chelating morin ligand on the imaging fiber modified with (3-aminopropyl)triethoxysilane and poly(acrylamide-co-NHSA). For a long time polymeric supports have been exploited in chemical synthesis.590 One such popular example includes solid-phase peptide synthesis using Merrifield resins. However, most heterogeneous systems suffer from prolong filtration and a tiresome workup for the recovery of the catalyst. An attractive alternative would be one where the reaction can proceed under solution-phase pseudo-homogeneous conditions. Also, the

for cancer therapy and diagnosis through both magnetic resonance as well as fluorescence microscopy.571 Unlike previous examples, where the activated ester group was used to introduce ligands for metal ions, Boyes et al. grafted fluorescent tagged copolymer poly(NIPAM-co-NHSAco-fluorescein-O-methacrylate) by means of its thiolate end group to the vacant orbitals on the Gd3+ ions at the surface of the Gd−MOF nanoparticles. Those NHS-ester groups were employed for attachment of therapeutic agent and cell targeting ligand. Besides bioimaging by MRI, positron emission tomography (PET) imaging with radioactive isotopes is another powerful tool for diagnosis. Hawker and co-workers572 prepared amphiphilic graft copolymer PMMA-co-PNHSMA-gPEG that self-assembled in water into polymeric nanoparticles. Covalent anchoring of DOTA at the NHS-ester sites followed by chelation of radioactive 64Cu nuclei allowed analysis of the biodistribution of these nanoparticles in medical imaging. Metal chelating polymers have been extensively exploited in bioassays.573 Modification of poly(acrylamide-co-NHSA) with nitrilotriacetic acid (NTA) ligand allowed immobilization of Ni2+ ions. The resulting polymers were employed as protein assays for detection of hexahistidine-tagged proteins that can bind selectively with Ni2+ ions through their imidazole sites. Integrating an additional thiol-based ligand, 3-(methylthio)propylamine (MTP), further supported immobilization of such metal-bound polymer−protein conjugates on gold nanoparticles.574 Lanthanide-bound polymeric ligands have been exploited as elemental tags to develop highly sensitive bioassays, where the signal for the lanthanide isotopes were analyzed by inductively coupled plasma mass spectrometry (ICP-MS).575−577 Gd3+ and Eu3+ chelating ligand-functionalized polymers, tagged with lectines578 and antibodies,579 respectively, through the free thiol group at the chain end were used for differentiation of various biomarkers such as glycoproteins and individual cells targeting proteins. The presence of multiple copies of the bound lanthanide isotopes attached as side groups of a single polymer chain offers greater sensitivity of polymer-supported elemental tags compared to fluorescence-based bioassays, making this technique more advantageous for immunoassays. Also, Ni3+ and Gd3+ chelating polymeric ligands obtained by treating poly(NHSA-co-MMA) with Nα,Nα-bis(carboxymethyl)-L-lysine have been exploited as disposable polymeric pMALDI chips for selective identification of phosphoproteins by MALDI-TOF/MS.580 However, massspectroscopy (MS)-based analysis of phosphoproteins suffers from certain disadvantages such as poor ionization of phosphopeptides due to the presence of nonphosphorylated counterparts in positive-ion mode. Also, the collision-induced dissociation process leads to the instability of the phosphate groups on phosphopeptides that suppress their identification by MS techniques. Immobilized metal affinity chromatography (IMAC) columns have been projected as a better alternative for phosphoproteome analysis. NHS ester-functionalized monolithic IMAC matrix was treated with nitrilotriacetic acid (NTA) to immobilize Ti4+ or Zr4+ that revealed higher affinity for phosphoproteins.581 Incorporating strong and directional metal−ligand interactions within macromolecular domains has been extensively investigated in making supramolecular cross-linked polymeric networks. These are useful materials in self-healing, shape memory, or controlled release soft adhesive substrates to name a few. The binding strength of the cross-linker is dictated by the selection of metal ions and the ligand immobilized on the AO


Chemical Reviews

Review


Scheme 68. Modification of Poly(NODAM-co-NHSA) into Different Metal Binding Polymers for Catalyzing Organic Reactions

between iodobenzene and phenylboronic acid in biphasing conditions.597 Product purification and catalyst regeneration was achieved by the thermoresponsive phase transfer of the catalytically active nanoparticle from organic to aqueous phase upon temperature drop.

catalyst can be easily recovered and reused as in heterogeneous catalysis, essential for environmental concern and economic advantages. Immobilization of catalysts and reagents on polymer support offered multiple advantages such as easy separation of the molecules attached to the polymer, enabling recovery of costly ligands and catalyst, and simplifying the purification steps. In addition, the use of polymer supports increased the surface area of the microenvironment for the catalyst or the reagents, which led to an improvement of the reaction conditions. Activated ester-containing polymers have been employed for developing polymeric supports for homogeneous catalysis. The activated ester residues act as anchors to attach those ligands that can selectively bind to certain transition metal ions, whose choice essentially depends on the nature of the reaction that will be catalyzed. Following this technique, Bergbreiter and coworkers developed a polymer-bound SCS−Pd(II) Heck catalyst for C−C coupling reaction by treating reactive poly(NODAMco-NHSA) with amine-based SCS-ligands followed by complexation with Pd(II) species (Scheme 68a).591 Such versatile and generalized design allows immobilization of other ligands to carry out different reactions from the same precursor polymer. This was exemplified by attachment of phosphine ligands to the same polymer for sequestering of Rh(I) or Pd(0) to catalyze alkene hydrogenation or allylic substitution reactions, respectively (Scheme 68b).592 Even phenanthroline-appended polymers could immobilize Cu species for a Huisgen 1,3-dipolar cycloaddition reaction (Scheme 68c).593 Owing to their multivalent supramolecular substrate binding capability, cyclodextrin-functionalized polymers prepared from polyNHSA revealed effective mass transfer ability. Those properties have been judicially utilized for Rh-catalyzed hydroformylation of hydrophobic olefins in aqueous biphasing catalysis.594 To ensure maximum recovery and reuse of the catalyst, a biphasing condition is usually created either by perturbing the solution or by addition of another immiscible solvent that separates the polymer from the catalyst or the product.595,592 For air- or moisture-susceptible polymeric catalyst, additional introduction of a closed and continuous microfluidic loop system in conjunction with thermomorphic multicomponent system conditions was found to be more advantageous.593 For a polyNIPAM support, catalyst recovery was achieved by simply varying the reaction temperature or salt concentration that affected the LCST of polyNIPAM and conferred stimuliresponsive precipitation of the polymer-bound catalyst.596 PolyNIPAM−cobalt hybrid nanoparticles were employed as amphiphilic supports for covalent anchoring of a Pd− phosphine complex to catalyze Suzuki cross-coupling reactions

6.5. Functionalized Surfaces

The modification of surfaces has been a vibrant research area to design functional surfaces with numerous applications. Yet, it comes as no surprise that postpolymerization modification reactions have also been employed for the modification of surfaces.598 Besides the formation of polymer brushes599 and their postmodification, various other routes are commonly used in the formation of polymer thin films. Various approaches also utilize activated ester chemistries to enable an efficient postmodification of polymer thin films. For example, thin polymers films containing PFP-esters were obtained by plasma polymerization of PFPMA (Scheme 69),600−602 making PFPMA a unique monomer suitable Scheme 69. Plasma Polymerization of PFPMA and BSA Attachment on the Obtained Layersa

a

Reprinted from ref 558 . Copyright 2013 American Chemical Society.

because of its volatile character. Such films found application for the immobilization of biomolecules, such as peptides and proteins.336,603,604 Postmodification yielding swellable hydrogel thin films found application in cell studies.605 An alternative route has been presented by Lahann and co-workers, who utilized a CVD copolymerization of [2.2]paracyclophanes featuring pentafluorophenyl ester groups and alkyne groups to prepare orthogonally reactive surfaces, which can be used to coimmobilize different biomolecules and cells.334,340,606,607 Polymer fibers spun from a PCL/polyPFPMA blend had been described, allowing a versatile surface functionalization of the fibers.487 In contrast, NHSA could only be grafted from polypropylene substrates by gamma irradiation, and the resulting poly(NIPAM-co-NHSA) films provided a useful biological platAP



Chemical Reviews

Review

form.608 However, polyNHSA polymer films can be grown from conductive substrates by an electrografting method.609,610 This allowed the growth of polymer chains from an AFM tip, which subsequently enabled the deposition of single polyNHSA chains onto amino-coated substrates.327 Additionally, the postpolymerization modification of the grafted polyNHSA chains on the AFM tip allowed the preparation of chemically modified AFM tips by simple conversion with various amines.611 As an alternative, the group of Schönherr utilized reactive microcontact printing on polyNHSMA films with the transfer of amino end-functionalized PEG, yielding biomolecular patterns.612,613 Copolymerization of NHSA, NAM, and bis-acrylamidoprop1-yl-PEG1900 in the presence of a glass slide that has been modified with 3-(trimethoxysilyl) propyl methacrylate to afford a sufficient attachment yielded NHS-ester hydrogel-coated glass slides.450 Similarly, PNPA has been utilized for the formation of functional hydrogel layers.614 Rather than pretreating the glass surface with 3-(trimethoxysilyl)propyl methacrylate, direct copolymerization of dimethylacrylamide, 3-(trimethoxysilyl)propyl methacrylate, and NHSA (Scheme 70) led to polymers

and essentially depend on the amine used for the functionalization, for example, antibacterial surfaces632 and molecular recognition probes.611 Theato and co-workers presented a very versatile approach by combining a graftingto and postmodification step on the basis of polysilsesquioxanebased hybrid polymers, which consist predominately of polyPFPA chains grown from a polysilsesquioxane precursor polymer. Secondary condensation reactions of the polysilsesquioxane part upon annealing allow for the deposition onto various surfaces. The subsequent conversion with amines results in surfaces with adjustable wettability347,633,634 or biological activity.635 The group of Klok demonstrated the grafting of PFPMA from a surface via RAFT polymerization, following a detailed investigation of the subsequent postpolymerization functionalization.98 Surface-initiated ATRP (SIATRP) of PFPM and postfunctionalization of the obtained polymer brushes had also been reported.588 The group of Locklin utilized activated ester polymer brushes grafted-from surfaces in a double PPM (Scheme 71).81 First, the activated ester polymer brushes were reacted with an amine-functionalized cyclopropenone, which was then successfully used in a second functionalization step via a catalyst-free cycloaddition reaction with azides.82 Besides the functionalization of macroscopic planar surfaces, activated ester polymers have also been valuable synthetic tools as polymeric ligands for nanoparticles. For example, polymers bearing either NHSMA or PFPA units have been used to decorate magnetic nanoparticles, which can then be the basis for an effective bioseparation process or immobilization process of proteins.551 Similarly, NHSA has been grafted from mesoporous silica nanoparticles via a grafting-from RAFT polymerization.636 Activated ester polymers on the basis of polyPFPA have been used for the synthesis of polymeric ligands for a variety of different nanoparticles.501,502,553,637,638 Different binding ligands have been incorporated, depending on the inorganic nanoparticle. Similar to the coating of planar surfaces, tercopolymers of NHSA, DMA, and 3-(trimethoxysilyl)propyl methacrylate were used to stabilize CdSe−ZnS quantum dots in water.639 A library of polymer-coated (core−shell-type) gold nanoparticles utilizing polyPFPMA prepared by RAFT polymerization has been presented by the group of Klok.640,641 Carbon nanotubes (CNTs) have also been functionalized by utilizing polymeric activated esters as precursors, which, for example, allowed the modification with DNA.506 Incorporation of pyrene side groups provided a good stabilization of CNTs, and further conversion of the activated ester units into a polyNIPAM resulted in stimuli-responsive CNTs, whose solubilization can be triggered by changes in temperature.132,133 Polymer conjugation onto CNTs via azides has also been achieved.378 Alternatively, PFPMA could be attached to the CNT surface via plasma polymerization.642 Lastly, semiconducting thin films of polythiophene or polypyrrole derivatives featuring activated ester groups have been described,300,310,313−315,643 and no real differentiation between the various activated esters (PFP or NHS) has been observed. Such reactive polythiophene layers have been used for protein immobilization644 or as electrochemical DNA sensors.318,645

Scheme 70. Structure of a Terpolymer Comprised of Dimethylacrylamine, 3-(Trimethoxysilyl)propyl Methacrylate and NHSA

that allow direct deposition of activated ester-containing polymers onto substrates.554,615,616 Similar surface functionalizations have been achieved with the tercopolymer prepared from NHSA, 3-(trimethoxysilyl)propyl methacrylate, and PEGMA617 or other variations to alter surface wetting properties618−621 or enable biomolecule conjugation.622,623 In particular, this approach has been used for the preparation of DNA microarray sensors.615,624−626 The biocompatibility of these approaches has also led to the exploration of NHSA in dental adhesives.627 Noteworthy, the trimethoxysilyl group provides an efficient possibility not only for the attachment onto SiO2 surfaces but also for the modification of AFM cantilevers yielding molecular recognition sensors.628 The activated ester moiety can also be utilized to enable covalent attachment of functional copolymers onto aminofunctionalized surfaces. For example, poly(NIPAM-co-NHSA) has been attached onto amino-modified silica nanoparticles, and the remaining activated ester moieties have then been used in deposition of covalent layer-by-layer self-assembly of these coated nanoparticles with polyethylenimine (PEI), resulting in stimuli-responsive nanocomposite films.629,630 Similarly, such a covalent cross-linking approach has also been utilized for the formation of nanostructured protein hydrogel films. For this a copolymer of NHSA and NAM was deposited simultaneously with a protein, wherein the amino groups exposed at the protein surface reacted with the activated ester groups, resulting in a cross-linked hydrogel film.451,631 There have also been reports focusing on more precisely prepared reactive polymers films by grafting-from approaches. The potential applications of these surfaces can be numerous

7. CONCLUDING REMARKS Activated esters have been used in polymer synthesis frequently and an established synthetic tool for more than 40 years. The rich structural variations of the different activated esters that AQ


Chemical Reviews

Review


Scheme 71. (a) Grafted Poly(NHS4VB) from a SiO2 Surface and Attachment of Cyclopropenone (1); (b) UV-Irradiated Activation into the Dibenzocyclooctyne (2) and Its Cycloaddition with Azides

to other click chemistries, making them very powerful synthetic handles in efficient, one-pot modifications. In this regard, further intensive use can be expected in the future. The excellent compatibility of activated ester chemistry with numerous polymerization methods, ranging from free radical polymerization, controlled radical polymerizations, ring-opening metathesis polymerizations, and other ring-opening polymerizations to plasma polymerization and electrochemical polymerizations, provides the basis of a very broad applicability in materials science and life science. Now, is there still something remaining to be done in basic research on activated esters in polymer chemistry? When looking at the monomer map, one can identify several empty areas that urgently need to be addressed. (A) Not all activated esters have been explored in all areas. Here their compatibility remains to be tested. (B) The possibility to conduct activated ester−amine conversions in water is another very challenging area. Even though some potential approaches have been presented, e.g., 4-sulfotetrafluorophenyl (STP) esters,64,65 so far, mostly sulfonated NHS-esters are used. However, it has to be noted that sulfonated NHS-esters are semistable aminereactive esters. (C) Activation of activated esters. The intrinsic existing reactivity of activated esters is synthetically very valuable; however, it would be exciting to have access to an activated ester that is dormant under normal conditions and can be activated upon exposure to a physical stimulus. One example has been reported in the literature;109 however, it is only a change from an activated ester into a deactivated ester, and the deactivation is irreversible. A reversible process is highly needed.

have found application in polymer synthesis document its lasting success. Activated esters represent an extremely successful method when it comes to postpolymerization modifications. The broad availability and accessibility of amines and the mild reaction conditions (catalyst free, room temperature) speak to the fact that conversions of activated esters with amines are superior in several aspects to other click reactions. However, one should also note the intrinsic disadvantage of activated ester−amine conversions. It remains a substitution reaction and becomes only economically viable when recycling the released auxiliary alcohol. The choice of activated ester depends on several factors. NHS-esters are historically the most frequently used activated esters in polymer chemistry; however, the suffer from the fact that their respective acrylate or methacrylate polymers are only soluble in DMSO or DMF. When used within copolymers, solubility is not an issue anymore. Modern times have seen a vital revival of activated ester applications with the advent of PFP-esters. Their solubility as well as their hydrolytic stability is advantageous when compared to NHS-esters. The additional charm of utilizing 19F NMR spectroscopy as a sensitive analytical tool has additionally contributed to the increased use of PFP-esters. When 1H NMR spectroscopy is required for detailed analysis, the use of tetrafluorophenyl esters may come in handy but at a higher cost of the required chemical compounds. A comparable alternative is the use of PNP-esters. Noteworthy, most polymers containing activated ester groups are stable, can be stored without special precaution, and can easily be shipped. It is worthwhile to note that activated ester−amine conversions are very compatible and often also fully orthogonal AR


Chemical Reviews

Review

Polymeric activated esters have been and will be attracting a lot of attention because of their synthetic potential for the synthesis of new functional polymer materials that find application in many research areas. The recent trend in combining postpolymerization modifications with modern advances in precision polymerization will result in an increasing use of activated ester chemistries.

within the WCU program. In 2011, he accepted a prize senior lectureship at the University of Sheffield. Shortly after he moved to the University of Hamburg, where he is currently an associate (W2) professor for polymer chemistry. He has edited 2 books and authored or coauthored more than 180 publications. His research interests are postpolymerization modifications, stimuli-responsive polymers, surface modifications, energy storage, functional nanoobjects, and nanofibers.

AUTHOR INFORMATION

ACKNOWLEDGMENTS A.D. is indebted to the Alexander-von-Humboldt Foundation for postdoctoral fellowship.

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

REFERENCES


Biographies

(1) Lutz, J.; Sumerlin, B.; Matyjaszewski, K. Precisely Controlled Polymer Architectures. Macromol. Rapid Commun. 2014, 35, 122. (2) van de Wetering, P.; Zuidam, N. J.; van Steenbergen, M. J.; van der Houwen, O. A. G. J.; Underberg, W. J. M.; Hennink, W. E. A Mechanistic Study of the Hydrolytic Stability of Poly(2(dimethylamino)ethyl Methacrylate). Macromolecules 1998, 31, 8063−8068. (3) Staudinger, H.; Fritschi, J. Ü ber Isopren Und Kautschuk. 5. Mitteilung. Ü ber Die Hydrierung Des Kautschuks Und Ü ber Seine Konstitution. Helv. Chim. Acta 1922, 5, 785−806. (4) Staudinger, H.; Geiger, E.; Huber, E. Ü ber Hochpolymere Verbindungen, 15. Mitteilung: Ü ber Die Reduktion Des Polystyrols. Ber. Dtsch. Chem. Ges. B 1929, 62, 263−267. (5) Serniuk, G. E.; Banes, F. W.; Swaney, M. W. Study of the Reaction of Buna Rubbers with Aliphatic Mercaptans1. J. Am. Chem. Soc. 1948, 70, 1804−1808. (6) Merrifield, R. B. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149−2154. (7) Iwakura, Y.; Kurosaki, T.; Nakabayashi, N. Reactive Fiber. Part I. Copolymerization and Copolymer of Acrylonitrile with Glycidyl Methacrylate and with Glycidyl Acrylate. Makromol. Chem. 1961, 44, 570−590. (8) Iwakura, Y.; Kurosaki, T.; Ariga, N.; Ito, T. Copolymerization of Methyl Methacrylate with Glycidyl Methacrylate and the Reaction of the Copolymer with Amines. Makromol. Chem. 1966, 97, 128−138. (9) Kern, W.; Schulz, R. C.; Braun, D. Macromolecules with Groups of High Reactivity. J. Polym. Sci. 1960, 48, 91−99. (10) Blatz, P. E. New Polyelectrolytes: Synthesis and Preliminary Characterization. J. Polym. Sci. 1962, 58, 755−768. (11) Gauthier, M. A.; Gibson, M. I.; Klok, H.-A. Synthesis of Functional Polymers by Post-Polymerization Modification. Angew. Chem., Int. Ed. 2009, 48, 48−58. (12) Günay, K. A.; Theato, P.; Klok, H.-A. Standing on the Shoulders of Hermann Staudinger: Post-Polymerization Modification from Past to Present. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 1−28. (13) Kakuchi, R.; Theato, P. In Functional Polymers by PostPolymerization Modification: Concepts, Guidelines and Applications, 1st ed.; Theato, P., Klok, H.-A., Eds.; WILEY-VCH: Weinheim, Germany, 2013. (14) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Funtion from a Few Good Reactions. Angew. Chem., Int. Ed. 2001, 40, 2004−2021. (15) Barner-Kowollik, C.; Du Prez, F. E.; Espeel, P.; Hawker, C. J.; Junkers, T.; Schlaad, H.; Van Camp, W. “Clicking” Polymers or Just Efficient Linking: What Is the Difference? Angew. Chem., Int. Ed. 2011, 50, 60−62. (16) Wang, J.-S.; Matyjaszewski, K. Controlled/“living” Radical Polymerization. Atom Transfer Radical Polymerization in the Presence of Transition-Metal Complexes. J. Am. Chem. Soc. 1995, 117, 5614− 5615. (17) Chiefari, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le, T. P. T.; Mayadunne, R. T. A.; Meijs, G. F.; Moad, C. L.; Moad, G.; et al. Living Free-Radical Polymerization by Reversible Addition−Fragmen-

Dr. Anindita Das was raised in Kolkata, India. After receiving her B.Sc. and M.Sc. degrees in Chemistry from the University of Calcutta she joined the research group of Dr. Suhrit Ghosh at Indian Association for the Cultivation of Science where she obtained her Ph.D. degree in 2014. The topic of her doctoral thesis was “hydrogen-bonding-induced assembly of aromatic donor−acceptor gelators and chromophore− conjugate amphiphilic macromolecules”. Currently, she is working as an Alexander von Humboldt Postdoctoral Fellow in the research group of Prof. Patrick Theato at the University of Hamburg. Her current research is focused on precise polymer assemblies by directional noncovalent interactions.

Prof. Patrick Theato studied chemistry at the University of Mainz and the University of Massachusetts, Amherst, and obtained his doctoral degree from the University of Mainz in 2001. After postdoctoral studies at Seoul National University supported by a Feodor Lynen Postdoctoral Research Fellowship and at Stanford University, he completed his Habilitation at the University of Mainz in 2007. From 2009 to 2012 he held a joint appointment at Seoul National University AS



Chemical Reviews

Review

tation Chain Transfer: The RAFT Process. Macromolecules 1998, 31, 5559−5562. (18) Percec, V.; Guliashvili, T.; Ladislaw, J. S.; Wistrand, A.; Stjerndahl, A.; Sienkowska, M. J.; Monteiro, M. J.; Sahoo, S. Ultrafast Synthesis of Ultrahigh Molar Mass Polymers by Metal-Catalyzed Living Radical Polymerization of Acrylates, Methacrylates, and Vinyl Chloride Mediated by SET at 25 °C. J. Am. Chem. Soc. 2006, 128, 14156−14165. (19) Hawker, C. J.; Bosman, A. W.; Harth, E. New Polymer Synthesis by Nitroxide Mediated Living Radical Polymerizations. Chem. Rev. 2001, 101, 3661−3688. (20) Rosen, B. M.; Percec, V. Single-Electron Transfer and SingleElectron Transfer Degenerative Chain Transfer Living Radical Polymerization. Chem. Rev. 2009, 109, 5069−5119. (21) Batz, H.-G.; Franzmann, G.; Ringsdorf, H. Pharmakologisch Aktive Polymere. Makromol. Chem. 1973, 172, 27−47. (22) Ferruti, P.; Bettelli, A.; Feré, A. High Polymers of Acrylic and Methacrylic Esters of N-Hydroxysuccinimide as Polyacrylamide and Polymethacrylamide Precursors. Polymer 1972, 13, 462−464. (23) Goodall, G. W.; Hayes, W. Advances in Cycloaddition Polymerizations. Chem. Soc. Rev. 2006, 35, 280−312. (24) Lutz, J. F. 1,3-Dipolar Cycloadditions of Azides and Alkynes: A Universal Ligation Tool in Polymer and Materials Science. Angew. Chem., Int. Ed. 2007, 46, 1018−1025. (25) Bodanszky, M. Principles of Peptide Synthesis; Spinger Verlag: Berlin, 1984; Vol. 16. (26) Wieland, T.; Schäfer, W.; Bokelmann, E. Ü ber Peptidsynthesen V. Ü ber Eine Bequeme Darstellungsweise von Acylthiophenolen Und Ihre Verwendung Zu Amid-Und Peptid-Synthesen. Justus Liebigs Ann. Chem. 1951, 573, 99−104. (27) Kisfaludy, L.; Löw, M.; Nyéki, O.; Szirtes, T.; Schő n, I. Die Verwendung von Pentafluorphenylestern Bei Peptidsynthesen. Justus Liebigs Ann. Chem. 1973, 1973, 1421−1429. (28) Schwyzer, R.; Iselin, B.; Feurer, M. Ü ber Aktivierte Ester. I. Aktivierte Ester Der Hippursäure Und Ihre Umsetzungen Mit Benzylamin. Helv. Chim. Acta 1955, 38, 69−79. (29) Farringrton, J. A.; Hextall, P. J.; Kenner, G. W.; Turner, J. M. 265. Peptides. Part VII. The Preparation and Use of P-Nitrophenyl Thiolesters. J. Chem. Soc. 1957, 1407−1413. (30) Pedone, E.; Li, X.; Koseva, N.; Alpar, O.; Brocchini, S. An Information Rich Biomedical Polymer Library. J. Mater. Chem. 2003, 13, 2825−2837. (31) Yoshikawa, M.; Adachi, Y.; Yokoi, H.; Sanui, K.; Ogata, N. Synthesis of Poly{1-[ (2-Methylpropenoyl)oxy]succinimide-Co-Acrylonitrile} and the Selective Separation of a Water-Ethanol Mixture through Its Membranes. Macromolecules 1986, 19, 47−50. (32) Alb, A. M.; Enohnyaket, P.; Drenski, M. F.; Shunmugam, R.; Tew, G. N.; Reed, W. F. Quantitative Contrasts in the Copolymerization of Acrylate- and Methacrylate-Based Comonomers. Macromolecules 2006, 39, 8283−8292. (33) D’ Agosto, F.; Charreyre, M.; Veron, L.; Llauro, M.; Pichot, C. Kinetic Study of Free-Radical Solution Copolymerization of NAcryloylmorpholine with an Activated Ester-Type Monomer, NAcryloxysuccinimide. Macromol. Chem. Phys. 2001, 202, 1689−1699. (34) Nazarova, O. V.; Solovskij, M. V.; Panarin, E. F.; Denisov, V. M.; Khachaturov, A. S.; Koltsov, A. I.; Purkina, A. V. Copolymerizations of N-Vinylpyrrolidone and Activated Esters of Unsaturated Acids. Eur. Polym. J. 1992, 28, 97−100. (35) Erout, M. N.; Elaïssari, A.; Pichot, C.; Llauro, M.-F. RadicalInitiated Copolymers of N-Vinyl Pyrrolidone and N-Acryloxy Succinimide: Kinetic and Microstructure Studies. Polymer 1996, 37, 1157−1165. (36) Yang, H. J.; Cole, C. A.; Monji, N.; Hoffman, A. S. Preparation of a Thermally Phase-Separating Copolymer, Poly(N-Isopropylacrylamide-co-N-Acryloxysuccinimide), with a Controlled Number of Active Esters per Polymer Chain. J. Polym. Sci., Part A: Polym. Chem. 1990, 28, 219−226.

(37) Uludag, H.; Wong, M.; Man, J. Reactivity of TemperatureSensitive, Protein-Conjugating Polymers Prepared by a Photopolymerization Process. J. Appl. Polym. Sci. 2000, 75, 583−592. (38) Murata, H.; Prucker, O.; Rühe, J. Synthesis of Functionalized Polymer Monolayers from Active Ester Brushes. Macromolecules 2007, 40, 5497−5503. (39) Deporter, S. M.; Hendricks, N. K.; Gray, M. A.; Mcnaughton, B. R. A One-Pot Synthesis of Micron-Sized and Nanoscale Poly (Nacryloxysuccinimide-co-N-Vinylpyrrolidone) Particles. Tetrahedron Lett. 2012, 53, 6436−6438. (40) Devenish, S. R. A.; Hill, J. B.; Blunt, J. W.; Morris, J. C.; Munro, M. H. G. Dual Side-Reactions Limit the Utility of a Key Polymer Therapeutic Precursor. Tetrahedron Lett. 2006, 47, 2875−2878. (41) Wong, S. Y.; Putnam, D. Overcoming Limiting Side Reactions Associated with an NHS-Activated Precursor of PolymethacrylamideBased Polymers. Bioconjugate Chem. 2007, 18, 970−982. (42) Eberhardt, M.; Mruk, R.; Zentel, R.; Théato, P. Synthesis of Pentafluorophenyl(meth)acrylate Polymers: New Precursor Polymers for the Synthesis of Multifunctional Materials. Eur. Polym. J. 2005, 41, 1569−1575. (43) Blazejewski, J.-C.; Hofstraat, J. W.; Lequesne, C.; Wakselman, C.; Wiersum, U. E. Halogenoaryl Acrylates: Preparation, Polymerization and Optical Properties. J. Fluorine Chem. 1999, 97, 191−199. (44) Tagaya, A.; Harada, T.; Koike, K.; Koike, Y.; Okamoto, Y.; Teng, H.; Yang, L. Improvement of the Physical Properties of Poly(methyl Methacrylate) by Copolymerization with Pentafluorophenyl Methacrylate. J. Appl. Polym. Sci. 2007, 106, 4219−4224. (45) Teng, H.; Yang, L.; Mikes, F.; Koike, Y.; Okamoto, Y. Property Modification of Poly(methyl Methacrylate) through Copolymerization with Fluorinated Aryl Methacrylate Monomers. Polym. Adv. Technol. 2007, 18, 453−457. (46) Nilles, K.; Theato, P. Synthesis and Polymerization of Active Ester Monomers Based on 4-Vinylbenzoic Acid. Eur. Polym. J. 2007, 43, 2901−2912. (47) Seuyep N, D. H.; Szopinski, D.; Luinstra, G. A.; Theato, P. PostPolymerization Modification of Reactive Polymers Derived from Vinylcyclopropane: A Poly(vinylcyclopropane) Derivative with Physical Gelation and UCST Behaviour in Ethanol−water Mixtures. Polym. Chem. 2014, 5, 5823−5828. (48) Batz, H.-G.; Franzmann, G.; Ringsdorf, H. Model Reactions for Synthesis of Pharmacologically Active Polymers by Way of Monomeric and Polymeric Reactive Esters. Angew. Chem., Int. Ed. Engl. 1972, 11, 1103−1104. (49) Rejmanovti, P.; Labsky, J.; Kopecek, J. Aminolyses of Monomeric and Polymeric 4-Nitrophenyl Esters of N-Methacryloylamino Acids. Makromol. Chem. 1977, 178, 2159−2168. (50) Thamizharasi, S.; Gnanasundaram, P.; Balasubramanian, S. Synthesis, Characterization, and Reactivity Ratios of Copolymers Derived from 4-Nitrophenyl Acrylate and N-Butyl Methacrylate. J. Appl. Polym. Sci. 2003, 88, 1817−1824. (51) Kiser, P. F.; Wilson, G.; Needham, D. Lipid-Coated Microgels for the Triggered Release of Doxorubicin. J. Controlled Release 2000, 68, 9−22. (52) Solovskij, M. V.; Panarin, E. F.; Gorbunova, O. P.; Korneeva, E. V.; Petuhkova, N. A.; Michajlova, N. A.; Pavlov, G. M. Investigation of the Formation and Properties of Water-Soluble Conjugates of Polymer P-Nitrophenyl Esters with Polymer Primary Amines. Eur. Polym. J. 2000, 36, 1127−1135. (53) Thamizharasi, S.; Gnanasundaram, P.; Balasubramanian, S. Copolymers Derived from 4-Nitrophenyl Methacrylate (Npma) and Methyl-Methacrylate (MMA)-Synthesis, Characterization, and Reactivity Ratio. J. Macromol. Sci., Part A: Pure Appl.Chem. 1998, 35, 1835− 1852. (54) Narita, M.; Teramoto, T.; Okawara, M. No Title. Bull. Chem. Soc. Jpn. 1972, 45, 3149−3155. (55) Su, C.; Morawetz, H. Reactivity of Polymer Substituents. Aminolysis of P-Nitrophenyl Ester Residues Attached to Various Polymer Backbones. J. Polym. Sci., Polym. Chem. Ed. 1977, 15, 185− 196. AT



Chemical Reviews

Review

(56) Akelah, A.; Selin, A.; El-Deen, N. S.; Kandil, S. H. Photochemical Reactions of Polymers Bearing Chalcone Residues. Polym. Int. 1992, 28, 307−312. (57) Akelah, A.; Selim, A.; El-deen, N. S. Photosensitive Polymers Containing Pendent Chalcone Moieties via Oxyethylene Group. Polym. Int. 1993, 32, 423−434. (58) Agosto, F. D.; Charreyre, M.; Pichot, C. Side-Product of NAcryloyloxysuccinimide Synthesis or Useful New Bifunctional Monomer? Macromol. Biosci. 2001, 1, 322−328. (59) Šubr, V.; Ulbrich, K. Synthesis and Properties of New N-(2Hydroxypropyl)methacrylamide Copolymers Containing Thiazolidine-2-Thione Reactive Groups. React. Funct. Polym. 2006, 66 (12), 1525−1538. (60) Staros, J. V. N-Hydroxysulfosuccinimide Active Esters: bis(NHydroxysulfosuccinimide) Esters of Two Dicarboxylic Acids Are Hydrophilic, Membrane-Impermeant, Protein Cross-Linkers. Biochemistry 1982, 21, 3950−3955. (61) Anjaneyulu, P. S. R.; Staros, J. V. Reactions of NHydroxysulfosuccinimide Active Esters. Int. J. Pept. Protein Res. 1987, 30, 117−124. (62) Rowley, J. A.; Madlambayan, G.; Mooney, D. J. Alginate Hydrogels as Synthetic Extracellular Matrix Materials. Biomaterials 1999, 20 (1), 45−53. (63) Micich, T. J.; Weil, J. K.; Linfield, W. M. Soap-Based Detergent Formulations. XVI. Surface Active Sulfosuccinimides. J. Am. Oil Chem. Soc. 1975, 52, 451−454. (64) Gee, K. R.; Archer, E. A.; Kang, H. C. 4-Sulfotetrafluorophenyl (STP) Esters: New Water-Soluble Amine-Reactive Reagents for Labeling Biomolecules. Tetrahedron Lett. 1999, 40, 1471−1474. (65) Medvedkin, V. N.; Zabolotskikh, V. F.; Permiakov, E. A.; Mitin, L.; Sorokina, M. N.; Klimenko, L. p-Sulfotetrafluorophenyl Hydrophilic Activated Esters of Amino Acids in Peptide Synthesis. Bioorg. Khim. 1995, 21, 684−690. (66) Metz, N.; Theato, P. Controlled Synthesis of Poly(acetone Oxime Acrylate) as a New Reactive Polymer: Stimuli-Responsive Reactive Copolymers. Eur. Polym. J. 2007, 43, 1202−1209. (67) He, L.; Szameit, K.; Zhao, H.; Hahn, U.; Theato, P. Postpolymerization Modification Using Less Cytotoxic Activated Ester Polymers for the Synthesis of Biological Active Polymers. Biomacromolecules 2014, 15, 3197−3205. (68) Godwin, A.; Hartenstein, M.; Müller, A. H. E.; Brocchini, S. Narrow Molecular Weight Distribution Precursors for Polymer-Drug Conjugates. Angew. Chem., Int. Ed. 2001, 40, 594−597. (69) Hu, Z.; Liu, Y.; Hong, C.; Pan, C. Synthesis of Well-Defined Glycoconjugate Polyacrylamides via Preactivated Polymers Prepared by ATRP. J. Appl. Polym. Sci. 2005, 98, 189−194. (70) Monge, S.; Haddleton, D. M. Synthesis of Precursors of Poly(acryl Amides) by Copper Mediated Living Radical Polymerization in DMSO. Eur. Polym. J. 2004, 40, 37−45. (71) Kong, L.-Z.; Pan, C.-Y. Preparation of Dendrimer-like Copolymers Based on Polystyrene and Poly(l-Lactide) and Formation of Hollow Microspheres. Polymer 2008, 49, 200−210. (72) Favier, A.; D’Agosto, F.; Charreyre, M. T.; Pichot, C. Synthesis of N-Acryloxysuccinimide Copolymers by RAFT Polymerization, as Reactive Building Blocks with Full Control of Composition and Molecular Weights. Polymer 2004, 45, 7821−7830. (73) Yanjarappa, M. J.; Gujraty, K. V.; Joshi, A.; Saraph, A.; Kane, R. S. Synthesis of Copolymers Containing an Active Ester of Methacrylic Acid by RAFT: Controlled Molecular Weight Scaffolds for Biofunctionalization. Biomacromolecules 2006, 7, 1665−1670. (74) Savariar, E. N.; Thayumanavan, S. Controlled Polymerization of N-Isopropylacrylamide with an Activated Methacrylic Ester. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 6340−6345. (75) Relógio, P.; Charreyre, M.-T.; Farinha, J. P. S.; Martinho, J. M. G.; Pichot, C. Well-Defined Polymer Precursors Synthesized by RAFT Polymerization of N,N-dimethylacrylamide/N-Acryloxysuccinimide: Random and Block Copolymers. Polymer 2004, 45, 8639−8649. (76) Vosloo, J. J.; Tonge, M. P.; Fellows, C. M.; D’ Agosto, F.; Sanderson, R. D.; Gilbert, R. G. Synthesis of Comblike Poly(butyl

Methacrylate) Using Reversible Addition-Fragmentation Chain Transfer and an Activated Ester. Macromolecules 2004, 37, 2371−2382. (77) Eschweiler, N.; Keul, H.; Millaruelo, M.; Weberskirch, R.; Moeller, M. Synthesis of α,ω-Isocyanate Telechelic Polymethacrylate Soft Segmentswith Activated Ester Side Functionalities and Their Use for Polyurethane Synthesis. Polym. Int. 2014, 63, 114−126. (78) Aamer, K. A.; Tew, G. N. RAFT Polymerization of a Novel Activated Ester Monomer and Conversion to a TerpyridineContaining Homopolymer. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 5618−5625. (79) Desai, A.; Atkinson, N.; Rivera, F.; Devonport, W.; Rees, I.; Branz, S. E.; Hawker, C. J. Hybrid Dendritic−Linear Graft Copolymers: Steric Considerations in “Coupling To” Approach. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 1033−1044. (80) Parvin, S.; Matsui, J.; Sato, E.; Miyashita, T. Side-Chain Effect on Langmuir and Langmuir−Blodgett Film Properties of poly(NAlkylmethacrylamide)-Coated Magnetic Nanoparticle. J. Colloid Interface Sci. 2007, 313, 128−134. (81) Orski, S. V.; Poloukhtine, A. A.; Arumugam, S.; Mao, L.; Popik, V. V.; Locklin, J. High Density Orthogonal Surface Immobilization via Photoactivated Copper-Free Click Chemistry. J. Am. Chem. Soc. 2010, 132, 11024−11026. (82) Orski, S. V.; Fries, K. H.; Sheppard, G. R.; Locklin, J. High Density Scaffolding of Functional Polymer Brushes: Surface Initiated Atom Transfer Radical Polymerization of Active Esters. Langmuir 2010, 26, 2136−2143. (83) Zhao, H.; Gu, W.; Thielke, M. W.; Sterner, E.; Tsai, T.; Russell, T. P.; Coughlin, E. B.; Theato, P. Functionalized Nanoporous Thin Films and Fibers from Photocleavable Block Copolymers Featuring Activated Esters. Macromolecules 2013, 46, 5195−5201. (84) Singha, N. K.; Gibson, M. I.; Koiry, B. P.; Danial, M.; Klok, H.A. Side-Chain Peptide-Synthetic Polymer Conjugates via Tandem “Ester-Amide/Thiol−Ene” Post-Polymerization Modification of Poly(pentafluorophenyl Methacrylate) Obtained Using ATRP. Biomacromolecules 2011, 12, 2908−2913. (85) Lee, Y.; Hanif, S.; Theato, P.; Zentel, R.; Lim, J.; Char, K. Facile Synthesis of Fluorescent Polymer Nanoparticles by Covalent Modification-Nanoprecipitation of Amine-Reactive Ester Polymers. Macromol. Rapid Commun. 2015, 36, 1089. (86) Eberhardt, M.; Théato, P. RAFT Polymerization of Pentafluorophenyl Methacrylate: Preparation of Reactive Linear Diblock Copolymers. Macromol. Rapid Commun. 2005, 26, 1488−1493. (87) Gibson, M. I.; Fröhlich, E.; Klok, H.-A. Postpolymerization Modification of Poly (Pentafluorophenyl Methacrylate): Synthesis of a Diverse Water-Soluble Polymer Library. J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 4332−4345. (88) Nuhn, L.; Barz, M.; Zentel, R. New Perspectives of HPMABased Copolymers Derived by Post-Polymerization Modification. Macromol. Biosci. 2014, 14, 607−618. (89) Mohr, N.; Barz, M.; Forst, R.; Zentel, R. A Deeper Insight into the Postpolymerization Modification of Polypenta Fluorophenyl Methacrylates to Poly(N-(2-Hydroxypropyl) Methacrylamide. Macromol. Rapid Commun. 2014, 35, 1522−1527. (90) Barz, M.; Luxenhofer, R.; Zentel, R.; Kabanov, A. V. The Uptake of N-(2-Hydroxypropyl)-Methacrylamide Based Homo, Random and Block Copolymers by Human Multi-Drug Resistant Breast Adenocarcinoma Cells. Biomaterials 2009, 30, 5682−5690. (91) Teodorescu, M.; Matyjaszewski, K. Atom Transfer Radical Polymerization of (Meth)acrylamides. Macromolecules 1999, 32, 4826−4831. (92) Scales, C. W.; Vasilieva, Y. A.; Convertine, A. J.; Lowe, A. B.; McCormick, C. L. Direct, Controlled Synthesis of the Nonimmunogenic, Hydrophilic Polymer, Poly(N-(2-Hydroxypropyl)methacrylamide) via RAFT in Aqueous Media. Biomacromolecules 2005, 6, 1846−1850. (93) Schüll, C.; Nuhn, L.; Mangold, C.; Christ, E.; Zentel, R.; Frey, H. Linear-Hyperbranched Graft-Copolymers via Grafting-to Strategy Based on Hyperbranched Dendron Analogues and Reactive Ester Polymers. Macromolecules 2012, 45, 5901−5910. AU



Chemical Reviews

Review

(94) Moers, C.; Nuhn, L.; Wissel, M.; Stangenberg, R.; Mondeshki, M.; Berger-Nicoletti, E.; Thomas, A.; Schaeffel, D.; Koynov, K.; Klapper, M.; et al. Supramolecular Linear-g-Hyperbranched Graft Polymers: Topology and Binding Strength of Hyperbranched Side Chains. Macromolecules 2013, 46, 9544−9553. (95) Nilles, K.; Theato, P. RAFT Polymerization of Activated 4Vinylbenzoates. J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 1696− 1705. (96) Nilles, K.; Theato, P. Sequential Conversion of Orthogonally Functionalized Diblock Copolymers Based on Pentafluorophenyl Esters. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 3683−3692. (97) Kakuchi, R.; Zamfir, M.; Lutz, J.-F.; Theato, P. Controlled Positioning of Activated Ester Moieties on Well-Defined Linear Polymer Chains. Macromol. Rapid Commun. 2012, 33, 54−60. (98) Günay, K. A.; Schüwer, N.; Klok, H.-A. Synthesis and PostPolymerization Modification of Poly(pentafluorophenyl Methacrylate) Brushes. Polym. Chem. 2012, 3, 2186−2192. (99) Zhao, H.; Gu, W.; Kakuchi, R.; Sun, Z.; Sterner, E.; Russell, T. P.; Coughlin, E. B.; Theato, P. Photocleavable Triblock Copolymers Featuring an Activated Ester Middle Block: “One-Step” Synthesis and Application as Locally Reactive Nanoporous Thin Films. ACS Macro Lett. 2013, 2, 966−969. (100) Zhao, H.; Theato, P. Copolymers Featuring Pentafluorophenyl Ester and Photolabile Amine Units: Synthesis and Application as Reactive Photopatterns. Polym. Chem. 2013, 4, 891−894. (101) Theato, P.; Kim, J.; Lee, J. Controlled Radical Polymerization of Active Ester Monomers: Precursor Polymers for Highly Functionalized Materials. Macromolecules 2004, 37 (15), 5475−5478. (102) Reddy, B. S. R.; Arshady, R.; George, M. H. Copolymerization of 2,4,5-Trichlorophenyl Acrylate with Styrene: Reactivity Ratios, Molecular Weights, and 13C NMR Spectra. Macromolecules 1983, 16, 1813−1817. (103) Liu, Y.; Wang, L.; Pan, C. Synthesis of Block Copoly(styreneb-p-nitrophenyl methacrylate) and Its Derivatives by Atom Transfer Radical Polymerization. Macromolecules 1999, 32, 8301−8305. (104) Hu, Y.-C.; Liu, Y.; Pan, C.-Y. Reversible Addition− Fragmentation Transfer Polymerization of p-Nitrophenyl Acrylate and Synthesis of Diblock Copolymers Poly(p-nitrophenyl acrylate)-bPolystyrene. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 4862−4872. (105) Li, R. C.; Hwang, J.; Maynard, H. D. Reactive Block Copolymer Scaffolds. Chem. Commun. 2007, 3631−3633. (106) Hwang, J.; Li, R. C.; Maynard, H. D. Well-Defined Polymers with Activated Ester and Protected Aldehyde Side Chains for BioFunctionalization. J. Controlled Release 2007, 122, 279−286. (107) Li, X. S.; Gan, L. H.; Gan, Y. Y. Controlled Polymerization of 2,3,5,6-Tetrafluorophenyl Methacrylate. Polymer 2008, 49, 1879− 1884. (108) Godula, K.; Bertozzi, C. R. Synthesis of Glycopolymers for Microarray Applications via Ligation of Reducing Sugars to a Poly(acryloyl Hydrazide) Scaffold. J. Am. Chem. Soc. 2010, 132, 9963−9965. (109) Kakuchi, R.; Theato, P. Changing the Reactivity of Polymeric Activated Esters by Temperature: On−Off Switching of the Reactivity of Poly(4-Acryloxyphenyldimethylsulfonium Triflate). Macromolecules 2012, 45, 1331−1338. (110) Nuhn, L.; Overhoff, I.; Sperner, M.; Kaltenberg, K.; Zentel, R. RAFT-Polymerized Poly(hexafluoroisopropyl Methacrylate)s as Precursors for Functional Water-Soluble Polymers. Polym. Chem. 2014, 5, 2484−2495. (111) Tesch, M.; Hepperle, J. A. M.; Klaasen, H.; Letzel, M.; Studer, A. Alternating Copolymerization by Nitroxide-Mediated Polymerization and Subsequent Orthogonal Functionalization. Angew. Chem., Int. Ed. 2015, 54, 5054−5059. (112) Samanta, S. R.; Cai, R.; Percec, V. A Rational Approach to Activated Polyacrylates and Polymethacrylates by Using a Combination of Model Reactions and SET-LRP of Hexafluoroisopropyl Acrylate and Methacrylate. Polym. Chem. 2015, 6, 3259−3270. (113) Thomas, J. L.; Tirrell, D. A. Polyelectrolyte-Sensitized Phospholipid Vesicles. Acc. Chem. Res. 1992, 25, 336−342.

(114) Zhao, Z.; Wang, J.; Mao, H.-Q.; Leong, K. W. Polyphosphoesters in Drug and Gene Delivery. Adv. Drug Delivery Rev. 2003, 55, 483−499. (115) Wan, A. C. A.; Mao, H.-Q.; Wang, S.; Phua, S. H.; Lee, G. P.; Pan, J.; Lu, S.; Wang, J.; Leong, K. W. Poly(phosphoester) Ionomers as Tissue-Engineering Scaffolds. J. Biomed. Mater. Res. 2004, 70B, 91− 102. (116) Stiriba, S.-E.; Frey, H.; Haag, R. Dendritic Polymers in Biomedical Applications: From Potential to Clinical Use in Diagnostics and Therapy. Angew. Chem., Int. Ed. 2002, 41, 1329−1334. (117) Chua, G. B. H.; Roth, P. J.; Duong, H. T. T.; Davis, T. P.; Lowe, A. B. Synthesis and Thermoresponsive Solution Properties of Poly[oligo(ethylene Glycol) (meth)acrylamide]s: Biocompatible PEG Analogues. Macromolecules 2012, 45, 1362−1374. (118) Stangl, M.; Hemmelmann, M.; Allmeroth, M.; Zentel, R.; Schneider, D. A Minimal Hydrophobicity Is Needed to Employ Amphiphilic p(HPMA)-co-p(LMA) Random Copolymers in Membrane Research. Biochemistry 2014, 53, 1410−1419. (119) Hemmelmann, M.; Kurzbach, D.; Koynov, K.; Hinderberger, D.; Zentel, R. Aggregation Behavior of Amphiphilic p(HPMA)-cop(LMA) Copolymers Studied by FCS and EPR Spectroscopy. Biomacromolecules 2012, 13, 4065−4074. (120) Chiu, H. C.; Lin, Y. W.; Huang, Y. F.; Chuang, C. K.; Chern, C. S. Polymer Vesicles Containing Small Vesicles within Interior Aqueous Compartments and pH-Responsive Transmembrane Channels. Angew. Chem., Int. Ed. 2008, 47, 1875−1878. (121) Hemmelmann, M.; Mohr, K.; Fischer, K.; Zentel, R.; Schmidt, M. Interaction of pHPMA − pLMA Copolymers with Human Blood Serum and Its Components. Mol. Pharmaceutics 2013, 10, 3769. (122) Dan, K.; Rajdev, P.; Deb, J.; Jana, S. S.; Ghosh, S. Remarkably Stable Amphiphilic Random Copolymer Assemblies: A StructureProperty Relationship Study. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4932−4943. (123) Dan, K.; Bose, N.; Ghosh, S. Vesicular Assembly and ThermoResponsive Vesicle-to-Micelle Transition from an Amphiphilic Random Copolymer. Chem. Commun. 2011, 47, 12491−12493. (124) Marcelo, G.; Martinho, J. M. G.; Farinha, J. P. S. PolymerCoated Nanoparticles by Adsorption of Hydrophobically Modified poly(N,N-Dimethylacrylamide). J. Phys. Chem. B 2013, 117, 3416− 3427. (125) Zhang, Q.; Schattling, P.; Theato, P.; Hoogenboom, R. Tuning the Upper Critical Solution Temperature Behavior of Poly(methyl Methacrylate) in Aqueous Ethanol by Modification of an Activated Ester Comonomer. Polym. Chem. 2012, 3, 1418−1426. (126) Schild, H. G. Poly(N-Isopropylacrylamide): Experiment, Theory and Application. Prog. Polym. Sci. 1992, 17, 163−249. (127) Ohashi, H.; Hiraoka, Y.; Yamaguchi, T. An Autonomous Phase Transition-Complexation/decomplexation Polymer System with a Molecular Recognition Property. Macromolecules 2006, 39, 2614− 2620. (128) Leon, C. M.; Lee, B. H.; Preul, M.; McLemore, R.; Vernon, B. L. Synthesis and Characterization of Radio-Opaque Thermosensitive poly[N-Isopropylacrylamide-2,2′-(ethylenedioxy)bis(ethylamine)2,3,5-Triiodobenzamide]. Polym. Int. 2009, 58, 847−850. (129) Relógio, P.; Martinho, J. M. G.; Farinha, J. P. S. Effect of Surfactant on the Intra- and Intermolecular Association of Hydrophobically Modified Poly(N, N-Dimethylacrylamide). Macromolecules 2005, 38, 10799−10811. (130) Mao, H.; Li, C.; Zhang, Y.; Furyk, S.; Cremer, P. S.; Bergbreiter, D. E. High-Throughput Studies of the Effects of Polymer Structure and Solution Components on the Phase Separation of Thermoresponsive Polymers. Macromolecules 2004, 37, 1031−1036. (131) Bergbreiter, D. E.; Hughes, R.; Besinaiz, J.; Li, C.; Osburn, P. L. Phase-Selective Solubility of poly(N-Alkylacrylamide)s. J. Am. Chem. Soc. 2003, 125, 8244−8249. (132) Etika, K. C.; Jochum, F. D.; Cox, M. A.; Schattling, P.; Theato, P.; Grunlan, J. C. Nanotube Friendly Poly(N-Isopropylacrylamide). Macromol. Rapid Commun. 2010, 31, 1368−1372. AV



Chemical Reviews

Review

(133) Etika, K. C.; Jochum, F. D.; Cox, M. A.; Schattling, P.; Theato, P.; Grunlan, J. C. Tailoring Properties of Carbon Nanotube Dispersions and Nanocomposites Using Temperature-Responsive Copolymers of Pyrene-Modified Poly(N-Cyclopropylacrylamide). Macromolecules 2010, 43, 9447−9453. (134) Desponds, A.; Freitag, R. Light-Responsive Bioconjugates as Novel Tools for Specific Capture of Biologicals by Photoaffinity Precipitation. Biotechnol. Bioeng. 2005, 91, 583−591. (135) Sun, J.; Ruchmann, J.; Pallier, A.; Jullien, L.; Desmadril, M.; Tribet, C. Unfolding of Cytochrome c upon Interaction with Azobenzene-Modified Copolymers. Biomacromolecules 2012, 13, 3736−3746. (136) Jochum, F. D.; Theato, P. Temperature and Light Sensitive Copolymers Containing Azobenzene Moieties Prepared via a Polymer Analogous Reaction. Polymer 2009, 50, 3079−3085. (137) Yang, Y.; Mijalis, A. J.; Fu, H.; Agosto, C.; Tan, K. J.; Batteas, J. D.; Bergbreiter, D. E. Reversible Changes in Solution pH Resulting from Changes in Thermoresponsive Polymer Solubility. J. Am. Chem. Soc. 2012, 134, 7378−7383. (138) Marie, E.; Tribet, C. Reverse Variation of Cloud Points of Light-Responsive Assemblies of Azobenzene-Modified Amphiphilic Polymers. Chem. Lett. 2012, 41, 1093−1095. (139) Liu, Y.-J.; Pallier, A.; Sun, J.; Rudiuk, S.; Baigl, D.; Piel, M.; Marie, E.; Tribet, C. Non-Monotonous Variation of the LCST of Light-Responsive, Amphiphilic poly(NIPAM) Derivatives. Soft Matter 2012, 8, 8446−8455. (140) Desponds, A.; Freitag, R. Synthesis and Characterization of Photoresponsive N-Isopropylacrylamide Cotelomers. Langmuir 2003, 19, 6261−6270. (141) Jochum, F. D.; Forst, F. R.; Theato, P. PNIPAM Copolymers Containing Light-Responsive Chromophores: A Method toward Molecular Logic Gates. Macromol. Rapid Commun. 2010, 31, 1456− 1461. (142) Jochum, F. D.; Theato, P. Temperature- and Light-Responsive Polyacrylamides Prepared by a Double Polymer Analogous Reaction of Activated Ester Polymers. Macromolecules 2009, 42, 5941−5945. (143) Uğuzdoğan, E.; Kayi, H.; Denkbaş, E. B.; Patir, S.; Tuncel, A. Stimuli-Responsive Properties of Aminophenylboronic Acid-Carrying Thermosensitive Copolymers. Polym. Int. 2003, 52, 649−657. (144) Pérez-Alvarez, L.; Sáez-Martínez, V.; Hernaez, E.; Herrero, M.; Katime, I. Specific pH-Responsive Folate-Conjugate Microgels Designed for Antitumor Therapy. Macromol. Chem. Phys. 2009, 210, 467−477. (145) Sáez-Martínez, V.; Pérez-Alvarez, L.; Hernáez, E.; Herrero, T.; Katime, I. Synthesis, Characterization, and Influence of Synthesis Parameters on Particle Sizes of a New Microgel Family. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 3833−3842. (146) Pérez-Á lvarez, L.; Sáez-Martínez, V.; Hernáez, E.; Katime, I. Novel pH- and Temperature-Responsive Methacrylamide Microgels. Macromol. Chem. Phys. 2009, 210, 1120−1126. (147) Sáez-Martínez, V.; Pérez-Á lvarez, L.; Merrero, M. T.; Hernáez, E.; Katime, I. pH-Sensitive Microgels Functionalized with Folic Acid. Eur. Polym. J. 2008, 44, 1309−1322. (148) Pérez-Á lvarez, L.; Sáez-Martínez, V.; Hernáez, E.; Katime, I. Synthesis and Characterization of pH-Sensitive Microgels by Derivatization of Npa-Based Reactive Copolymers. Mater. Chem. Phys. 2008, 112, 516−524. (149) Overstreet, D. J.; Dhruv, H. D.; Vernon, B. L. Bioresponsive Copolymers of Poly (N-Isopropylacrylamide) with Enzyme-Dependent Lower Critical Solution Temperatures. Biomacromolecules 2010, 11, 1154−1159. (150) Fu, H.; Policarpio, D. M.; Batteas, J. D.; Bergbreiter, D. E. Redox-Controlled “smart” Polyacrylamide Solubility. Polym. Chem. 2010, 1, 631. (151) Schattling, P.; Jochum, F. D.; Theato, P. Multi-Responsive Copolymers: Using Thermo-, Light- and Redox Stimuli as Three Independent Inputs towards Polymeric Information Processing. Chem. Commun. 2011, 47, 8859−8861.

(152) Beija, M.; Li, Y.; Lowe, A. B.; Davis, T. P.; Boyer, C. Factors Influencing the Synthesis and the Post-Modification of PEGylated Pentafluorophenyl Acrylate Containing Copolymers. Eur. Polym. J. 2013, 49, 3060−3071. (153) Onoda, M.; Uchiyama, S.; Ohwada, T. Fluorogenic Ion Sensing System Working in Water, Based on Stimulus-Responsive Copolymers Incorporating a Polarity-Sensitive Fluorophore. Macromolecules 2007, 40, 9651−9657. (154) Gunkel, G.; Huck, W. T. S. Cooperative Adsorption of Lipoprotein Phospholipids, Triglycerides, and Cholesteryl Esters Are a Key Factor in Nonspecific Adsorption from Blood Plasma to Antifouling Polymer Surfaces. J. Am. Chem. Soc. 2013, 135, 7047− 7052. (155) Lalani, R.; Liu, L. Electrospun Zwitterionic Poly(Sulfobetaine Methacrylate) for Nonadherent, Superabsorbent, and Antimicrobial Wound Dressing Applications. Biomacromolecules 2012, 13, 1853− 1863. (156) Fang, J.; Wallikewitz, B. H.; Gao, F.; Tu, G.; Müller, C.; Pace, G.; Friend, R. H.; Huck, W. T. S. Conjugated Zwitterionic Polyelectrolyte as the Charge Injection Layer for High-Performance Polymer Light-Emitting Diodes. J. Am. Chem. Soc. 2011, 133, 683− 685. (157) Woodfield, P. A.; Zhu, Y.; Pei, Y.; Roth, P. J. Hydrophobically Modified Sulfobetaine Copolymers with Tunable Aqueous UCST through Postpolymerization Modification of Poly(pentafluorophenyl Acrylate). Macromolecules 2014, 47, 750−762. (158) Dai, F.; Liu, W. Enhanced Gene Transfection and Serum Stability of Polyplexes by PDMAEMA-Polysulfobetaine Diblock Copolymers. Biomaterials 2011, 32, 628−638. (159) Hamley, I. In Block Copolymers in Solution: Fundamentals and Applications; Hamley, I., Ed.; John Wiley & Sons, Ltd.: New York, 2012. (160) O’ Reilly, R. K.; Hawker, C. J.; Wooley, K. L. Cross-Linked Block Copolymer Micelles: Functional Nanostructures of Great Potential and Versatility. Chem. Soc. Rev. 2006, 35, 1068−1083. (161) Moffitt, M.; Khougaz, K.; Eisenberg, A. Micellization of Ionic Block Copolymers. Acc. Chem. Res. 1996, 29, 95−102. (162) Esser-Kahn, A. P.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Triggered Release from Polymer Capsules. Macromolecules 2011, 44, 5539−5553. (163) Elsabahy, M.; Wooley, K. L. Design of Polymeric Nanoparticles for Biomedical Delivery Applications. Chem. Soc. Rev. 2012, 41, 2545−2561. (164) Zalusky, A. S.; Olayo-Valles, R.; Wolf, J. H.; Hillmyer, M. A. Ordered Nanoporous Polymers from Polystyrene-Polylactide Block Copolymers. J. Am. Chem. Soc. 2002, 124, 12761−12773. (165) Bang, J.; Jeong, U.; Ryu, D. Y.; Russell, T. P.; Hawker, C. J. Block Copolymer Nanolithography: Translation of Molecular Level Control to Nanoscale Patterns. Adv. Mater. 2009, 21, 4769−4792. (166) Romulus, J.; Henssler, J. T.; Weck, M. Postpolymerization Modification of Block Copolymers. Macromolecules 2014, 47, 5437− 5449. (167) Engler, A. C.; Chan, J. M. W.; Coady, D. J.; O’Brien, J. M.; Sardon, H.; Nelson, A.; Sanders, D. P.; Yang, Y. Y.; Hedrick, J. L. Accessing New Materials through Polymerization and Modification of a Polycarbonate with a Pendant Activated Ester. Macromolecules 2013, 46, 1283−1290. (168) Rademacher, J. T.; Baum, M.; Pallack, M. E.; Brittain, W. J.; Simonsick, W. J. Atom Transfer Radical Polymerization of N, NDimethylacrylamide. Macromolecules 2000, 33, 284−288. (169) Shunmugam, R.; Tew, G. N. Efficient Route to WellCharacterized Homo, Block, and Statistical Polymers Containing Terpyridine in the Side Chain. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 5831−5843. (170) Tew, G. N.; Aamer, K. A.; Shunmugam, R. Incorporation of Terpyridine into the Side Chain of Copolymers to Create MultiFunctional Materials. Polymer 2005, 46 (19), 8440−8447. (171) Schneider, Y.; Modestino, M. A.; McCulloch, B. L.; Hoarfrost, M. L.; Hess, R. W.; Segalman, R. A. Ionic Conduction in AW



Chemical Reviews

Review

Nanostructured Membranes Based on Polymerized Protic Ionic Liquids. Macromolecules 2013, 46, 1543−1548. (172) Klaikherd, A.; Ghosh, S.; Thayumanavan, S. A Facile Method for the Synthesis of Cleavable Block Copolymers from ATRP-Based Homopolymers. Macromolecules 2007, 40, 8518−8520. (173) Chae, S.; Kim, J.-H.; Theato, P.; Zentel, R.; Sohn, B.-H. Dual Functionalization of Nanostructures of Block Copolymers with Quantum Dots and Organic Fluorophores. Macromol. Chem. Phys. 2014, 215, 654−661. (174) Meuer, S.; Oberle, P.; Theato, P.; Tremel, W.; Zentel, R. Liquid Crystalline Phases from Polymer-Functionalized TiO2 Nanorods. Adv. Mater. 2007, 19, 2073−2078. (175) Zorn, M.; Meuer, S.; Tahir, M. N.; Khalavka, Y.; Sönnichsen, C.; Tremel, W.; Zentel, R. Liquid Crystalline Phases from Polymer Functionalised Semiconducting Nanorods. J. Mater. Chem. 2008, 18, 3050−3058. (176) Zorn, M.; Tahir, M. N.; Bergmann, B.; Tremel, W.; Grigoriadis, C.; Floudas, G.; Zentel, R. Orientation and Dynamics of ZnO Nanorod Liquid Crystals in Electric Fields. Macromol. Rapid Commun. 2010, 31, 1101−1107. (177) Oschmann, B.; Bresser, D.; Tahir, M. N.; Fischer, K.; Tremel, W.; Passerini, S.; Zentel, R. Polyacrylonitrile Block Copolymers for the Preparation of a Thin Carbon Coating Around TiO2 Nanorods for Advanced Lithium-Ion Batteries. Macromol. Rapid Commun. 2013, 34, 1693−1700. (178) Meuer, S.; Fischer, K.; Mey, I.; Janshoff, A.; Schmidt, M.; Zentel, R. Liquid Crystals from Polymer-Functionalized TiO2 Nanorod Mesogens. Macromolecules 2008, 41, 7946−7952. (179) Zorn, M.; Weber, S. A. L.; Tahir, M. N.; Tremel, W.; Butt, H.J.; Berger, R.; Zentel, R. Light Induced Charging of Polymer Functionalized Nanorods. Nano Lett. 2010, 10, 2812−2816. (180) Borg, L. Z.; Domanski, A. L.; Breivogel, A.; Bürger, M.; Berger, R.; Heinze, K.; Zentel, R. Light-Induced Charge Separation in a Donor−chromophore−acceptor Nanocomposite poly[TPA-Ru(tpy)2]@ZnO. J. Mater. Chem. C 2013, 1, 1223−1230. (181) Nilles, K.; Theato, P. Polymerization of an Activated Ester Monomer Based on 4-Vinylsulfonic Acid and Its Polymer Analogous Reaction. Polym. Chem. 2011, 2, 376−384. (182) Lin, Y.-L.; Jiang, G.; Birrell, L. K.; El-Sayed, M. E. H. Degradable, pH-Sensitive, Membrane-Destabilizing, Comb-like Polymers for Intracellular Delivery of Nucleic Acids. Biomaterials 2010, 31, 7150−7166. (183) Yoshioka, H.; Mikami, M.; Mori, Y.; Tsuchida, E. Preparation of Poly(N-Msopropylacrylamide)-B-Poly(Ethylene Glycol) and Calorimetric Analysis of Its Aqueous Solution. J. Macromol. Sci., Part A: Pure Appl.Chem. 1994, 31, 109−112. (184) Hasneen, A.; Cho, I. S.; Kim, K. W.; Paik, H. J. Synthesis of Poly(ethylene Glycol)-b-Poly(mercapto Ethylacrylamide) Diblock Copolymer via Atom Transfer Radical Polymerization. Polym. Bull. 2012, 68, 681−691. (185) Tang, X.; Hu, Y.; Pan, C. Multiple Morphologies of SelfAssembled Star Aggregates of Amphiphilic PEO-b-PNPMA Diblock Copolymers in Solution, Synthesis and Micellization. Polymer 2007, 48, 6354−6365. (186) Basak, D.; Ghosh, S. pH-Regulated Controlled Swelling and Sustained Release from the Core Functionalized Amphiphilic Block Copolymer Micelle. ACS Macro Lett. 2013, 2, 799−804. (187) Zhou, Z.; Bong, D. Small-Molecule/Polymer Recognition Triggers Aqueous-Phase Assembly and Encapsulation. Langmuir 2013, 29, 144−150. (188) Yan, Q.; Zhou, R.; Fu, C.; Zhang, H.; Yin, Y.; Yuan, J. CO2Responsive Polymeric Vesicles that Breathe. Angew. Chem., Int. Ed. 2011, 50, 4923−4927. (189) Ahmed, E.; Morton, S. W.; Hammond, P. T.; Swager, T. M. Fluorescent Multiblock Π-Conjugated Polymer Nanoparticles for In Vivo Tumor Targeting. Adv. Mater. 2013, 25, 4504−4510. (190) Cordovilla, C.; Swager, T. M. Strain Release in Organic Photonic Nanoparticles for Protease Sensing. J. Am. Chem. Soc. 2012, 134, 6932−6935.

(191) Utama, R. H.; Drechsler, M.; Förster, S.; Zetterlund, P. B.; Stenzel, M. H. Synthesis of pH-Responsive Nanocapsules via Inverse Miniemulsion Periphery RAFT Polymerization and Post-Polymerization Reaction. ACS Macro Lett. 2014, 3, 935−939. (192) Yu, R.; Zhao, H.; Zhao, Z.; Wan, Y.; Yuan, H.; Lan, M.; Lindoy, L. F.; Wei, G. A pH Dependent Thermo-Sensitive Copolymer Drug Carrier Incorporating 4-Amino-2,2,6,6-Tetramethylpiperidin-1-Oxyl (4-NH2-TEMPO) Residues for Electron Spin Resonance (ESR) Labeling. J. Colloid Interface Sci. 2011, 362, 584−593. (193) De Lambert, B.; Chaix, C.; Charreyre, M.-T.; Laurent, A.; Aigoui, A.; Perrin-Rubens, A.; Pichot, C. Polymer-Oligonucleotide Conjugate Synthesis from an Amphiphilic Block Copolymer. Applications to DNA Detection on Microarray. Bioconjugate Chem. 2005, 16, 265−274. (194) Handke, N.; Trimaille, T.; Luciani, E.; Rollet, M.; Delair, T.; Verrier, B.; Bertin, D.; Gigmes, D. Elaboration of Densely Functionalized Polylactide Nanoparticles from N-Acryloxysuccinimide-Based Block Copolymers. J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 1341−1350. (195) Chen, C.-Y.; Kim, T. H.; Wu, W.-C.; Huang, C.-M.; Wei, H.; Mount, C. W.; Tian, Y.; Jang, S.-H.; Pun, S. H.; Jen, A. K.-Y. pHDependent, Thermosensitive Polymeric Nanocarriers for Drug Delivery to Solid Tumors. Biomaterials 2013, 34, 4501−4509. (196) Quan, C.-Y.; Wu, D.-Q.; Chang, C.; Zhang, G.-B.; Cheng, S.X.; Zhang, X.-Z.; Zhuo, R.-X. Synthesis of Thermo-Sensitive Micellar Aggregates Self-Assembled from Biotinylated PNAS-b-PNIPAAm-bPCL Triblock Copolymers for Tumor Targeting. J. Phys. Chem. C 2009, 113, 11262−11267. (197) Messerschmidt, M.; Komber, H.; Häußler, L.; Hanzelmann, C.; Stamm, M.; Raether, B.; da Costa e Silva, O.; Uhlmann, P. Amphiphilic ABC Triblock Copolymers Tailored via RAFT Polymerization as Textile Surface Modifiers with Dual-Action Properties. Macromolecules 2013, 46, 2616−2627. (198) Ku, T.-H.; Chien, M.-P.; Thompson, M. P.; Sinkovits, R. S.; Olson, N. H.; Baker, T. S.; Gianneschi, N. C. Controlling and Switching the Morphology of Micellar Nanoparticles with Enzymes. J. Am. Chem. Soc. 2011, 133, 8392−8395. (199) Carrillo, A.; Yanjarappa, M. J.; Gujraty, K. V.; Kane, R. S. Biofunctionalized Block Copolymer Nanoparticles Based on RingOpening Metathesis Polymerization. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 928−939. (200) Das, A.; Ghosh, S. Luminescent Invertible Polymersome by Remarkably Stable Supramolecular Assembly of Naphthalene Diimide (NDI) Π-System. Macromolecules 2013, 46, 3939−3949. (201) Xu, J.; Tao, L.; Boyer, C.; Lowe, A. B.; Davis, T. P. Facile Access to Polymeric Vesicular Nanostructures: Remarkable Ω-End Group Effects in Cholesterol and Pyrene Functional (Co)Polymers. Macromolecules 2011, 44, 299−312. (202) Sun, J.; Jia, L.; Emond, M.; Li, M.-H.; Marie, E.; Jullien, L.; Tribet, C. Photocontrolled Ionization in the Corona of Rodlike Assemblies of Diblock Copolymers. Macromolecules 2014, 47, 1684− 1692. (203) Lu, X.; Watts, E.; Jia, F.; Tan, X.; Zhang, K. Polycondensation of Polymer Brushes via DNA Hybridization. J. Am. Chem. Soc. 2014, 136, 10214−10217. (204) Roth, P. J.; Quek, J. Y.; Zhu, Y.; Blunden, B. M.; Lowe, A. B. Mechano-Responsive Polymer Solutions Based on CO2 Supersaturation: Shaking-Induced Phase Transitions and Self-Assembly or Dissociation of Polymeric Nanoparticles. Chem. Commun. 2014, 50, 9561−9564. (205) Quek, J. Y.; Roth, P. J.; Evans, R. A.; Davis, T. P.; Lowe, A. B. Reversible Addition−Fragmentation Chain Transfer Synthesis of Amidine-Based, CO2-Responsive Homo and AB Diblock (Co)Polymers Comprised of Histamine and Their Gas-Triggered SelfAssembly in Water Self-Assembly in Water. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 394−404. (206) Schattling, P.; Pollmann, I.; Theato, P. Synthesis of CO2Responsive Polymers by Post-Polymerization Modification. React. Funct. Polym. 2014, 75, 16−21. AX



Chemical Reviews

Review

(207) Lin, S.; Schattling, P.; Theato, P. Thermo- and CO2Responsive Linear Polymers and Hydrogels as CO2 Capturing Materials. Sci. Adv. Mater. 2015, 7, 948−955. (208) Basuki, J. S.; Duong, H. T. T.; MacMillan, A.; Whan, R.; Boyer, C.; Davis, T. P. Polymer-Grafted, Nonfouling, Magnetic Nanoparticles Designed to Selectively Store and Release Molecules via Ionic Interactions. Macromolecules 2013, 46, 7043−7054. (209) Nuhn, L.; Hartmann, S.; Palitzsch, B.; Gerlitzki, B.; Schmitt, E.; Zentel, R.; Kunz, H. Water-Soluble Polymers Coupled with Glycopeptide Antigens and T-Cell Epitopes as Potential Antitumor Vaccines. Angew. Chem., Int. Ed. 2013, 52, 10652−10656. (210) Barz, M.; Tarantola, M.; Fischer, K.; Schmidt, M.; Luxenhofer, R.; Janshoff, A.; Theato, P.; Zentel, R. From Defined Reactive Diblock Copolymers to Functional HPMA-Based Self-Assembled Nanoaggregates. Biomacromolecules 2008, 9, 3114−3118. (211) Herth, M. M.; Barz, M.; Moderegger, D.; Allmeroth, M.; Jahn, M.; Thews, O.; Zentel, R.; Rösch, F. Radioactive Labeling of Defined HPMA-Based Polymeric Structures Using [18F]FETos for In Vivo Imaging by Positron Emission Tomography. Biomacromolecules 2009, 10, 1697−1703. (212) Scheibe, P.; Barz, M.; Hemmelmann, M.; Zentel, R. LangmuirBlodgett Films of Biocompatible Poly(HPMA)-Block-Poly(lauryl Methacrylate) and Poly(HPMA)-Random-Poly(lauryl Methacrylate): Influence of Polymer Structure on Membrane Formation and Stability. Langmuir 2010, 26, 5661−5669. (213) Kelsch, A.; Tomcin, S.; Rausch, K.; Barz, M.; Mailänder, V.; Schmidt, M.; Landfester, K.; Zentel, R. HPMA Copolymers as Surfactants in the Preparation of Biocompatible Nanoparticles for Biomedical Application. Biomacromolecules 2012, 13, 4179−4187. (214) Allmeroth, M.; Moderegger, D.; Gündel, D.; Koynov, K.; Buchholz, H. G.; Mohr, K.; Rösch, F.; Zentel, R.; Thews, O. HPMALMA Copolymer Drug Carriers in Oncology: An in Vivo PET Study to Assess the Tumor Line-Specific Polymer Uptake and Body Distribution. Biomacromolecules 2013, 14, 3091−3101. (215) Zhang, K.; Lackey, M. a.; Wu, Y.; Tew, G. N. Universal Cyclic Polymer Templates. J. Am. Chem. Soc. 2011, 133, 6906−6909. (216) Altintas, O.; Vogt, A. P.; Barner-Kowollik, C.; Tunca, U. Constructing Star Polymers via Modular Ligation Strategies. Polym. Chem. 2012, 3, 34−45. (217) Cameron, D. J. A.; Shaver, M. P. Aliphatic Polyester Polymer Stars: Synthesis, Properties and Applications in Biomedicine and Nanotechnology. Chem. Soc. Rev. 2011, 40, 1761−1776. (218) Lahann, J. Vapor Based Polymer Coatings for Potential Biomedical Applications. Polym. Int. 2006, 55, 1361−1370. (219) Börner, H. G.; Sütterlin, R. I.; Theato, P.; Wiss, K. T. Topology-Dependent Swichability of Peptide Secondary Structures in Bioconjugates with Complex Architectures. Macromol. Rapid Commun. 2014, 35, 180−185. (220) Li, Y.; Beija, M.; Laurent, S.; Elst, L. V.; Muller, R. N.; Duong, H. T. T.; Lowe, A. B.; Davis, T. P.; Boyer, C. Macromolecular Ligands for Gadolinium MRI Contrast Agents. Macromolecules 2012, 45, 4196−4204. (221) Wei, H.; Zhang, X.-Z.; Chen, W.-Q.; Cheng, S.-X.; Zhuo, R.-X. Self-Assembled Thermosensitive Micelles Based on poly(L-LactideStar block-N-Isopropylacrylamide) for Drug Delivery. J. Biomed. Mater. Res., Part A 2007, 83A, 980−989. (222) Wei, H.; Zhang, X.; Cheng, C.; Cheng, S. X.; Zhuo, R. X. SelfAssembled, Thermosensitive Micelles of a Star Block Copolymer Based on PMMA and PNIPAAm for Controlled Drug Delivery. Biomaterials 2007, 28, 99−107. (223) Wei, H.; Chen, W. Q.; Chang, C.; Cheng, C.; Cheng, S. X.; Zhang, X. Z.; Zhuo, R. X. Synthesis of Star Block, Thermosensitive poly(L-Lactide)-Star block-poly(N-Isopropylacrylamide-co-N-Hydroxymethylacrylamide) Copolymers and Their Self-Assembled Micelles for Controlled Release. J. Phys. Chem. C 2008, 112, 2888−2894. (224) Yu, X.; Tang, X.; Pan, C. Synthesis, Characterization and SelfAssembly Behavior of Six-Armed Star Block Copolymers with Triphenylene Core. Polymer 2005, 46, 11149−11156.

(225) Zheng, Q.; Pan, C.-Y. Synthesis and Characterization of Dendrimer-Star Polymer Using Dithiobenzoate-Terminated Poly(propylene Imine) Dendrimer via Reversible Addition-Fragmentation Transfer Polymerization. Macromolecules 2005, 38, 6841−6848. (226) Zheng, Q.; Pan, C. Preparation and Characterization of Dendrimer-Star PNIPAAM Using Dithiobenzoate-Terminated PPI Dendrimer via RAFT Polymerization. Eur. Polym. J. 2006, 42, 807− 814. (227) Chen, G.; Huynh, D.; Felgner, P. L.; Guan, Z. Tandem Chain Walking Polymerization and Atom Transfer Radical Polymerization for Efficient Synthesis of Dendritic Nanoparticles for Bioconjugation. J. Am. Chem. Soc. 2006, 128, 4298−4302. (228) Boyer, C.; Whittaker, M.; Davis, T. P. Synthesis and Postfunctionalization of Well-Defined Star Polymers via “‘Double’” Click Chemistry. J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 5245− 5256. (229) Fukukawa, K.; Rossin, R.; Hagooly, A.; Pressly, E. D.; Hunt, J. N.; Messmore, B. W.; Wooley, K. L.; Welch, M. J.; Hawker, C. J. Synthesis and Characterization of Core − Shell Star Copolymers for In Vivo PET Imaging Applications. Biomacromolecules 2008, 9, 1329− 1339. (230) Lv, W.; Liu, L.; Luo, Y.; Wang, X.; Liu, Y. Biotinylated Thermoresponsive Core Cross-Linked Nanoparticles via RAFT Polymerization and “Click” Chemistry. J. Colloid Interface Sci. 2011, 356, 16−23. (231) Harvison, M. A.; Roth, P. J.; Davis, T. P.; Lowe, A. B. End Group Reactions of RAFT-Prepared (Co)polymers. Aust. J. Chem. 2011, 64, 992−1006. (232) Boyer, C.; Bulmus, V.; Davis, T. P.; Ladmiral, V.; Liu, J.; Perrier, S. Bioapplications of RAFT Polymerization. Chem. Rev. 2009, 109, 5402−5436. (233) Mansfeld, U.; Pietsch, C.; Hoogenboom, R.; Becer, C. R.; Schubert, U. S. Clickable Initiators, Monomers and Polymers in Controlled Radical Polymerizations − a Prospective Combination in Polymer Science. Polym. Chem. 2010, 1, 1560−1598. (234) Lecolley, F.; Tao, L.; Mantovani, G.; Durkin, I.; Lautru, S.; Haddleton, D. M. A New Approach to Bioconjugates for Proteins and Peptides (“pegylation”) Utilising Living Radical Polymerisation. Chem. Commun. 2004, 2026−2027. (235) Ladmiral, V.; Monaghan, L.; Mantovani, G.; Haddleton, D. M. A-Functional Glycopolymers: New Materials for (poly)peptide Conjugation. Polymer 2005, 46, 8536−8545. (236) Nicolas, J.; Miguel, V. S.; Mantovani, G.; Haddleton, D. M. Fluorescently Tagged Polymer Bioconjugates from Protein Derived Macroinitiators. Chem. Commun. 2006, 4697−4699. (237) Nicolas, J.; Khoshdel, E.; Haddleton, D. M. Bioconjugation onto Biological Surfaces with Fluorescently Labeled Polymers. Chem. Commun. 2007, 1722−1724. (238) Zarafshani, Z.; Obata, T.; Lutz, J.-F. Smart PEGylation of Trypsin. Biomacromolecules 2010, 11, 2130−2135. (239) Samanta, D.; McRae, S.; Cooper, B.; Hu, Y.; Emrick, T.; Pratt, J.; Charles, S. A. End-Functionalized Phosphorylcholine Methacrylates and Their Use in Protein Conjugation. Biomacromolecules 2008, 9, 2891−2897. (240) Lewis, A.; Tang, Y.; Brocchini, S.; Choi, J.; Godwin, A. Poly(2Methacryloyloxyethyl Phosphorylcholine) for Protein Conjugation. Bioconjugate Chem. 2008, 19, 2144−2155. (241) Conradi, M.; Junkers, T. Fast and Efficient [2 + 2] UV Cycloaddition for Polymer Modification via Flow Synthesis. Macromolecules 2014, 47, 5578−5585. (242) Li, H.; Bapat, A. P.; Li, M.; Sumerlin, B. S. Protein Conjugation of Thermoresponsive Amine-Reactive Polymers Prepared by RAFT. Polym. Chem. 2011, 2, 323−327. (243) Li, H.; Li, M.; Yu, X.; Bapat, A. P.; Sumerlin, B. S. Block Copolymer Conjugates Prepared by Sequentially Grafting from Proteins via RAFT. Polym. Chem. 2011, 2, 1531−1535. (244) Bathfield, M.; D’Agosto, F.; Spitz, R.; Charreyre, M.-T.; Delair, T. Versatile Precursors of Functional RAFT Agents. Application to the AY



Chemical Reviews

Review

Synthesis of Bio-Related End-Functionalized Polymers. J. Am. Chem. Soc. 2006, 128, 2546−2547. (245) Jia, Z.; Bobrin, V. A.; Truong, N. P.; Gillard, M.; Monteiro, M. J. Multifunctional Nanoworms and Nanorods through a One-Step Aqueous Dispersion Polymerization. J. Am. Chem. Soc. 2014, 136, 5824−5827. (246) Prazeres, T. J. V; Beija, M.; Charreyre, M.-T.; Farinha, J. P. S.; Martinho, J. M. G. RAFT Polymerization and Self-Assembly of Thermoresponsive poly(N-Decylacrylamide-b-N,N-Diethylacrylamide) Block Copolymers Bearing a Phenanthrene Fluorescent AEnd Group. Polymer 2010, 51, 355−367. (247) Dos Santos, A. M.; Pohn, J.; Lansalot, M.; D’Agosto, F. Combining Steric and Electrostatic Stabilization Using Hydrophilic MacroRAFT Agents in an Ab Initio Emulsion Polymerization of Styrene. Macromol. Rapid Commun. 2007, 28, 1325−1332. (248) You, Y.-Z.; Oupicky, D. Synthesis of Temperature-Responsive Heterobifunctional Block Copolymers of Poly(ethylene Glycol) and Poly(N-Isopropylacrylamide). Biomacromolecules 2007, 8, 98−105. (249) Warren, N. J.; Mykhaylyk, O. O.; Mahmood, D.; Ryan, A. J.; Armes, S. P. RAFT Aqueous Dispersion Polymerization Yields Poly(ethylene Glycol)-Based Diblock Copolymer Nano-Objects with Predictable Single Phase Morphologies. J. Am. Chem. Soc. 2014, 136, 1023−1033. (250) Briquel, R.; Mazzolini, J.; Le Bris, T.; Boyron, O.; Boisson, F.; Delolme, F.; D’Agosto, F.; Boisson, C.; Spitz, R. Polyethylene Building Blocks by Catalyzed Chain Growth and Efficient End Functionalization Strategies, Including Click Chemistry. Angew. Chem., Int. Ed. 2008, 47, 9311−9313. (251) Zhang, X.; Li, J.; Li, W.; Zhang, A. Synthesis and Characterization of Thermo- and pH-Responsive Double-Hydrophilic Diblock Copolypeptides. Biomacromolecules 2007, 8, 3557−3567. (252) Xing, T.; Yan, L. pH-Responsive Amphiphilic Block Copolymer Prodrug Conjugated near Infrared Fluorescence Probe. RSC Adv. 2014, 4, 28186−28194. (253) Godula, K.; Rabuka, D.; Nam, K. T.; Bertozzi, C. R. Synthesis and Microcontact Printing of Dual End-Functionalized Mucin-like Glycopolymers for Microarray Applications. Angew. Chem., Int. Ed. 2009, 48, 4973−4976. (254) Parvole, J.; Ahrens, L.; Blas, H.; Vinas, J.; Boissiere, C.; Sanchez, C.; Save, M.; Charleux, B. Grafting Polymer Chains Bearing an N-Succinimidyl Activated Ester End-Group onto Primary AmineCoated Silica Particles and Application of a Simple, One-Step Approach via Nitroxide-Mediated Controlled/Living Free-Radical Polymerization. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 173−185. (255) Vinas, J.; Chagneux, N.; Gigmes, D.; Trimaille, T.; Favier, A.; Bertin, D. SG1-Based Alkoxyamine Bearing a N-Succinimidyl Ester: A Versatile Tool for Advanced Polymer Synthesis. Polymer 2008, 49, 3639−3647. (256) Yang, H.; Liang, F.; Wang, X.; Chen, Y.; Zhang, C.; Wang, Q.; Qu, X.; Li, J.; Wu, D.; Yang, Z. Responsive Janus Composite Nanosheets. Macromolecules 2013, 46, 2754−2759. (257) Tan, I.; Zarafshani, Z.; Lutz, J.-F.; Titirici, M.-M. PEGylated Chromatography: Efficient Bioseparation on Silica Monoliths Grafted with Smart Biocompatible Polymers. ACS Appl. Mater. Interfaces 2009, 1, 1869−1872. (258) Wiss, K. T.; Theato, P. Facilitating Polymer Conjugation via Combination of RAFT Polymerization and Activated Ester Chemistry. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 4758−4767. (259) Pötzsch, R.; Fleischmann, S.; Tock, C.; Komber, H.; Voit, B. I. Combining RAFT and Staudinger Ligation: A Potentially New Synthetic Tool for Bioconjugate Formation. Macromolecules 2011, 44, 3260−3269. (260) Roth, P. J.; Jochum, F. D.; Theato, P. UCST-Type Behavior of Poly[oligo(ethylene Glycol) Methyl Ether Methacrylate] (POEGMA) in Aliphatic Alcohols: Solvent, Co-Solvent, Molecular Weight, and End Group Dependences. Soft Matter 2011, 7, 2484−2492. (261) Roth, P. J.; Jochum, F. D.; Forst, F. R.; Zentel, R.; Theato, P. Influence of End Groups on the Stimulus-Responsive Behavior of

Poly[oligo(ethylene Glycol) Methacrylate] in Water. Macromolecules 2010, 43, 4638−4645. (262) Roth, P. J.; Jochum, F. D.; Zentel, R.; Theato, P. Synthesis of Hetero-Telechelic α, ω Bio-Functionalized Polymers. Biomacromolecules 2010, 11, 238−244. (263) Roth, P. J.; Haase, M.; Basché, T.; Theato, P.; Zentel, R. Synthesis of Heterotelechelic α,ω Dye-Functionalized Polymer by the RAFT Process and Energy Transfer between the End Groups. Macromolecules 2010, 43, 895−902. (264) Roth, P. J.; Kim, K.-S.; Bae, S. H.; Sohn, B. H.; Theato, P.; Zentel, R. Hetero-Telechelic Dye-Labeled Polymer for Nanoparticle Decoration. Macromol. Rapid Commun. 2009, 30, 1274−1278. (265) Jochum, F. D.; zur Borg, L.; Roth, P. J.; Theato, P. Thermoand Light-Responsive Polymers Containing Photoswitchable Azobenzene End Groups. Macromolecules 2009, 42, 7854−7862. (266) Roth, P. J.; Wiss, K. T.; Zentel, R.; Theato, P. Synthesis of Reactive Telechelic Polymers Based on Pentafluorophenyl Esters. Macromolecules 2008, 41, 8513−8519. (267) Gao, H.; Cheng, T.; Liu, J.; Liu, J.; Yang, C.; Chu, L.; Zhang, Y.; Ma, R.; Shi, L. Self-Regulated Multifunctional Collaboration of Targeted Nanocarriers for Enhanced Tumor Therapy. Biomacromolecules 2014, 15, 3634−3642. (268) Sun, P.; Zhang, Y.; Shi, L.; Gan, Z. Thermosensitive Nanoparticles Self-Assembled from PCL-b-PEO-b-PNIPAAm Triblock Copolymers and Their Potential for Controlled Drug Release. Macromol. Biosci. 2010, 10, 621−631. (269) Wiss, K. T.; Krishna, O. D.; Roth, P. J.; Kiick, K. L.; Theato, P. A Versatile Grafting-to Approach for the Bioconjugation of Polymers to Collagen-like Peptides Using an Activated Ester Chain Transfer Agent Kerstin. Macromolecules 2009, 42, 3860−3863. (270) Krishna, O. D.; Wiss, K. T.; Luo, T.; Pochan, D. J.; Theato, P.; Kiick, K. L. Morphological Transformations in a Dually Thermoresponsive Coil−rod−coil Bioconjugate. Soft Matter 2012, 8, 3832−3840. (271) Liu, J.; Lam, J. W. Y.; Tang, B. Z. Acetylenic Polymers: Syntheses, Structures, and Functions. Chem. Rev. 2009, 109, 5799− 5867. (272) Janata, J.; Josowicz, M. Conducting Polymers in Electronic Chemical Sensors. Nat. Mater. 2003, 2, 19−24. (273) Ates, M.; Karazehir, T.; Sarac, A. S. Conducting Polymers and Their Applications. Curr. Phys. Chem. 2012, 2, 224−240. (274) Lam, J. W. Y.; Tang, B. Z. Functional Polyacetylenes. Acc. Chem. Res. 2005, 38, 745−754. (275) Pauly, A. C.; Theato, P. Synthesis and Characterization of Poly(phenylacetylenes) Featuring Activated Ester Side Groups. J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 211−224. (276) Pauly, A. C.; Theato, P. Control of Reactivity of Constitutional Isomers of Pentafluorophenyl Ethynylbenzoates for the Synthesis of Functional Poly(phenylacetylenes). Polym. Chem. 2012, 3, 1769− 1782. (277) Zhang, X. A.; Chen, M. R.; Zhao, H.; Gao, Y.; Wei, Q.; Zhang, S.; Qin, A.; Sun, J. Z.; Tang, B. Z. A Facile Synthetic Route to Functional Poly(phenylacetylene)s with Tunable Structures and Properties. Macromolecules 2011, 44, 6724−6737. (278) Zhang, X. A.; Qin, A.; Tong, L.; Zhao, H.; Zhao, Q.; Sun, J. Z.; Tang, B. Z. Synthesis of Functional Disubstituted Polyacetylenes Bearing Highly Polar Functionalities via Activated Ester Strategy. ACS Macro Lett. 2012, 1, 75−79. (279) Strong, L. E.; Kiessling, L. L. A General Synthetic Route to Defined, Biologically Active Multivalent Arrays. J. Am. Chem. Soc. 1999, 121, 6193−6196. (280) Owen, R. M.; Gestwicki, J. E.; Young, T.; Kiessling, L. L. Synthesis and Applications of End-Labeled Neoglycopolymers. Org. Lett. 2002, 4, 2293−2296. (281) Gordon, E. J.; Gestwicki, J. E.; Strong, L. E.; Kiessling, L. L. Synthesis of End-Labeled Multivalent Ligands for Exploring CellSurface-Receptor-Ligand Interactions. Chem. Biol. 2000, 7, 9−16. (282) Kolonko, E. M.; Kiessling, L. L. A Polymeric Domain That Promotes Cellular Internalization. J. Am. Chem. Soc. 2008, 130, 5626− 5627. AZ



Chemical Reviews

Review

(283) Tezgel, A. Ö .; Telfer, J. C.; Tew, G. N. De Novo Designed Protein Transduction Domain Mimics from Simple Synthetic Polymers. Biomacromolecules 2011, 12, 3078−3083. (284) Gabriel, G. J.; Madkour, A. E.; Dabkowski, J. M.; Nelson, C. F.; Nüsslein, K.; Tew, G. N. Synthetic Mimic of Antimicrobial Peptide with Nonmembrane-Disrupting Antibacterial Properties. Biomacromolecules 2008, 9, 2980−2983. (285) Drechsler, U.; Thibault, R. J.; Rotello, V. M. Formation of Recognition-Induced Polymersomes Using Complementary Rigid Random Copolymers. Macromolecules 2002, 35, 9621−9623. (286) Vogel, N.; Théato, P. Controlled Synthesis of Reactive Polymeric Architectures Using 5-Norbornene-2-Carboxylic Acid Pentafluorophenyl Ester. Macromol. Symp. 2007, 249−250, 383−391. (287) Carrillo, A.; Yanjarappa, M. J.; Gujraty, K. V.; Kane, R. S. Biofunctionalized Block Copolymer Nanoparticles Based on RingOpening Metathesis Polymerization. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 928−939. (288) Kolonko, E. M.; Pontrello, J. K.; Mangold, S. L.; Kiessling, L. L. General Synthetic Route to Cell-Permeable Block Copolymers via ROMP. J. Am. Chem. Soc. 2009, 131, 7327−7333. (289) Schaefer, M.; Hanik, N.; Kilbinger, A. F. M. ROMP Copolymers for Orthogonal Click Functionalizations. Macromolecules 2012, 45, 6807−6818. (290) Zhou, Y.; Zhuo, R.; Liu, Z. Synthesis and Characterization of Novel Aliphatic Poly (carbonate-Ester)s with Functional Pendent Groups. Macromol. Rapid Commun. 2005, 26, 1309−1314. (291) Sanders, D. P.; Fukushima, K.; Coady, D. J.; Nelson, A.; Fujiwara, M.; Yasumoto, M.; Hedrick, J. L. A Simple and Efficient Synthesis of Functionalized Cyclic Carbonate Monomers Using a Versatile Pentafluorophenyl Ester Intermediate. J. Am. Chem. Soc. 2010, 132, 14724−14726. (292) Engler, A. C.; Tan, J. P. K.; Ong, Z. Y.; Coady, D. J.; Ng, V. W. L.; Yang, Y. Y.; Hedrick, J. L. Antimicrobial Polycarbonates: Investigating the Impact of Balancing Charge and Hydrophobicity Using a Same-Centered Polymer Approach. Biomacromolecules 2013, 14, 4331−4339. (293) Chan, J. M. W.; Sardon, H.; Engler, A. C.; García, J. M.; Hedrick, J. L. Tetra-N-Butylammonium Fluoride as an Efficient Transesterification Catalyst for Functionalizing Cyclic Carbonates and Aliphatic Polycarbonates. ACS Macro Lett. 2013, 2, 860−864. (294) Teo, P. Y.; Yang, C.; Hedrick, J. L.; Engler, A. C.; Coady, D. J.; Ghaem-Maghami, S.; George, A. J. T.; Yang, Y. Y. Hydrophobic Modification of Low Molecular Weight Polyethylenimine for Improved Gene Transfection. Biomaterials 2013, 34, 7971−7979. (295) Engler, A. C.; Ke, X.; Gao, S.; Chan, J. M. W.; Coady, D. J.; Ono, R. J.; Lubbers, R.; Nelson, A.; Yang, Y. Y.; Hedrick, J. L. Hydrophilic Polycarbonates: Promising Degradable Alternatives to Poly(ethylene Glycol)-Based Stealth Materials. Macromolecules 2015, 48, 1673−1678. (296) Engler, A. C.; Chan, J. M. W.; Fukushima, K.; Coady, D. J.; Yang, Y. Y.; Hedrick, J. L. Polycarbonate-Based Brush Polymers with Detachable Disulfide-Linked Side Chains. ACS Macro Lett. 2013, 2, 332−336. (297) Waltman, R. J.; Bargon, J. Electrically Conducting Polymers: A Review of the Electropolymerization Reaction, of the Effects of Chemical Structure on Polymer Film Properties, and of Applications towards Technology. Can. J. Chem. 1986, 64, 76−95. (298) Diaz, A. F.; Kanazawa, K. K.; Gardini, G. P. Electrochemical Polymerization of Pyrrole. J. Chem. Soc., Chem. Commun. 1979, 14, 635−636. (299) Kaneto, K.; Yoshino, K.; Inuishi, Y. Electrical Properties of Conducting Polymer, Poly-Thiophene, Prepared by Electrochemical Polymerization. Jpn. J. Appl. Phys. 1982, 21, L567−L568. (300) Ryder, K. S.; Morris, D. G.; Cooper, J. M. Functionalisation and Characterisation of Novel Conducting Polymer Interfaces. J. Chem. Soc., Chem. Commun. 1995, 14, 1471−1473. (301) Passos, M. S.; Queiros, M. A.; Le Gall, T.; Ibrahim, S. K.; Pickett, C. J. Solid-Phase Chemistry of Electropolymers. J. Electroanal. Chem. 1997, 435, 189−203.

(302) Pickett, C. J.; Ryder, K. S. Bioinorganic Reaction Centres on Electrodes. Modified Electrodes Possessing Amino Acid, Peptide and Ferredoxin-Type Groups on a Poly(pyrrole) Backbone. J. Chem. Soc., Dalton Trans. 1994, 14, 2181−2189. (303) Glidle, A.; Hadyoon, C. S.; Cass, A. E. G.; Cooper, J. M. Modifications of Electrodeposited Polymers by Ion Chelation to Produce Templates for Biomolecule Immobilisation. Electrochim. Acta 2000, 45, 3823−3831. (304) Ibrahim, S. K.; Liu, X.; Tard, C.; Pickett, C. J. Electropolymeric Materials Incorporating Subsite Structures Related to Iron-Only Hydrogenase: Active Ester Functionalised Poly(pyrroles) for Covalent Binding of {2Fe3S}-Carbonyl/cyanide Assemblies. Chem. Commun. 2007, 1535−1537. (305) Le Gall, T.; Passos, M. S.; Ibrahim, S. K.; Morlat-Therias, S.; Sudbrake, C.; Fairhurst, S. A.; Queiros, M. A.; Pickett, C. J. Synthesis of N-Derivatised Pyrroles: Precursors to Highly Functionalised Electropolymers. J. Chem. Soc., Perkin Trans. 1 1999, 1657−1664. (306) Glidle, A.; Bailey, L.; Hadyoon, C. S.; Hillman, A. R.; Jackson, A.; Ryder, K. S.; Saville, P. M.; Swann, M. J.; Webster, J. R. P.; Wilson, R. W.; et al. Temporal and Spatial Profiling of the Modification of an Electroactive Polymeric Interface Using Neutron Reflectivity. Anal. Chem. 2001, 73, 5596−5606. (307) Hadyoon, C. S.; Glidle, A.; Morris, D. G.; Cooper, J. M. Electrochemically Controlled Micropatterning of Immobilised Species on Functionalised Electrode Interfaces. Chem. Commun. 1999, 1683− 1684. (308) Glidle, A.; Pearson, P. E.; Smith, E. L.; Cooper, J. M.; Cubitt, R.; Dalgliesh, R. M.; Hillman, A. R.; Ryder, K. S. Determining Compositional Profiles within Conducting Polymer Films Following Reaction with Vapor Phase Reagents. J. Phys. Chem. B 2007, 111, 4043−4053. (309) Glidle, A.; Swann, M. J.; Hadyoon, C. S.; Cui, L.; Davis, J.; Ryder, K. S.; Cooper, J. M. XPS Assaying of Electrodeposited Copolymer Composition to Optimise Sensor Materials. J. Electron Spectrosc. Relat. Phenom. 2001, 121, 131−148. (310) Glidle, A.; Hadyoon, C. S.; Gadegaard, N.; Cooper, J. M.; Hillman, A. R.; Wilson, R. W.; Ryder, K. S.; Webster, J. R. P.; Cubitt, R. Evaluating the Influence of Deposition Conditions on Solvation of Reactive Conducting Polymers with Neutron Reflectivity. J. Phys. Chem. B 2005, 109, 14335−14343. (311) Li, G.; Bhosale, S.; Tao, S.; Bhosale, S.; Fuhrhop, J. H. Conducting Polythiophenes with a Broad Spectrum of Reactive Groups. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 4547−4558. (312) Li, G.; Koßmehl, G.; Welzel, H.; Plieth, W.; Zhu, H. Synthesis and Electropolymerization of New P-Nitrophenyl-Functionalized Thiophene Derivatives. Macromol. Chem. Phys. 1998, 199, 2737−2746. (313) Li, G.; Koßmehl, G.; Welzel, H.-P.; Engelmann, G.; Hunnius, W.-D.; Plieth, W.; Zhu, H. Reactive Groups on Polymer Coated Electrodes, 8 Novel Conducting Polymer Interfaces Produced by Electrochemical Copolymerization of Functionalized Thiophene Activated Esters with 3-Methylthiophene. Macromol. Chem. Phys. 1998, 199, 2255−2266. (314) Li, G.; Koßmehl, G.; Hunnius, W.; Zhu, H.; Kautek, W.; Plieth, W.; Melsheimer, J.; Doblhofer, K. Reactive Groups on Polymer Coated Electrodes: 10. Electrogenerated Conducting Polyalkylthiophenes Bearing Activated Ester Groups. Polymer 2000, 41, 423−432. (315) Ryder, K. S.; Schweiger, L. F.; Glidle, A.; Cooper, J. M. Strategies towards Functionalised Electronically Conducting Organic Copolymers: Part 2. Copolymerisation. J. Mater. Chem. 2000, 10, 1785−1793. (316) Baek, M.-G.; Stevens, R. C.; Charych, D. H. Design and Synthesis of Novel Glycopolythiophene Assemblies for Colorimetric Detection of Influenza Virus and E. Coli. Bioconjugate Chem. 2000, 11, 777−788. (317) Hiller, M.; Kranz, C.; Huber, J.; Bäuerle, P.; Schuhmann, W. Amperometic Biosensors Produced by Immobilization of Redox Enzymes at Polythiophene-Modified Electrode Surfaces. Adv. Mater. 1996, 8, 219−222. BA



Chemical Reviews

Review

(318) Cha, J.; Han, J. I.; Choi, Y.; Yoon, D. S.; Oh, K. W.; Lim, G. DNA Hybridization Electrochemical Sensor Using Conducting Polymer. Biosens. Bioelectron. 2003, 18, 1241−1247. (319) Peng, T.; Cheng, Q.; Cheng, Q. Determination of Short DNA Oligomers Using an Electrochemical Biosensor with a Conductive Self-Assembled Membrane. Electroanalysis 2002, 14, 455−458. (320) Zhang, L.; Sun, H.; Li, D.; Song, S.; Fan, C.; Wang, S. A Conjugated Polymer-Based Electrochemical DNA Sensor: Design and Application of a Multi-Functional and Water-Soluble Conjugated Polymer. Macromol. Rapid Commun. 2008, 29, 1489−1494. (321) Kaewtong, C.; Jiang, G.; Ponnapati, R.; Pulpoka, B.; Advincula, R. Redox Nanoreactor Dendrimer Boxes: In Situ Hybrid Gold Nanoparticles via Terthiophene and Carbazole Peripheral Dendrimer Oxidation. Soft Matter 2010, 6, 5316−5319. (322) Bélanger, D.; Pinson, J. Electrografting: A Powerful Method for Surface Modification. Chem. Soc. Rev. 2011, 40, 3995−4048. (323) Baute, N.; Teyssié, P.; Martinot, L.; Mertens, M.; Dubois, P.; Jérôme, R. Electrografting of Acrylic and Methacrylic Monomers onto Metals: Influence of the Relative Polarity and Donor−Acceptor Properties of the Monomer and the Solvent. Eur. J. Inorg. Chem. 1998, 1998, 1711−1720. (324) Baute, N.; Jérôme, C.; Martinot, L.; Mertens, M.; Geskin, V. M.; Lazzaroni, R.; Brédas, J.-L.; Jérôme, R. Electrochemical Strategies for the Strengthening of Polymer−Metal Interfaces. Eur. J. Inorg. Chem. 2001, 31, 1097−1107. (325) Jérôme, C.; Gabriel, S.; Voccia, S.; Detrembleur, C.; Ignatova, M.; Gouttebaron, R.; Jérôme, R. Preparation of Reactive Surfaces by Electrografting. Chem. Commun. 2003, 2500−2501. (326) Cuenot, S.; Gabriel, S.; Jerome, R.; Jerome, C.; Fustin, C.-A.; Jonas, A. M.; Duwez, A.-S. First Insights into Electrografted Polymers by AFM-Based Force Spectroscopy. Macromolecules 2006, 39, 8428− 8433. (327) Duwez, A.-S.; Cuenot, S.; Jérôme, C.; Gabriel, S.; Jérôme, R.; Rapino, S.; Zerbetto, F. Mechanochemistry: Targeted Delivery of Single Molecules. Nat. Nanotechnol. 2006, 1, 122−125. (328) Jérôme, C.; Willet, N.; Jérôme, R.; Duwez, A. S. Electrografting of Polymers onto AFM Tips: A Novel Approach for Chemical Force Microscopy and Force Spectroscopy. ChemPhysChem 2004, 5, 147− 149. (329) Cuenot, S.; Gabriel, S.; Jérôme, C.; Jérôme, R.; Duwez, A.-S. Are Electrografted Polymers Chemisorbed or Physisorbed onto Their Substrate? Macromol. Chem. Phys. 2005, 206, 1216−1220. (330) Zhang, Y.; Shen, Y.; Li, J.; Niu, L.; Dong, S.; Ivaska, A. Electrochemical Functionalization of Single-Walled Carbon Nanotubes in Large Quantities at a Room-Temperature Ionic Liquid Supported Three-Dimensional Network Electrode. Langmuir 2005, 21, 4797− 4800. (331) Rapino, S.; Valenti, G.; Marcu, R.; Giorgio, M.; Marcaccio, M.; Paolucci, F. Microdrawing and Highlighting a Reactive Surface. J. Mater. Chem. 2010, 20, 7272−7275. (332) Friedrich, J. Mechanisms of Plasma Polymerization − Reviewed from a Chemical Point of View. Plasma Processes Polym. 2011, 8, 783−802. (333) Duque, L.; Menges, B.; Borros, S.; Förch, R. Immobilization of Biomolecules to Plasma Polymerized Pentafluorophenyl Methacrylate. Biomacromolecules 2010, 11, 2818−2823. (334) Lahann, J.; Balcells, M.; Lu, H.; Rodon, T.; Jensen, K. F.; Langer, R. Reactive Polymer Coatings: A First Step toward Surface Engineering of Microfluidic Devices. Anal. Chem. 2003, 75, 2117− 2122. (335) Francesch, L.; Borros, S.; Knoll, W.; Förch, R. Surface Reactivity of Pulsed-Plasma Polymerized Pentafluorophenyl Methacrylate (PFM) toward Amines and Proteins in Solution. Langmuir 2007, 23, 3927−3931. (336) Duque, L.; Queralto, N.; Francesch, L.; Bumbu, G. G.; Borros, S.; Berger, R.; Förch, R. Reactions of Plasma-Polymerised Pentafluorophenyl Methacrylate with Simple Amines. Plasma Processes Polym. 2010, 7, 915−925.

(337) O’Shaughnessy, W. S.; Marí-Buyé, N.; Borrós, S.; Gleason, K. K. Initiated Chemical Vapor Deposition of a Surface-Modifiable Copolymer for Covalent Attachment and Patterning of Nucleophilic Ligands. Macromol. Rapid Commun. 2007, 28, 1877−1882. (338) Francesch, L.; Garreta, E.; Balcells, M.; Edelman, E. R.; Borrós, S. Fabrication of Bioactive Surfaces by Plasma Polymerization Techniques Using a Novel Acrylate-Derived Monomer. Plasma Processes Polym. 2005, 2, 605−611. (339) Seo, J.; Schattling, P.; Lang, T.; Jochum, F.; Nilles, K.; Theato, P.; Char, K. Covalently Bonded Layer-by-Layer Assembly of Multifunctional Thin Films Based on Activated Esters. Langmuir 2010, 26, 1830−1836. (340) Lahann, J.; Balcells, M.; Rodon, T.; Lee, J.; Choi, I. S.; Jensen, K. F.; Langer, R. Reactive Polymer Coatings: A Platform for Patterning Proteins and Mammalian Cells onto a Broad Range of Materials. Langmuir 2002, 18, 3632−3638. (341) Couturaud, B.; Bondia, A. M.; Faye, C.; Garrelly, L.; Mas, A.; Robin, J. J. Grafting of Poly-L-Lysine Dendrigrafts onto Polypropylene Surface Using Plasma Activation for ATP Immobilization-Nanomaterial for Potential Applications in Biotechnology. J. Colloid Interface Sci. 2013, 408, 242−251. (342) Iha, R. K.; Wooley, K. L.; Nyström, A. M.; Burke, D. J.; Kade, M. J.; Hawker, C. J. Applications of Orthogonal “Click” Chemistries in the Synthesis of Functional Soft Materials. Chem. Rev. 2009, 109, 5620−5686. (343) Ghosh, S.; Basu, S.; Thayumanavan, S. Simultaneous and Reversible Functionalization of Copolymers for Biological Applications. Macromolecules 2006, 39, 5595−5597. (344) Pontrello, J. K.; Allen, M. J.; Underbakke, E. S.; Kiessling, L. L. Solid-Phase Synthesis of Polymers Using the Ring-Opening Metathesis Polymerization. J. Am. Chem. Soc. 2005, 127, 14536−14537. (345) Yilmaz, I. I.; Arslan, M.; Sanyal, A. Design and Synthesis of Novel “Orthogonally” Functionalizable Maleimide-Based Styrenic Copolymers. Macromol. Rapid Commun. 2012, 33, 856−862. (346) Noy, J.-M.; Koldevitz, M.; Roth, P. J. Thiol-Reactive Functional Poly(meth)acrylates: Multicomponent Monomer Synthesis, RAFT (co)polymerization and Highly Efficient Thiol−para-Fluoro Postpolymerization Modification. Polym. Chem. 2015, 6, 436−447. (347) Kessler, D.; Nilles, K.; Theato, P. Modular Approach towards Multi-Functional Surfaces with Adjustable and Dual-Responsive Wettability Using a Hybrid Polymer Toolbox. J. Mater. Chem. 2009, 19, 8184−8189. (348) Li, Y.; Duong, H. T. T.; Jones, M. W.; Basuki, J. S.; Hu, J.; Boyer, C.; Davis, T. P. Selective Postmodification of Copolymer Backbones Bearing Different Activated Esters with Disparate Reactivities. ACS Macro Lett. 2013, 2, 912−917. (349) He, L.; Shang, J.; Theato, P. Preparation of Dual StimuliResponsive Block Copolymers Based on Different Activated Esters with Distinct Reactivities. Eur. Polym. J. 2015, 69, 523. (350) Cengiz, N.; Kabadayioglu, H.; Sanyal, R. Orthogonally Functionalizable Copolymers Based on a Novel Reactive Carbonate Monomer. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 4737−4746. (351) Malkoch, M.; Thibault, R. J.; Drockenmuller, E.; Messerschmidt, M.; Voit, B.; Russell, T. P.; Hawker, C. J. Orthogonal Approaches to the Simultaneous and Cascade Functionalization of Macromolecules Using Click Chemistry. J. Am. Chem. Soc. 2005, 127, 14942−14949. (352) Ntoukan, D. H. S.; Luinstra, G. A.; Theato, P. Postpolymerization Modification of Reactive Polymers Derived from Vinylcyclopropane. III. Polymer Sequential Functionalization Using a Combination of Amines with Alkoxyamines, Hydrazides, Isocyanates, or Acyl Halides. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2841− 2849. (353) Kakuchi, R.; Theato, P. Sequential Post-Polymerization Modification Reactions of Poly(pentafluorophenyl 4-Vinylbenzenesulfonate). Polym. Chem. 2014, 5, 2320−2325. (354) Srichan, S.; Kayunkid, N.; Oswald, L.; Lotz, B.; Lutz, J.-F. Synthesis and Characterization of Sequence-Controlled SemicrystalBB



Chemical Reviews

Review

line Comb Copolymers: Influence of Primary Structure on Materials Properties. Macromolecules 2014, 47, 1570−1577. (355) Zamfir, M.; Lutz, J.-F. Ultra-Precise Insertion of Functional Monomers in Chain-Growth Polymerizations. Nat. Commun. 2012, 3, 1138. (356) Srichan, S.; Mutlu, H.; Badi, N.; Lutz, J.-F. Precision PEGylated Polymers Obtained by Sequence-Controlled Copolymerization and Postpolymerization Modification. Angew. Chem., Int. Ed. 2014, 53, 9231−9235. (357) Zamfir, M.; Theato, P.; Lutz, J.-F. Controlled Folding of Polystyrene Single Chains: Design of Asymmetric Covalent Bridges. Polym. Chem. 2012, 3, 1796−1802. (358) Roy, R. K.; Lutz, J. Compartmentalization of Single Polymer Chains by Stepwise Intramolecular Cross-Linking of SequenceControlled Macromolecules. J. Am. Chem. Soc. 2014, 136, 12888− 12891. (359) Wooley, K. L. Shell Crosslinked Polymer Assemblies: Nanoscale Constructs Inspired from Biological Systems. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 1397−1407. (360) Farokhzad, O. C.; Langer, R. Impact of Nanotechnology on Drug Delivery. ACS Nano 2009, 3, 16−20. (361) Allen, T. M.; Cullis, P. R. Drug Delivery Systems: Entering the Mainstream. Science 2004, 303, 1818−1822. (362) Bronich, T. K.; Keifer, P. A.; Shlyakhtenko, L. S.; Kabanov, A. V. Polymer Micelle with Cross Linked Ionic Core. J. Am. Chem. Soc. 2005, 127, 8236−8237. (363) Thurmond, K. B.; Kowalewski, T.; Wooley, K. L. WaterSoluble Knedel-like Structures: The Preparation of Shell-Cross-Linked Small Particles. J. Am. Chem. Soc. 1996, 118, 7239−7240. (364) Liu, Y.; Wang, L.; Pan, C. Preparation of Nanospheres with Polystyrene Shells and Cross-Linked Poly (methacrylamide) Cores: A Solution Approach. Polymer 2002, 43, 7063−7068. (365) Lin, L. Y.; Karwa, A.; Kostelc, J. G.; Lee, N. S.; Dorshow, R. B.; Wooley, K. L. Paclitaxel-Loaded SCK Nanoparticles: An Investigation of Loading Capacity and Cell Killing Abilities in Vitro. Mol. Pharmaceutics 2012, 9, 2248−2255. (366) Thurmond, K. B.; Kowalewski, T.; Wooley, K. L. Shell CrossLinked Knedels: A Synthetic Study of the Factors Affecting the Dimensions and Properties of Amphiphilic Core-Shell Nanospheres. J. Am. Chem. Soc. 1997, 119, 6656−6665. (367) Joralemon, M. J.; O’Reilly, R. K.; Hawker, C. J.; Wooley, K. L. Shell Click-Crosslinked (SCC) Nanoparticles: A New Methodology for Synthesis and Orthogonal Functionalization. J. Am. Chem. Soc. 2005, 127, 16892−16899. (368) Chiang, W.-H.; Hsu, Y.-H.; Lou, T.-W.; Chern, C.-S.; Chiu, H.C. Effects of mPEG Grafts on Morphology and Cross-Linking of Thermally Induced Micellar Assemblies from PAAc-Based Graft Copolymers in Aqueous Phase. Macromolecules 2009, 42, 3611−3619. (369) Chiang, W.-H.; Ho, V. T.; Huang, W. C.; Huang, Y.-F.; Chern, C.-S.; Chiu, H.-C. Dual Stimuli-Responsive Polymeric Hollow Nanogels Designed as Carriers for Intracellular Triggered Drug Release. Langmuir 2012, 28, 15056−15064. (370) Chiang, W.-H.; Hsu, Y.-H.; Tang, F.-F.; Chern, C.-S.; Chiu, H.C. Temperature/pH-Induced Morphological Regulations of Shell Cross-Linked Graft Copolymer Assemblies. Polymer 2010, 51, 6248− 6257. (371) Nuhn, L.; Hirsch, M.; Krieg, B.; Koynov, K.; Fischer, K.; Schmidt, M.; Helm, M.; Zentel, R. Cationic Nanohydrogel Particles as Potential siRNA Carriers for Cellular Delivery. ACS Nano 2012, 6, 2198−2214. (372) Nuhn, L.; Tomcin, S.; Miyata, K.; Mailänder, V.; Landfester, K.; Kataoka, K.; Zentel, R. Size-Dependent Knockdown Potential of siRNA-Loaded Cationic Nanohydrogel Particles. Biomacromolecules 2014, 15, 4111−4121. (373) Zhang, J.; Jiang, X.; Zhang, Y.; Li, Y.; Liu, S. Facile Fabrication of Reversible Core Cross-Linked Micelles Possessing Thermosensitive Swellability. Macromolecules 2007, 40, 9125−9132.

(374) Ueki, T.; Sawamura, S.; Nakamura, Y.; Kitazawa, Y.; Kokubo, H.; Watanabe, M. Thermoreversible Nanogel Shuttle between Ionic Liquid and Aqueous Phases. Langmuir 2013, 29, 13661−13665. (375) Kaihara, S.; Narikawa, M.; Fujimoto, K. Preparation of Thermosensitive Polymer Nanoparticles by Protein-Mimetic CrossLinking. Colloid Polym. Sci. 2012, 290, 1317−1325. (376) Zhuang, J.; Jiwpanich, S.; Deepak, V. D.; Thayumanavan, S. Facile Preparation of Nanogels Using Activated Ester Containing Polymers. ACS Macro Lett. 2012, 1, 175−179. (377) Wan, X.; Liu, T.; Liu, S. Thermoresponsive Core Cross-Linked Micelles for Selective Ratiometric Fluorescent Detection of Hg2+ Ions. Langmuir 2011, 27, 4082−4090. (378) Li, Y.; Yang, D.; Adronov, A.; Gao, Y.; Luo, X.; Li, H. Covalent Functionalization of Single-Walled Carbon Nanotubes with Thermoresponsive Core Cross-Linked Polymeric Micelles. Macromolecules 2012, 45, 4698−4706. (379) Pascual, S.; Monteiro, M. J. Shell-Crosslinked Nanoparticles through Self-Assembly of Thermoresponsive Block Copolymers by RAFT Polymerization. Eur. Polym. J. 2009, 45, 2513−2519. (380) Quan, C.-Y.; Wei, H.; Shi, Y.; Li, Z.-Y.; Cheng, S.-X.; Zhang, X.-Z.; Zhuo, R.-X. Fabrication of Multifunctional Shell Cross-Linked Micelles for Targeting Drug Release. Colloid Polym. Sci. 2011, 289, 667−675. (381) Li, B. Y.; Akiba, I.; Harrisson, S.; Wooley, K. L. Facile Formation of Uniform Shell-Crosslinked Nanoparticles with Built-in Functionalities from N-Hydroxysuccinimide-Activated Amphiphilic Block Copolymers. Adv. Funct. Mater. 2008, 18, 551−559. (382) Samarajeewa, S.; Shrestha, R.; Li, Y.; Wooley, K. L. Degradability of Poly(Lactic Acid)-Containing Nanoparticles: Enzymatic Access through a Cross-Linked Shell Barrier. J. Am. Chem. Soc. 2012, 134, 1235−1242. (383) Li, Y.; Lokitz, B. S.; McCormick, C. L. RAFT Synthesis of a Thermally Responsive ABC Triblock Copolymer Incorporating NAcryloxysuccinimide for Facile in Situ Formation of Shell CrossLinked Micelles in Aqueous Media. Macromolecules 2006, 39, 81−89. (384) Li, Y.; Lokitz, B. S.; Armes, S. P.; McCormick, C. L. Synthesis of Reversible Shell Cross-Linked Micelles for Controlled Release of Bioactive Agents. Macromolecules 2006, 39, 2726−2728. (385) Sun, G.; Berezin, M. Y.; Fan, J.; Lee, H.; Ma, J.; Zhang, K.; Wooley, K. L.; Achilefu, S. Bright Fluorescent Nanoparticles for Developing Potential Optical Imaging Contrast Agents. Nanoscale 2010, 2, 548−558. (386) Sun, G.; Cui, H.; Lin, L. Y.; Lee, N. S.; Yang, C.; Neumann, W. L.; Freskos, J. N.; Shieh, J. J.; Dorshow, R. B.; Wooley, K. L. Multicompartment Polymer Nanostructures with Ratiometric DualEmission pH-Sensitivity. J. Am. Chem. Soc. 2011, 133, 8534−8543. (387) Sun, G.; Lee, N. S.; Neumann, W. L.; Freskos, J. N.; Shieh, J. J.; Dorshow, R. B.; Wooley, K. L. A Fundamental Investigation of CrossLinking Efficiencies within Discrete Nanostructures, Using the CrossLinker as a Reporting Molecule. Soft Matter 2009, 5, 3422−3429. (388) Huynh, V. T.; Binauld, S.; de Souza, P. L.; Stenzel, M. H. Acid Degradable Cross-Linked Micelles for the Delivery of Cisplatin: A Comparison with Nondegradable Cross-Linker. Chem. Mater. 2012, 24, 3197−3211. (389) Cordovilla, C.; Swager, T. M. Strain Release in Organic Photonic Nanoparticles for Protease Sensing. J. Am. Chem. Soc. 2012, 134, 6932−6935. (390) Balakrishnan, B.; Banerjee, R. Biopolymer-Based Hydrogels for Cartilage Tissue Engineering. Chem. Rev. 2011, 111, 4453−4474. (391) Vermonden, T.; Censi, R.; Hennink, W. E. Hydrogels for Protein Delivery. Chem. Rev. 2012, 112, 2853−2888. (392) Hoffman, A. S. Hydrogels for Biomedical Applications. Adv. Drug Delivery Rev. 2012, 64, 18−23. (393) Bindu Sri, M.; Ashok, V.; Arkendu, C. As A Review on Hydrogels as Drug Delivery in the Pharmaceutical Field. Int. J. Pharm. Chem. Sci. 2012, 1, 642−661. (394) White, E. M.; Yatvin, J.; Grubbs, J. B.; Bilbrey, J. A.; Locklin, J. Advances in Smart Materials: Stimuli-Responsive Hydrogel Thin Films. J. Polym. Sci., Part B: Polym. Phys. 2013, 51, 1084−1099. BC



Chemical Reviews

Review

(395) Tokarev, I.; Minko, S. Stimuli-Responsive Hydrogel Thin Films. Soft Matter 2009, 5, 511−524. (396) Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Biodegradable Block Copolymers as Injectable Drug-Delivery Systems. Nature 1997, 388, 860−862. (397) Lee, Y. J.; Wu, B.; Raymond, J. E.; Zeng, Y.; Fang, X.; Wooley, K. L.; Liu, W. R. A Genetically Encoded Acrylamide Functionality. ACS Chem. Biol. 2013, 8, 1664−1670. (398) Sedlacík, T.; Studenovská, H.; Rypácě k, F. Enzymatic Degradation of the Hydrogels Based on Synthetic Poly(α-Amino Acid)s. J. Mater. Sci.: Mater. Med. 2011, 22, 781−788. (399) Okawa, K.; Miyata, T.; Uragami, T. Fluorescence Resonance Energy Transfer by Quencher Adsorption into Hydrogels Containing Fluorophores. J. Polym. Sci., Part B: Polym. Phys. 2006, 44, 3245−3252. (400) Miyata, T.; Jige, M.; Nakaminami, T.; Uragami, T. Tumor Marker-Responsive Behavior of Gels Prepared by Biomolecular Imprinting. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 1190−1193. (401) Wang, L.; Zhang, M.; Yang, Z.; Xu, B. The First Pamidronate Containing Polymer and Copolymer. Chem. Commun. 2006, 2795− 2797. (402) Ng, C. C.; Cheng, Y.; Pennefather, P. S. One-Step Synthesis of a Fluorescent Phospholipid-Hydrogel Conjugate for Driving SelfAssembly of Supported Lipid Membranes. Macromolecules 2001, 34, 5759−5765. (403) Miyata, T.; Asami, N.; Uragami, T. Preparation of an AntigenSensitive Hydrogel Using Antigen-Antibody Bindings. Macromolecules 1999, 32, 2082−2084. (404) Ye, G.; Yang, C.; Wang, X. Sensing Diffraction Gratings of Antigenresponsive Hydrogel for Human Immunoglobulin-G Detection. Macromol. Rapid Commun. 2010, 31, 1332−1336. (405) Miyata, T.; Asami, N.; Uragami, T. A Reversibly AntigenResponsive Hydrogel. Nature 1999, 399, 766−769. (406) Murakami, Y.; Maeda, M. DNA-Responsive Hydrogels That Can Shrink or Swell. Biomacromolecules 2005, 6, 2927−2929. (407) Sicilia, G.; Grainger-Boultby, C.; Francini, N.; Magnusson, J. P.; Saeed, A. O.; Fernández-Trillo, F.; Spain, S. G.; Alexander, C. Programmable Polymer-DNA Hydrogels with Dual Input and Multiscale Responses. Biomater. Sci. 2014, 2, 203. (408) Samra, B. K.; Galaev, I. Y.; Mattiasson, B. Thermosensitive, Reversibly Cross-Linking Gels with a Shape “Memory. Angew. Chem., Int. Ed. 2000, 39, 2364−2367. (409) Yoshioka, H.; Mori, Y.; Cushman, J. a. A Synthetic Hydrogel with Therrnoreversible Gelation, III: An NMR Study of the Sol-Gel Transition. Polym. Adv. Technol. 1994, 5, 122−127. (410) Yoshioka, H.; Mikami, M.; Mori, Y.; Tsuchida, E. A Synthetic Hydrogel with Thermoreversible Gelation. I. Preparation and Rheological Properties. J. Macromol. Sci., Part A: Pure Appl.Chem. 1994, 31, 113−120. (411) Chung, H.; Grubbs, R. H. Rapidly Cross-Linkable DOPA Containing Terpolymer Adhesives and PEG-Based Cross-Linkers for Biomedical Applications. Macromolecules 2012, 45, 9666−9673. (412) Percot, A.; Lafleur, M.; Zhu, X. X. New Hydrogels Based on NIsopropylacrylamide Copolymers Crosslinked with Polylysine: Membrane Immobilization Systems. Polymer 2000, 41, 7231−7239. (413) Li, F.; Griffith, M.; Li, Z.; Tanodekaew, S.; Sheardown, H.; Hakim, M.; Carlsson, D. J. Recruitment of Multiple Cell Lines by Collagen-Synthetic Copolymer Matrices in Corneal Regeneration. Biomaterials 2005, 26, 3093−3104. (414) Fathi, A.; Mithieux, S. M.; Wei, H.; Chrzanowski, W.; Valtchev, P.; Weiss, A. S.; Dehghani, F. Elastin Based Cell-Laden Injectable Hydrogels with Tunable Gelation, Mechanical and Biodegradation Properties. Biomaterials 2014, 35, 5425−5435. (415) Shigehara, K.; Kudoh, H.; Sakai, T.; Osada, Y.; Murakami, Y.; Shikinaka, K. Thermoresponsive Synthetic Polymer-Microtubule Hybrids. Langmuir 2013, 29, 11786−11792. (416) Nuhn, L.; Gietzen, S.; Mohr, K.; Fischer, K.; Toh, K.; Miyata, K.; Matsumoto, Y.; Kataoka, K.; Schmidt, M.; Zentel, R. Aggregation Behavior of Cationic Nanohydrogel Particles in Human Blood Serum. Biomacromolecules 2014, 15, 1526−1533.

(417) Kaneko, Y.; Sakai, K.; Kikuchi, A.; Yoshida, R.; Sakurai, Y.; Okano, T. Influence of Freely Mobile Grafted Chain Length on Dynamic Properties of Comb-Type Grafted Poly(N-Isopropylacrylamide) Hydrogels. Macromolecules 1995, 28, 7717−7723. (418) Xu, X.; Zhang, X.; Yang, J.; Cheng, S.; Zhuo, R.; Huang, Y.-Q. Strategy to Introduce a Pendent Micellar Structure into Poly(NIsopropylacrylamide) Hydrogels. Langmuir 2007, 23, 4231−4236. (419) Percot, A.; Zhu, X. X.; Lafleur, M. A Simple FTIR Spectroscopic Method for the Determination of the Lower Critical Solution Temperature of N-Isopropylacrylamide Copolymers and Related Hydrogels. J. Polym. Sci., Part B: Polym. Phys. 2000, 38, 907− 915. (420) Li, F.; Zhu, Y.; You, B.; Zhao, D.; Ruan, Q.; Zeng, Y.; Ding, C. Smart Hydrogels Co-Switched by Hydrogen Bonds and Π-Π Stacking for Continuously Regulated Controlledrelease System. Adv. Funct. Mater. 2010, 20, 669−676. (421) Polomoscanik, S. C.; Cannon, C. P.; Neenan, T. X.; HolmesFarley, S. R.; Mandeville, W. H.; Dhal, P. K. Hydroxamic AcidContaining Hydrogels for Nonabsorbed Iron Chelation Therapy: Synthesis, Characterization, and Biological Evaluation. Biomacromolecules 2005, 6, 2946−2953. (422) Moghaddam, M. J.; Matsuda, T. Molecular Design of ThreeDimensional Artificial Extracellular Matrix: Photosensitive Polymers Containing Cell Adhesive Peptide. J. Polym. Sci., Part A: Polym. Chem. 1993, 31, 1589−1597. (423) Wang, Z. C.; Xu, X. D.; Chen, C. S.; Yun, L.; Song, J. C.; Zhang, X. Z.; Zhuo, R. X. In Situ Formation of Thermosensitive Pnipaam-Based Hydrogels by Michael-Type Addition Reaction. ACS Appl. Mater. Interfaces 2010, 2, 1009−1018. (424) Robb, S. A.; Lee, B. H.; McLemore, R.; Vernon, B. L. Simultaneously Physically and Chemically Gelling Polymer System Utilizing a poly(NIPAAm-co-Cysteamine)-Based Copolymer. Biomacromolecules 2007, 8, 2294−2300. (425) Bearat, H. H.; Preul, M. C.; Vernon, B. L. Cytotoxicity, in Vitro Models and Preliminary in Vivo Study of Dual Physical and Chemical Gels for Endovascular Embolization of Cerebral Aneurysms. J. Biomed. Mater. Res., Part A 2013, 101A, 2515−2525. (426) Jia, Y.-G.; Zhu, X. X. Self-Healing Supramolecular Hydrogel Made of Polymers Bearing Cholic Acid and β-Cyclodextrin Pendants. Chem. Mater. 2015, 27, 387−393. (427) Mazumder, M. A. J.; Fitzpatrick, S. D.; Muirhead, B.; Sheardown, H. Cell-Adhesive Thermogelling PNIPAAm/hyaluronic Acid Cell Delivery Hydrogels for Potential Application as Minimally Invasive Retinal Therapeutics. J. Biomed. Mater. Res., Part A 2012, 100A, 1877−1887. (428) Kim, J.; Kim, I. S.; Cho, T. H.; Lee, K. B.; Hwang, S. J.; Tae, G.; Noh, I.; Lee, S. H.; Park, Y.; Sun, K. Bone Regeneration Using Hyaluronic Acid-Based Hydrogel with Bone Morphogenic Protein-2 and Human Mesenchymal Stem Cells. Biomaterials 2007, 28, 1830− 1837. (429) Xu, X.; Gurski, L. A.; Zhang, C.; Harrington, D. A.; FarachCarson, M. C.; Jia, X. Recreating the Tumor Microenvironment in a Bilayer, Hyaluronic Acid Hydrogel Construct for the Growth of Prostate Cancer Spheroids. Biomaterials 2012, 33, 9049−9060. (430) Lam, J.; Segura, T. The Modulation of MSC Integrin Expression by RGD Presentation. Biomaterials 2013, 34, 3938−3947. (431) Tokatlian, T.; Cam, C.; Segura, T. Non-Viral DNA Delivery from Porous Hyaluronic Acid Hydrogels in Mice. Biomaterials 2014, 35, 825−835. (432) Kim, J.; Park, Y.; Tae, G.; Kyu, B. L.; Chang, M. H.; Soon, J. H.; In, S. K.; Noh, I.; Sun, K. Characterization of Low-MolecularWeight Hyaluronic Acid-Based Hydrogel and Differential Stem Cell Responses in the Hydrogel Microenvironments. J. Biomed. Mater. Res., Part A 2009, 88A, 967−975. (433) Lee, K. H.; Lee, K. H.; Lee, J.; Choi, H.; Lee, D.; Park, Y.; Lee, S. H. Integration of Microfluidic Chip with Biomimetic Hydrogel for 3D Controlling and Monitoring of Cell Alignment and Migration. J. Biomed. Mater. Res., Part A 2014, 102, 1164−1172. BD



Chemical Reviews

Review

(434) Gojgini, S.; Tokatlian, T.; Segura, T. Utilizing Cell-Matrix Interactions to Modulate Gene Transfer to Stem Cells inside Hyaluronic Acid Hydrogels. Mol. Pharmaceutics 2011, 8, 1582−1591. (435) Jha, A.; Tharp, K.; Ye, J.; Santiago-Ortiz, J.; Jackson, W.; Stahl, A.; Schaffer, D.; Yeghiazarians, Y.; Healy, K. Enhanced Survival and Engraftment of Transplanted Stem Cells Using Growth Factor Sequestering Hydrogels. Biomaterials 2015, 47, 1−12. (436) Nelson, D. M.; Ma, Z.; Leeson, C. E.; Wagner, W. R. Extended and Sequential Delivery of Protein from Injectable Thermoresponsive Hydrogels. J. Biomed. Mater. Res., Part A 2012, 100A, 776−785. (437) Guan, J.; Hong, Y.; Ma, Z.; Wagner, W. R. Protein-Reactive, Thermoresponsive Copolymers with High Flexibility and Biodegradability. Biomacromolecules 2008, 9, 1283−1292. (438) Li, Z.; Guo, X.; Guan, J. A Thermosensitive Hydrogel Capable of Releasing bFGF for Enhanced Differentiation of Mesenchymal Stem Cell into Cardiomyocyte-like Cells under Ischemic Conditions. Biomacromolecules 2012, 13, 1956−1964. (439) Song, M.; Jang, H.; Lee, J.; Kim, J. H.; Kim, S. H.; Sun, K.; Park, Y. Regeneration of Chronic Myocardial Infarction by Injectable Hydrogels Containing Stem Cell Homing Factor SDF-1 and Angiogenic Peptide Ac-SDKP. Biomaterials 2014, 35, 2436−2445. (440) Deng, C. C.; Brooks, W. L. A.; Abboud, K. A.; Sumerlin, B. S. Boronic Acid-Based Hydrogels Undergo Self-Healing at Neutral and Acidic pH. ACS Macro Lett. 2015, 4, 220−224. (441) Pérez-Alvarez, L.; Sáez-Martínez, V.; Hernaez, E.; Herrero, M.; Katime, I. Specific pH-Responsive Folate-Conjugate Microgels Designed for Antitumor Therapy. Macromol. Chem. Phys. 2009, 210, 467−477. (442) Pérez, L.; Sáez, V.; Hernáez, E.; Herrero, M. T.; Rodríguez, E.; Katime, I. Synthesis and Characterization of Reactive Copolymeric Microgels. Polym. Int. 2005, 54, 963−971. (443) Blanco, M. D.; Guerrero, S.; Benito, M.; Fernández, A.; Teijón, C.; Olmo, R.; Katime, I.; Teijón, J. M. In Vitro and In Vivo Evaluation of a Folate-Targeted Copolymeric Submicrohydrogel Based on NIsopropylacrylamide as 5-Fluorouracil Delivery System. Polymers 2011, 3, 1107−1125. (444) Marí-Buyé, N.; O’Shaughnessy, S.; Colominas, C.; Semino, C. E.; Gleason, K. K.; Borrós, S. Functionalized, Swellable Hydrogel Layers as a Platform for Cell Studies. Adv. Funct. Mater. 2009, 19, 1276−1286. (445) Musah, S.; Morin, S.; Wrighton, P.; Zwick, D.; Jin, S.; Kiessling, L. Glycosaminoglycan-Binding Hydrogels Enable Mechanical Control of Human Pluripotent Stem Cell Self-Renewal. ACS Nano 2012, 6, 10168−10177. (446) Sola, L.; Gagni, P.; Cretich, M.; Chiari, M. Surface Immobilized Hydrogels as Versatile Reagent Reservoirs for Microarrays. J. Immunol. Methods 2013, 391, 95−102. (447) Lee, E. J.; Ahn, K. Y.; Lee, J. H.; Park, J. S.; Song, J. A.; Sim, S. J.; Lee, E. B.; Cha, Y. J.; Lee, J. A Novel Bioassay Platform Using Ferritin-Based Nanoprobe Hydrogel. Adv. Mater. 2012, 24, 4739− 4744. (448) Rubina, A. Y.; Pan’kov, S. V.; Dementieva, E. I.; Pen’kov, D. N.; Butygin, A. V.; Vasiliskov, V. A.; Chudinov, A. V.; Mikheikin, A. L.; Mikhailovich, V. M.; Mirzabekov, A. D. Hydrogel Drop Microchips with Immobilized DNA: Properties and Methods for Large-Scale Production. Anal. Biochem. 2004, 325, 92−106. (449) Marszalek, P. E.; Markin, V. S.; Tanaka, T.; Kawaguchi, H.; Fernandez, J. M. Pulsed-Laser Imaging Demonstrates the Mechanism of Current Rectification at a Hydrogel Interface. Langmuir 1995, 11, 4196−4198. (450) Marsden, D. M.; Nicholson, R. L.; Ladlow, M.; Spring, D. R. 3D Small-Molecule Microarrays. Chem. Commun. 2009, 7107−7109. (451) Tanaka, H.; Isojima, T.; Hanasaki, M.; Ifuku, Y.; Takeuchi, H.; Kawaguchi, H.; Shiroya, T. Porous Protein-Based Nanoparticle Hydrogel for Protein Chips with Improved Sensitivity. Macromol. Rapid Commun. 2008, 29, 1287−1292. (452) Zhang, J.-T.; Chao, X.; Liu, X.; Asher, S. A. Two-Dimensional Array Debye Ring Diffraction Protein Recognition Sensing. Chem. Commun. 2013, 49, 6337−6339.

(453) Chen, J. P.; Chiu, S. H. A poly(N-Isopropylacrylamide-co-NAcryloxysuccinimide-co-2-Hydroxyethyl Methacrylate) Composite Hydrogel Membrane for Urease Immobilization to Enhance Urea Hydrolysis Rate by Temperature Swing. Enzyme Microb. Technol. 2000, 26, 359−367. (454) Sun, Y. M.; Chen, J. P.; Chu, D. H. Preparation and Characterization of Alpha-Amylase-Immobilized Thermal-Responsive Composite Hydrogel Membranes. J. Biomed. Mater. Res. 1999, 45, 125−132. (455) Su, T.; Zhang, D.; Tang, Z.; Wu, Q.; Wang, Q. HRP-Mediated Polymerization Forms Tough Nanocomposite Hydrogels with High Biocatalytic Performance. Chem. Commun. 2013, 49, 8033−8035. (456) Kibrom, A.; Roskamp, R. F.; Jonas, U.; Menges, B.; Knoll, W.; Paulsen, H.; Naumann, R. L. C. Hydrogel-Supported Protein-Tethered Bilayer Lipid Membranes: A New Approach toward PolymerSupported Lipid Membranes. Soft Matter 2011, 7, 237−246. (457) Malmstadt, N.; Jeon, T.-J.; Schmidt, J. J. Long-Lived Planar Lipid Bilayer Membranes Anchored to an In Situ Polymerized Hydrogel. Adv. Mater. 2008, 20, 84−89. (458) Théato, P.; Zentel, R.; Schwarz, S. Synthesis of EndFunctionalized Lipopolymers and Their Characterization with Regard to Polymer-Supported Lipid Membranes. Macromol. Biosci. 2002, 2 (8), 387−394. (459) Théato, P.; Zentel, R. Formation of Lipid Bilayers on a New Amphiphilic Polymer Support. Langmuir 2000, 16, 1801−1805. (460) Théato, P.; Zentel, R. α,ω-Functionalized Poly-N-Isopropylacrylamides: Controlling the Surface Activity for Vesicle Adsorption by Temperature. J. Colloid Interface Sci. 2003, 268, 258−262. (461) Simon, J.; Kühner, M.; Ringsdorf, H.; Sackmanna, E. PolymerInduced Shape Changes and Capping in Giant Liposomes. Chem. Phys. Lipids 1995, 76, 241−258. (462) Huang, Y.-F.; Chiang, W.-H.; Tsai, P.-L.; Chern, C.-S.; Chiu, H.-C. Novel Hybrid Vesicles Co-Assembled from a Cationic Lipid and PAAc-G-mPEG with pH-Triggered Transmembrane Channels for Controlled Drug Release. Chem. Commun. 2011, 47, 10978−10980. (463) Huang, W. C.; Chiang, W. H.; Lin, S. J.; Lan, Y. J.; Chen, H. L.; Chern, C. S.; Chiu, H. C. Lipid-Containing Polymer Vesicles with pH/ Ca 2+-Ion-Manipulated, Size-Selective Permeability. Adv. Funct. Mater. 2012, 22, 2267−2275. (464) Sinner, E.-K.; Knoll, W. Functional Tethered Membranes. Curr. Opin. Chem. Biol. 2001, 5, 705−711. (465) Hausch, M.; Zentel, R.; Knoll, W. Synthesis and Characterization of Hydrophilic Lipopolymers for the Support of Lipid Bilayers. Macromol. Chem. Phys. 1999, 200, 174−179. (466) Hausch, M.; Beyer, D.; Knoll, W.; Zentel, R. Ultrathin Polymer Films on Gold Supports: LB-Transfer versus Self Assembly. Langmuir 1998, 14, 7213−7216. (467) Théato, P.; Zentel, R. Stabilization of Lipid Bilayers on Surfaces Through Charged Polymers. J. Macromol. Sci., Part A: Pure Appl.Chem. 1999, 36, 1001−1015. (468) Burns, J. A.; Gibson, M. I.; Becer, C. R. In Glycopolymers via Post-Polymerization Modification Techniques. 1st ed.; Theato, P., Klok, H.-A., Eds.; Wiley-VCH: New York, 2012. (469) Tengdelius, M.; Lee, C.-J.; Grenegard, M.; Griffith, M.; Pahlsson, P.; Konradsson, P. Synthesis and Biological Evaluation of Fucoidan-Mimetic Glycopolymers through Cyanoxyl-Mediated FreeRadical Polymerization. Biomacromolecules 2014, 15, 2359−2368. (470) Lipinski, T.; Kitov, P. I.; Szpacenko, A.; Paszkiewicz, E.; Bundle, D. R. Synthesis and Immunogenicity of a Glycopolymer Conjugate. Bioconjugate Chem. 2011, 22, 274−281. (471) Schnaar, R. L.; Weigel, P. H.; Kuhlenschmidt, M. S.; Lee, Y. C.; Roseman, S. Adhesion of Chicken Hepatocytes to Polyacrylamide Gels Derivatized with N-Aacetylglucosamine. J. Biol. Chem. 1978, 253, 7940−7951. (472) Weigel, P. H.; Schnaar, R. L.; Kuhlenschmidt, M. S.; Schmell, E.; Lee, R. T.; Lee, Y. C.; Roseman, S. Adhesion of Hepatocytes to Immobilized Sugars. J. Biol. Chem. 1979, 254, 10830−10838. BE



Chemical Reviews

Review

(473) Huang, M.; Shen, Z.; Zhang, Y.; Zeng, X.; Wang, P. G. Alkanethiol Containing Glycopolymers: A Tool for the Detection of Lectin Binding. Bioorg. Med. Chem. Lett. 2007, 17, 5379−5383. (474) Teng, D.; Yin, W.; Zhang, X.; Wang, Z.; Li, C. New Glycoconjugate Polyacrylamide with Water-Solubility and Additional Activated Groups: Synthesis and Characterization. J. Polym. Res. 2009, 16, 311−316. (475) Mammen, M.; Dahmann, G.; Whitesides, G. M. Effective Inhibitors of Hemagglutination by Influenza Virus Synthesized from Polymers Having Active Ester Groups. Insight into Mechanism of Inhibition. J. Med. Chem. 1995, 38, 4179−4190. (476) Siriwardena, A.; Jørgensen, M. R.; Wolfert, M. A.; Vandenplas, M. L.; Moore, J. N.; Boons, G. J. Synthesis and Proinflammatory Effects of Peptidoglycan-Derived Neoglycopeptide Polymers. J. Am. Chem. Soc. 2001, 123, 8145−8146. (477) Baek, M.-G.; Roy, R. Relative Lectin Binding Properties of TAntigen-Containing Glycopolymers: Copolymerization of N-Acryloylated T-Antigen Monomer vs. Graft Conjugation of Aminated TAntigen Ligands onto Poly(N-Acryloxysuccinimide). Macromol. Biosci. 2001, 1, 305−311. (478) Baek, M.-G.; Roy, R. Design and Synthesis of Water-Soluble Glycopolymers Bearing Breast Tumor Marker and Enhanced Lipophilicity for Solid-Phase Assays. Biomacromolecules 2000, 1, 768−770. (479) Wang, J.-Q.; Chen, X.; Zhang, W.; Zacharek, S.; Chen, Y.; Wang, P. G. Enhanced Inhibition of Human Anti-Gal Antibody Binding to Mammalian Cells by Synthetic α-Gal Epitope Polymers. J. Am. Chem. Soc. 1999, 121, 8174−8181. (480) Mohamed-Ahmed, A. H. A.; Les, K. A.; Croft, S. L.; Brocchini, S. Preparation and Characterisation of Amphotericin B-Copolymer Complex for the Treatment of Leishmaniasis. Polym. Chem. 2013, 4, 584−591. (481) Bovin, N. V.; Korchagina, E. Y.; Zemlyanukhina, T. V.; Byramova, N. E.; Galanina, O. E.; Zemlyakov, A. E.; Ivanov, A. E.; Zubov, V. P.; Mochalova, L. V. Synthesis of Polymeric Neoglycoconjugates Based on N-Substituted Polyacrylamides. Glycoconjugate J. 1993, 10, 142−151. (482) Dikusar, M. A.; Kubrakova, I. V.; Chinarev, A. A.; Bovin, N. V. Polymerization of 4-Nitrophenyl Acrylate under Microwave Heating Conditions. Russ. J. Bioorg. Chem. 2001, 27, 408−412. (483) Zemlyakov, A. E. Immobilization of Synthetic Glycopeptides on Polymeric Supports. Chem. Nat. Compd. 1998, 34, 80−85. (484) Khatuntseva, E. A.; Yudina, O. N.; Tsvetkov, Y. E.; Grachev, A. A.; Stepanenko, R. N.; Vlasenko, R. Y.; Lvov, V. L.; Nifantiev, N. E. Synthesis of 3-Aminopropyl β-Glycoside of Sialyl-3′-Lactose and Derived Neoglycoconjugates as a Tumor Vaccine Prototype and Artificial Antigens for the Control of Immune Response. Russ. Chem. Bull. 2006, 55, 2095−2102. (485) Boyer, C.; Davis, T. P. One-Pot Synthesis and Biofunctionalization of Glycopolymers via RAFT Polymerization and Thiol-Ene Reactions. Chem. Commun. 2009, 6029−6031. (486) Hayward, A. S.; Eissa, A. M.; Maltman, D.; Sano, N.; Przyborski, S. A.; Cameron, N. R. Galactose-Functionalized PolyHIPE Scaffolds for Use in Routine Three Dimensional Culture of Mammalian Hepatocytes. Biomacromolecules 2013, 14, 4271−4277. (487) Gentsch, R.; Pippig, F.; Nilles, K.; Theato, P.; Kikkeri, R.; Maglinao, M.; Lepenies, B.; Seeberger, P. H.; Börner, H. G. Modular Approach toward Bioactive Fiber Meshes Carrying Oligosaccharides. Macromolecules 2010, 43, 9239−9247. (488) Richards, S.; Jones, M. W.; Hunaban, M.; Haddleton, D. M.; Gibson, M. I. Probing Bacterial-Toxin Inhibition with Synthetic Glycopolymers Prepared by Tandem Post-Polymerization Modification: Role of Linker Length and Carbohydrate Density. Angew. Chem., Int. Ed. 2012, 51, 7812−7816. (489) Courtney, A. H.; Bennett, N. R.; Zwick, D. B.; Hudon, J.; Kiessling, L. L. Synthetic Antigens Reveal Dynamics of BCR Endocytosis during Inhibitory Signaling. ACS Chem. Biol. 2014, 9, 202−210.

(490) Yang, Z.-Q.; Puffer, E. B.; Pontrello, J. K.; Kiessling, L. L. Synthesis of a Multivalent Display of a CD22-Binding Trisaccharide. Carbohydr. Res. 2002, 337, 1605−1613. (491) Manning, D. D.; Strong, L. E.; Hu, X.; Beck, P. J.; Kiessling, L. L. Neoglycopolymer Inhibitors of the Selectins. Tetrahedron 1997, 53, 11937−11952. (492) Okoth, R.; Basu, A. End-Labeled Amino Terminated Monotelechelic Glycopolymers Generated by ROMP and Cu(I)Catalyzed Azide-Alkyne Cycloaddition. Beilstein J. Org. Chem. 2013, 9, 608−612. (493) Ferraton, N.; Delair, T.; Laayoun, A.; Cros, P.; Mandrand, B. Covalent Immobilization of Nucleic Acid Probes onto Reactive Synthetic Polymers. J. Appl. Polym. Sci. 1997, 66, 233−242. (494) Erout, M. N.; Troesch, A.; Pichot, C.; Cros, P. Preparation of Conjugates between Oligonucleotides and N-Vinylpyrrolidone/NAcryloxysuccinimide Copolymers and Applications in Nucleic Acid Assays To Improve Sensitivity. Bioconjugate Chem. 1996, 7, 568−575. (495) Minard-Basquin, C.; Chaix, C.; D’Agosto, F.; Charreyre, M. T.; Pichot, C. Oligonucleotide Synthesis onto poly(N-Acryloylmorpholine-Co-N-Acryloxysuccinimide): Assessment of the Resulting Conjugates in a DNA Sandwich Hybridization Test. J. Appl. Polym. Sci. 2004, 92, 3784−3795. (496) Kondo, S.; Shichijyou, D.; Sasai, Y.; Yamauchi, Y.; Kuzuya, M. Synthesis of DNA Conjugate by Mechanochemical Solid-State Polymerization and Its Affinity Separation of Oligonucleotides Having Single-Base Difference by Capillary Electrophoresis. Chem. Pharm. Bull. 2005, 53, 863−865. (497) Fluegel, S.; Maskos, M. Cylindrical Poly (oligo-DNA). Biomacromolecules 2007, 8, 700−702. (498) Nuhn, L.; Hirsch, M.; Krieg, B.; K, K.; Fischer, K.; Schmidt, M.; Helm, M.; Zentel, R. Cationic Nanohydrogel Particles as Potential siRNA Carriers for Cellular Delivery. ACS Nano 2012, 6, 2198−2214. (499) Yan, M.; Liang, M.; Wen, J.; Liu, Y.; Lu, Y.; Chen, I. S. Y. Single siRNA Nanocapsules for Enhanced RNAi Delivery. J. Am. Chem. Soc. 2012, 134, 13542−13545. (500) Cavalieri, F.; Postma, A.; Lee, L.; Caruso, F. Assembly and Functionalization of DNA-Polymer Microcapsules. ACS Nano 2009, 3, 234−240. (501) Shukoor, M. I.; Natalio, F.; Metz, N.; Glube, N.; Tahir, M. N.; Therese, H. A.; Ksenofontov, V.; Theato, P.; Langguth, P.; Boissel, J.P.; et al. dsRNA-Functionalized Multifunctional γ-Fe2O3 Nanocrystals: A Tool for Targeting Cell Surface Receptors. Angew. Chem., Int. Ed. 2008, 47, 4748−4752. (502) Shukoor, M. I.; Natalio, F.; Tahir, M. N.; Wiens, M.; Tarantola, M.; Therese, H. A.; Barz, M.; Weber, S.; Terekhov, M.; Schröder, H. C.; et al. Pathogen-Mimicking MnO Nanoparticles for Selective Activation of the TLR9 Pathway and Imaging of Cancer Cells. Adv. Funct. Mater. 2009, 19, 3717−3725. (503) Shukoor, M. I.; Natalio, F.; Tahir, M. N.; Barz, M.; Weber, S.; Brochhausen, C.; Zentel, R.; Schreiber, L. M.; Brieger, J.; Tremel, W. CpG-DNA Loaded Multifunctional MnO Nanoshuttles for TLR9Specific Cellular Cargo Delivery, Selective Immune-Activation and MRI. J. Mater. Chem. 2012, 22, 8826−8834. (504) Sicilia, G.; Grainger-Boultby, C.; Francini, N.; Magnusson, J. P.; Saeed, A. O.; Fernández-Trillo, F.; Spain, S. G.; Alexander, C. Programmable Polymer-DNA Hydrogels with Dual Input and Multiscale Responses. Biomater. Sci. 2014, 2, 203−211. (505) Cretich, M.; Sedini, V.; Damin, F.; Pelliccia, M.; Sola, L.; Chiari, M. Coating of Nitrocellulose for Colorimetric DNA Microarrays. Anal. Biochem. 2010, 397, 84−88. (506) Martinez, M. T.; Tseng, Y.-C.; Ormategui, N.; Loinaz, I.; Eritja, R.; Bokor, J. Label-Free DNA Biosensors Based on Functionalized Carbon Nanotube Field Effect Transistors. Nano Lett. 2009, 9 (2), 530−536. (507) Ulianas, A.; Heng, L. Y.; Hanifah, S. A.; Ling, T. L. An Electrochemical DNA Microbiosensor Based on Succinimide-Modified Acrylic Microspheres. Sensors 2012, 12, 5445−5460. (508) Shoemaker, S. G.; Hoffman, A. S.; Priest, J. H. Synthesis and Properties of Vinyl Monomer/Enzyme Conjugates-Conjugation of LBF



Chemical Reviews

Review

Asparaginase with N-Succinimidyl Acrylate. Appl. Biochem. Biotechnol. 1987, 15, 11−24. (509) Park, T. G.; Hoffman, A. S. Synthesis and Characterization of a Soluble, Temperature-Sensitive Polymer-Conjugated Enzyme. J. Biomater. Sci., Polym. Ed. 1993, 4, 493−504. (510) Chen, J. P.; Yang, H. J.; Hoffman, A. S. Polymer-Protein Conjugates. Biomaterials 1990, 11, 625−630. (511) Chen, J. P.; Hoffman, A. S. Polymer-Protein Conjugates. Biomaterials 1990, 11, 631−634. (512) Hao, Y.; Andersson, M.; Virto, C.; Galaev, I. Y.; Mattiasson, B.; Hatti-Kaul, R. Stability Properties of Thermoresponsive Poly(NIsopropylacrylamide)-Trypsin Conjugates. Biocatal. Biotransform. 2001, 19, 341−359. (513) Ivanov, A. E.; Edink, E.; Kumar, A.; Galaev, I. Y.; Arendsen, A. F.; Bruggink, A.; Mattiasson, B. Conjugation of Penicillin Acylase with the Reactive Copolymer of N-Isopropylacrylamide: A Step Toward a Thermosensitive Industrial Biocatalyst. Biotechnol. Prog. 2003, 19, 1167−1175. (514) Chen, J.-P.; Hsu, M.-S. Preparations and Properties of Temperature-Sensitive Poly (N-Isopropylacrylamide)-Chymotrypsin Conjugates. J. Mol. Catal. B: Enzym. 1997, 2, 233−241. (515) Korenbrot, J. I.; Perry, R.; Copenhagen, D. R. Development and Characterization of a Polymer Gel with an Immobilized Enzyme to Measure L-Glutamate. Anal. Biochem. 1987, 161, 187−199. (516) Tatsuma, T.; Fujimoto, Y.; Oyama, N. Controllable Electrocatalytic Activity of Heme Peptide in a Phase Transition Gel. Electrochem. Solid-State Lett. 1999, 3, 283−285. (517) Pollak, A.; Baughn, R. L.; Adalsteinsson, Ö .; Whitesides, G. M. Immobilization of Synthetically Useful Enzymes by Condensation Polymerization. J. Am. Chem. Soc. 1978, 100, 302−304. (518) Pierre, B. S. J.; Thies, J. C.; Dureault, A.; Cameron, N. R.; van Hest, J. C. M.; Carette, N.; Michon, T.; Weberskirch, R. Covalent Enzyme Immobilization onto Photopolymerized Highly Porous Monoliths. Adv. Mater. 2006, 18, 1822−1826. (519) Wei, W.; Du, J.; Li, J.; Yan, M.; Zhu, Q.; Jin, X.; Zhu, X.; Hu, Z.; Tang, Y.; Lu, Y. Construction of Robust Enzyme Nanocapsules for Effective Organophosphate Decontamination, Detoxification, and Protection. Adv. Mater. 2013, 25, 2212−2218. (520) Willems, L. I.; Li, N.; Florea, B. I.; Ruben, M.; van der Marel, G. A.; Overkleeft, H. S. Triple Bioorthogonal Ligation Strategy for Simultaneous Labeling of Multiple Enzymatic Activities. Angew. Chem., Int. Ed. 2012, 51, 4431−4434. (521) Cobo, I.; Li, M.; Sumerlin, B. S.; Perrier, S. Smart Hybrid Materials by Conjugation of Responsive Polymers to Biomacromolecules. Nat. Mater. 2014, 14, 143−159. (522) Sumerlin, B. S. Proteins as Initiators of Controlled Radical Polymerization: Grafting-from via ATRP and RAFT. ACS Macro Lett. 2012, 1, 141−145. (523) Tappertzhofen, K.; Metz, V. V.; Hubo, M.; Barz, M.; Postina, R.; Jonuleit, H.; Zentel, R. Synthesis of Maleimide-Functionalyzed HPMA-Copolymers and in Vitro Characterization of the aRAGE-and Human Immunoglobulin (huIgG)− Polymer Conjugates. Macromol. Biosci. 2013, 13, 203−214. (524) Gujraty, K. V.; Joshi, A.; Saraph, A.; Poon, V.; Mogridge, J.; Kane, R. S. Synthesis of Polyvalent Inhibitors of Controlled Molecular Weight: Structure-Activity Relationship for Inhibitors of Anthrax Toxin. Biomacromolecules 2006, 7, 2082−2085. (525) Nguyen, A. L.; Luong, J. H. T. Syntheses and Applications of Water-Soluble Reactive Polymers for Purification and Immobilization of Biomolecules. Biotechnol. Bioeng. 1989, 34, 1186−1190. (526) Sonoda, T.; Nogami, T.; Oishi, J.; Murata, M.; Niidome, T.; Katayama, Y. A Peptide Sequence Controls the Physical Properties of Nanoparticles Formed by Peptide-Polymer Conjugates That Respond to a Protein Kinase A Signal. Bioconjugate Chem. 2005, 16, 1542−1546. (527) Zhou, M.; Sivaramakrishnan, A.; Ponnamperuma, K.; Low, W.K.; Li, C.; Liu, J. O.; Bergbreiter, D. E.; Romo, D. Synthesis, Characterization, and Utility of Thermoresponsive Natural/Unnatural Product Macroligands for Affinity Chromatography. Org. Lett. 2006, 8, 5247−5250.

(528) Uludag, H.; Norrie, B.; Kousinioris, N.; Gao, T. Engineering Temperature-Sensitive Poly(N-Isopropylacrylamide) Polymers as Carriers of Therapeutic Proteins. Biotechnol. Bioeng. 2001, 73, 510− 521. (529) Singha, N. K.; Gibson, M. I.; Koiry, B. P.; Danial, M.; Klok, H.A. Side-Chain Peptide-Synthetic Polymer Conjugates via Tandem “Ester-Amide/Thiol-Ene” Post-Polymerization Modification of Poly(pentafluorophenyl Methacrylate) Obtained Using ATRP. Biomacromolecules 2011, 12, 2908−2913. (530) Raissi, A. J.; Scangarello, F. A.; Hulce, K. R.; Pontrello, J. K.; Paradis, S. Enhanced Potency of the Metalloprotease Inhibitor TAPI-2 by Multivalent Display. Bioorg. Med. Chem. Lett. 2014, 24, 2002−2007. (531) Yerushalmi, S. M.; Buck, M. E.; Lynn, D. M.; Lemcoff, N. G.; Meijler, M. M. Multivalent Alteration of Quorum Sensing in Staphylococcus Aureus. Chem. Commun. 2013, 49, 5177−5179. (532) Danial, M.; Root, M. J.; Klok, H.-A. Polyvalent Side Chain Peptide−Synthetic Polymer Conjugates as HIV-1 Entry Inhibitors. Biomacromolecules 2012, 13, 1438−1447. (533) Kolonko, E. M.; Kiessling, L. L. A Polymeric Domain That Promotes Cellular Internalization. J. Am. Chem. Soc. 2008, 130, 5626− 5627. (534) Song, Y.; Cheng, P.-N.; Zhu, L.; Moore, E. G.; Moore, J. S. Multivalent Macromolecules Redirect Nucleation-Dependent Fibrillar Assembly into Discrete Nanostructures. J. Am. Chem. Soc. 2014, 136, 5233−5236. (535) Puffer, E. B.; Pontrello, J. K.; Hollenbeck, J. J.; Kink, J. A.; Kiessling, L. L. Activating B Cell Signaling with Defined Multivalent Ligands. ACS Chem. Biol. 2007, 2, 252−262. (536) Shishkan, O.; Zamfir, M.; Gauthier, M. A.; Börner, H. G.; Lutz, J.-F. Complex Single-Chain Polymer Topologies Locked by Positionable Twin Disulfide Cyclic Bridges. Chem. Commun. 2014, 50, 1570− 1572. (537) Luo, T.; He, L.; Theato, P.; Kiick, K. L. Thermoresponsive Self-Assembly of Nanostructures from a Collagen-Like PeptideContaining Diblock Copolymer. Macromol. Biosci. 2015, 15, 111−123. (538) Smith, E.; Bai, J.; Oxenford, C.; Yang, J.; Somayaji, R.; Uludag, H. Conjugation of Arginine−Glycine−Aspartic Acid Peptides to Thermoreversible N-Isopropylacrylamide Polymers. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 3989−4000. (539) Na, K.; Choi, H.; Akaike, T.; Park, K.-H. Conjugation of ArgGly-Asp (RGD) Sequence in Copolymer Bearing Sugar Moiety for Insulinoma Cell Line (MIN6) Culture. Biosci., Biotechnol., Biochem. 2001, 65, 1284−1289. (540) Smith, E.; Yang, J.; McGann, L.; Sebald, W.; Uludag, H. RGDGrafted Thermoreversible Polymers to Facilitate Attachment of BMP2 Responsive C2C12 Cells. Biomaterials 2005, 26, 7329−7338. (541) Fujimoto, K.; Iwasaki, C.; Arai, C.; Kuwako, M.; Yasugi, E. Control of Cell Death by the Smart Polymeric Vehicle. Biomacromolecules 2000, 1, 515−518. (542) Baessler, K. A.; Lee, Y.; Sampson, N. S. B1 Integrin Is an Adhesion Protein for Sperm Binding to Eggs. ACS Chem. Biol. 2009, 4, 357−366. (543) Roberts, K. S.; Sampson, N. S. A Facile Synthetic Method to Prepare Fluorescently Labeled ROMP Polymers. Org. Lett. 2004, 6, 3253−3255. (544) Chaix, C.; Pacard, E.; Elaïssari, A.; Hilaire, J.-F.; Pichot, C. Surface Functionalization of Oil-in-Water Nanoemulsion with a Reactive Copolymer: Colloidal Characterization and Peptide Immobilization. Colloids Surf., B 2003, 29, 39−52. (545) Chen, J.-P.; Su, D.-R. Latex Particles with Thermo-Flocculation and Magnetic Properties for Immobilization of α-Chymotrypsin. Biotechnol. Prog. 2001, 17, 369−375. (546) Jia, H.; Zhu, G.; Wang, P. Catalytic Behaviors of Enzymes Attached to Nanoparticles: The Effect of Particle Mobility. Biotechnol. Bioeng. 2003, 84, 406−414. (547) Santos, J. L.; Li, Y.; Culver, H. R.; Yu, M. S.; Herrera-Alonso, M. Conducting Polymer Nanoparticles Decorated with Collagen Mimetic Peptides for Collagen Targeting. Chem. Commun. 2014, 50, 15045−15048. BG



Chemical Reviews

Review

Copolymers Containing Terpyridines. Macromolecules 2002, 35, 6090−6093. (567) Shunmugam, R.; Tew, G. N. Unique Emission from Polymer Based Lanthanide Alloys. J. Am. Chem. Soc. 2005, 127, 13567−13572. (568) Fang, Z.; Ito, A.; Stuart, A. C.; Luo, H.; Chen, Z.; Vinodgopal, K.; You, W.; Meyer, T. J.; Taylor, D. K. Soluble Reduced Graphene Oxide Sheets Grafted with Polypyridylruthenium-Derivatized Polystyrene Brushes as Light Harvesting Antenna for Photovoltaic Applications. ACS Nano 2013, 7, 7992−8002. (569) Grogna, M.; Cloots, R.; Luxen, A.; Jérôme, C.; Desreux, J.-F.; Detrembleur, C. Design and Synthesis of Novel DOTA(Gd3+)− polymer Conjugates as Potential MRI Contrast Agents. J. Mater. Chem. 2011, 21, 12917−12926. (570) Beija, M.; Li, Y.; Duong, H. T.; Laurent, S.; van der Elst, L.; Muller, R. N.; Lowe, A. B.; Davis, T. P.; Boyer, C. Polymer−gold Nanohybrids with Potential Use in Bimodal MRI/CT: Enhancing the Relaxometric Properties of Gd(III) Complexes. J. Mater. Chem. 2012, 22 (40), 21382−21386. (571) Rowe, M. D.; Tham, D. H.; Kraft, S. L.; Boyes, S. G. PolymerModified Gadolinium Metal-Organic Framework Nanoparticles Used as Multifunctional Nanomedicines for the Targeted Imaging and Treatment of Cancer. Biomacromolecules 2009, 10, 983−993. (572) Pressly, E. D.; Rossin, R.; Hagooly, A.; Fukukawa, K.; Messmore, B. W.; Welch, M. J.; Wooley, K. L.; Lamm, M. S.; Hule, R. A.; Pochan, D. J.; et al. Structural Effects on the Biodistribution and Positron Emission Tomography (PET) Imaging of Well-Defined 64Cu-Labeled Nanoparticles Comprised of Amphiphilic Block Graft Copolymers. Biomacromolecules 2007, 8, 3126−3134. (573) Sloop, F. V.; Brown, G. M.; Foote, R. S.; Jacobson, K. B.; Sachleben, R. A. Synthesis of 3-(triethylstannyl)propanoic Acid: An Organotin Mass Label for DNA. Bioconjugate Chem. 1993, 4 (18), 406−409. (574) Thompson, L. B.; Mack, N. H.; Nuzzo, R. G. Bifunctional Polyacrylamide Based Polymers for the Specific Binding of Hexahistidine Tagged Proteins on Gold Surfaces. Phys. Chem. Chem. Phys. 2010, 12, 4301−4308. (575) Tanner, S. D.; Bandura, D. R.; Ornatsky, O.; Baranov, V. I.; Nitz, M.; Winnik, M. A. Flow Cytometer with Mass Spectrometer Detection for Massively Multiplexed Single-Cell Biomarker Assay. Pure Appl. Chem. 2008, 80, 2627−2641. (576) Thickett, S. C.; Abdelrahman, A. I.; Ornatsky, O.; Bandura, D.; Baranov, V.; Winnik, M. A. Bio-Functional, Lanthanide-Labeled Polymer Particles by Seeded Emulsion Polymerization and Their Characterization by Novel ICP-MS Detection. J. Anal. At. Spectrom. 2010, 25, 269−281. (577) Eichenbaum, G. M.; Kiser, P. F.; Shah, D.; Meuer, W. P.; Needham, D.; Simon, S. A. Alkali Earth Metal Binding Properties of Ionic Microgels. Macromolecules 2000, 33, 4087−4093. (578) Leipold, M. D.; Herrera, I.; Ornatsky, O.; Baranov, V.; Nitz, M. ICP-MS-Based Multiplex Profiling of Glycoproteins Using Lectins Conjugated to Lanthanide-Chelating Polymers. J. Proteome Res. 2009, 8, 443−449. (579) Lou, X.; Zhang, G.; Herrera, I.; Kinach, R.; Ornatsky, O.; Baranov, V.; Nitz, M.; Winnik, M. a. Polymer-Based Elemental Tags for Sensitive Bioassays. Angew. Chem., Int. Ed. 2007, 46, 6111−6114. (580) Ibáñez, A. J.; Muck, A.; Svatoš, A. Metal-Chelating Plastic MALDI (pMALDI) Chips for the Enhancement of PhosphorylatedPeptide/protein Signals. J. Proteome Res. 2007, 6, 3842−3848. (581) Zhang, L.; Wang, H.; Liang, Z.; Yang, K.; Zhang, L.; Zhang, Y. Facile Preparation of Monolithic Immobilized Metal Affinity Chromatography Capillary Columns for Selective Enrichment of Phosphopeptides. J. Sep. Sci. 2011, 34, 2122−2130. (582) Rossow, T.; Hackelbusch, S.; van Assenbergh, P.; Seiffert, S. Polymer Chemistry A Modular Construction Kit for Supramolecular Polymer. Polym. Chem. 2013, 4, 2515−2527. (583) Hackelbusch, S.; Rossow, T.; van Assenbergh, P.; Seiffert, S. Chain Dynamics in Supramolecular Polymer Networks. Macromolecules 2013, 46, 6273−6286.

(548) Lange, B.; Metz, N.; Tahir, M. N.; Fleischhaker, F.; Theato, P.; Schröder, H.-C.; Müller, W. E. G.; Tremel, W.; Zentel, R. Functional Polymer-Opals from Core−Shell Colloids. Macromol. Rapid Commun. 2007, 28, 1987−1994. (549) Cordovilla, C.; Swager, T. M. Strain Release in Organic Photonic Nanoparticles for Protease Sensing. J. Am. Chem. Soc. 2012, 134, 6932−6935. (550) Ku, T.-H.; Chien, M.-P.; Thompson, M. P.; Sinkovits, R. S.; Olson, N. H.; Baker, T. S.; Gianneschi, N. C. Controlling and Switching the Morphology of Micellar Nanoparticles with Enzymes. J. Am. Chem. Soc. 2011, 133, 8392−8395. (551) Gelbrich, T.; Reinartz, M.; Schmidt, A. M. Active Ester Functional Single Core Magnetic Nanostructures as a Versatile Immobilization Matrix for Effective Bioseparation and Catalysis. Biomacromolecules 2010, 11, 635−642. (552) Shukoor, M. I.; Natalio, F.; Therese, H. A.; Tahir, M. N.; Ksenofontov, V.; Panthöfer, M.; Eberhardt, M.; Theato, P.; Schröder, H. C.; Müller, W. E. G.; et al. Fabrication of a Silica Coating on Magnetic γ-Fe2O3 Nanoparticles by an Immobilized Enzyme. Chem. Mater. 2008, 20, 3567−3573. (553) Tahir, M. N.; Eberhardt, M.; Therese, H. A.; Kolb, U.; Theato, P.; Müller, W. E. G.; Schröder, H. C.; Tremel, W. From Single Molecules to Nanoscopically Structured Functional Materials: Au Nanocrystal Growth on TiO2 Nanowires Controlled by Surface-Bound Silicatein. Angew. Chem., Int. Ed. 2006, 45, 4803−4809. (554) Cretich, M.; di Carlo, G.; Longhi, R.; Gotti, C.; Spinella, N.; Coffa, S.; Galati, C.; Renna, L.; Chiari, M. High Sensitivity Protein Assays on Microarray Silicon Slides Marina. Anal. Chem. 2009, 81, 5197−5203. (555) Cretich, M.; Bagnati, M.; Damin, F.; Sola, L.; Chiari, M. Overcoming Mass Transport Limitations to Achieve Femtomolar Detection Limits on Silicon Protein Microarrays. Anal. Biochem. 2011, 418, 164−166. (556) Battistella, S.; Damin, F.; Chiari, M.; Delgrosso, K.; Surrey, S.; Fortina, P.; Ferrari, M.; Cremonesi, L. Genotyping β-Globin Gene Mutations on Copolymer-Coated Glass Slides with the Ligation Detection Reaction. Clin. Chem. 2008, 54, 1657−1663. (557) Cretich, M.; Breda, D.; Damin, F.; Borghi, M.; Sola, L.; Unlu, S. M.; Burastero, S. E.; Chiari, M. Allergen Microarrays on HighSensitivity Silicon Slides. Anal. Bioanal. Chem. 2010, 398, 1723−1733. (558) Cifuentes, A.; Borrós, S. Comparison of Two Different Plasma Surface-Modification Techniques for the Covalent Immobilization of Protein Monolayers. Langmuir 2013, 29, 6645−6651. (559) Rickert, E. L.; Trebley, J. P.; Peterson, A. C.; Morrell, M. M.; Weatherman, R. V. Synthesis and Characterization of Bioactive Tamoxifen-Conjugated Polymers. Biomacromolecules 2007, 8, 3608− 3612. (560) Blanco, M. D.; Guerrero, S.; Benito, M.; Teijon, C.; Olmo, R.; Muniz, E.; Katime, I.; Teijon, J. M. Tamoxifen-Loaded FolateConjugate Poly[(p-Nitrophenyl Acrylate)-co-(N-Isopropylacrylamide)] Sub-Microgel as Antitumoral Drug Delivery System. J. Biomed. Mater. Res., Part A 2010, 95A, 1028−1040. (561) Schieferstein, H.; Kelsch, A.; Reibel, A.; Koynov, K.; Barz, M.; Buchholz, H.-G.; Bausbacher, N.; Thews, O.; Zentel, R.; Ross, T. L. 18F-Radiolabeling, Preliminary Evaluation of Folate-pHPMA Conjugates via PET. Macromol. Biosci. 2014, 14, 1396−1405. (562) Relogio, P.; Bathfield, M.; Haftek-Terreau, Z.; Beija, M.; Favier, A.; Giraud-Panis, M.-J.; D’Agosto, F.; Mandrand, B.; Farinha, J. P. S.; Charreyre, M.-T.; et al. Biotin-End-Functionalized Highly Fluorescent Water-Soluble Polymers. Polym. Chem. 2013, 4, 2968−2981. (563) Heredia, K. L.; Maynard, H. D. Synthesis of Protein-Polymer Conjugates. Org. Biomol. Chem. 2007, 5, 45−53. (564) Manners, I. Putting Metals into Polymers. Science 2001, 294, 1664−1667. (565) Lohmeijer, B. G. G.; Schubert, U. S. Playing LEGO with Macromolecules: Design, Synthesis, and Self-Organization with Metal Complexes. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 1413−1427. (566) Calzia, K. J.; Tew, G. N. Methacrylate Polymers Containing Metal Binding Ligands for Use in Supramolecular Materials: Random BH



Chemical Reviews

Review

(604) O’ Shaughnessy, W. S.; Mari-Buye, N.; Borros, S.; Gleason, K. K. Initiated Chemical Vapor Deposition of a Surface-Modifiable Copolymer for Covalent Attachment and Patterning of Nucleophilic Ligands. Macromol. Rapid Commun. 2007, 28, 1877−1882. (605) Montero, L.; Baxamusa, S. H.; Borros, S.; Gleason, K. K. Thin Hydrogel Films With Nanoconfined Surface Reactivity by Photoinitiated Chemical Vapor Deposition. Chem. Mater. 2009, 21, 399− 403. (606) Deng, X.; Eyster, T. W.; Elkasabi, Y.; Lahann, J. BioOrthogonal Polymer Coatings for Co-Presentation of Biomolecules. Macromol. Rapid Commun. 2012, 33, 640−645. (607) Lahann, J.; Choi, I. S.; Lee, J.; Jensen, K. F.; Langer, R. A New Method toward Microengineered Surfaces Based on Reactive Coating. Angew. Chem., Int. Ed. 2001, 40, 3166−3169. (608) García-Uriostegui, L.; Burillo, G.; Bucio, E. Radiation Grafting of NIPAAm and Acryloxysuccinimide onto PP Films and Sequent Crosslinking with Polylysine. Eur. Polym. J. 2010, 46, 1074−1083. (609) Gabriel, S.; Duwez, A.-S.; Jerome, R.; Jerome, C. Thermoresponsive Coatings Strongly Adhering to (Semi) Conducting Surfaces. Langmuir 2007, 23, 159−161. (610) Cuenot, S.; Gabriel, S.; Jerome, R.; Jerome, C.; Fustin, C.-A.; Jonas, A. M.; Duwez, A.-S. First Insights into Electrografted Polymers by AFM-Based Force Spectroscopy. Macromolecules 2006, 39, 8428− 8433. (611) Cecchet, F.; Lussis, P.; Jérôme, C.; Gabriel, S.; Silva-Goncalves, E.; Jérôme, R.; Duwez, A.-S. A Generic Chemical Platform for Molecular Recognition and Stimuli-Responsive Probes Based on Scanning Probe Microscopy. Small 2008, 4, 1101−1104. (612) Feng, C. L.; Vancso, G. J.; Schönherr, H. Fabrication of Robust Biomolecular Patterns by Reactive Microcontact Printing on NHydroxysuccinimide Ester-Containing Polymer Films. Adv. Funct. Mater. 2006, 16, 1306−1312. (613) Feng, C. L.; Zhang, Z.; Förch, R.; Knoll, W.; Vancso, G. J.; Schönherr, H. Reactive Thin Polymer Films as Platforms for the Immobilization of Biomolecules. Biomacromolecules 2005, 6, 3243− 3251. (614) Guerrero-Ramírez, L. G.; Nuño-Donlucas, S. M.; Cesteros, L. C.; Katime, I. Smart Copolymeric Nanohydrogels: Synthesis, Characterization and Properties. Mater. Chem. Phys. 2008, 112, 1088−1092. (615) Yalçin, A.; Damin, F.; Ö zkumur, E.; di Carlo, G.; Goldberg, B. B.; Chiari, M.; Ü nlü, M. S. Direct Observation of Conformation of a Polymeric Coating with Implications in Microarray Applications. Anal. Chem. 2009, 81, 625−630. (616) Zhang, X.; Daaboul, G. G.; Spuhler, P. S.; Freedman, D. S.; Yurt, A.; Ahn, S.; Avci, O.; Ü nlü, M. S. Nanoscale Characterization of DNA Conformation Using Dual-Color Fluorescence Axial Localization and Label-Free Biosensing. Analyst 2014, 139, 6440−6449. (617) Terada, Y.; Hashimoto, W.; Endo, T.; Seto, H.; Murakami, T.; Hisamoto, H.; Hoshino, Y.; Miura, Y. Signal Amplified TwoDimensional Photonic Crystal Biosensor Immobilized with GlycoNanoparticles. J. Mater. Chem. B 2014, 2, 3324−3332. (618) Zilio, C.; Sola, L.; Damin, F.; Faggioni, L.; Chiari, M. Universal Hydrophilic Coating of Thermoplastic Polymers Currently Used in Microfluidics. Biomed. Microdevices 2014, 16, 107−114. (619) Petti, D.; Torti, A.; Damin, F.; Sola, L.; Rusnati, M.; Albisetti, E.; Bugatti, A.; Bertacco, R.; Chiari, M. Functionalization of Gold Surfaces with copoly(DMA-NAS-MAPS) by Dip Coating: Surface Characterization and Hybridization Tests. Sens. Actuators, B 2014, 190, 234−242. (620) Platt, G. W.; Damin, F.; Swann, M. J.; Metton, I.; Skorski, G.; Cretich, M.; Chiari, M. Allergen Immobilisation and Signal Amplification by Quantum Dots for Use in a Biosensor Assay of IgE in Serum. Biosens. Bioelectron. 2014, 52, 82−88. (621) Sola, L.; Chiari, M. Modulation of Electroosmotic Flow in Capillary Electrophoresis Using Functional Polymer Coatings. J. Chromatogr. A 2012, 1270, 324−329.

(584) Skodova, M.; Hruby, M.; Filippov, S. K.; Karlsson, G.; Mackova, H.; Spirkova, M.; Kankova, D.; Steinhart, M.; Stepanek, P.; Ulbrich, K. Novel Polymeric Nanoparticles Assembled by Metal Ion Addition. Macromol. Chem. Phys. 2011, 212, 2339−2348. (585) Phillips, D. J.; Prokes, I.; Davies, G.; Gibson, M. I. Isothermally-Responsive Polymers Triggered by Selective Binding of Fe 3+ to Siderophoric Catechol End-Groups. ACS Macro Lett. 2014, 3, 1225−1229. (586) Bergbreiter, D. E.; Koshti, N.; Franchina, J. G.; Frels, J. D. Sequestration of Trace Metals Using Water-Soluble and Fluorous Phase-Soluble Polymers. Angew. Chem., Int. Ed. 2000, 39, 1039−1042. (587) Bergbreiter, D. E.; Franchina, J. G.; Case, B. L. FluoroacrylateBound Fluorous-Phase Soluble Hydrogenation Catalysts. Org. Lett. 2000, 2, 393−395. (588) Xu, L. Q.; Neoh, K.-G.; Kang, E.-T.; Fu, G. D. Rhodamine Derivative-Modified Filter Papers for Colorimetric and Fluorescent Detection of Hg2+ in Aqueous Media. J. Mater. Chem. A 2013, 1, 2526−2532. (589) Szunerits, S.; Walt, D. R. Aluminum Surface Corrosion and the Mechanism of Inhibitors Using pH and Metal Ion Selective Imaging Fiber Bundles. Anal. Chem. 2002, 74 (4), 886−894. (590) McNamara, C. a.; Dixon, M. J.; Bradley, M. Recoverable Catalysts and Reagents Using Recyclable Polystyrene-Based Supports. Chem. Rev. 2002, 102, 3275−3300. (591) Bergbreiter, D. E.; Osburn, P. L.; Frels, J. D. Mechanistic Studies of SCS-Pd Complexes Used in Heck Catalysis. Adv. Synth. Catal. 2005, 347, 172−184. (592) Bergbreiter, D. E.; Osburn, P. L.; Frels, J. D. Nonpolar Polymers for Metal Sequestration Ligand and Catalyst Recovery in Thermomorphic Systems. J. Am. Chem. Soc. 2001, 123, 11105−11106. (593) Sharma, S.; Basavaraju, K. C.; Singh, A. K.; Kim, D.-P. Continuous Recycling of Homogeneous Pd/Cu Catalysts for CrossCoupling Reactions. Org. Lett. 2014, 16, 3974−3977. (594) Potier, J.; Menuel, S.; Fournier, D.; Fourmentin, S.; Woisel, P.; Monflier, E.; Hapiot, F. Cooperativity in Aqueous Organometallic Catalysis: Contribution of Cyclodextrin-Substituted Polymers. ACS Catal. 2012, 2, 1417−1420. (595) Bergbreiter, D. E.; Osburn, P. L.; Smith, T.; Li, C.; Frels, J. D. Using Soluble Polymers in Latent Biphasic Systems. J. Am. Chem. Soc. 2003, 125 (8), 6254−6260. (596) Bergbreiter, D. E.; Case, B. L.; Liu, Y.; Caraway, J. W. Poly (NIsopropylacrylamide) Soluble Polymer Supports in Catalysis and Synthesis. Macromolecules 1998, 31, 6053−6062. (597) Zeltner, M.; Schät z, A.; Hefti, M. L.; Stark, W. J. Magnetothermally Responsive C/Co@PNIPAM-Nanoparticles Enable Preparation of Self-Separating Phase-Switching Palladium Catalysts. J. Mater. Chem. 2011, 21, 2991−2996. (598) Galvin, C. J.; Genzer, J. Applications of Surface-Grafted Macromolecules Derived from Post-Polymerization Modification Reactions. Prog. Polym. Sci. 2012, 37, 871−906. (599) Barbey, R.; Lavanant, L.; Paripovic, D.; Schüwer, N.; Sugnaux, C.; Tugulu, S.; Klok, H.-A. Polymer Brushes via Surface-Initiated Controlled Radical Polymerization: Synthesis, Characterization, Properties, and Applications. Chem. Rev. 2009, 109, 5437−5527. (600) Alf, B. M. E.; Asatekin, A.; Barr, M. C.; Baxamusa, S. H.; Chelawat, H.; Ozaydin-Ince, G.; Petruczok, C. D.; Sreenivasan, R.; Tenhaeff, W. E.; Trujillo, N. J.; et al. Chemical Vapor Deposition of Conformal, Functional, and Responsive Polymer Films. Adv. Mater. 2010, 22, 1993−2027. (601) Horna, D.; Ramírez, J. C.; Cifuentes, A.; Bernad, A.; Borrós, S.; González, M. A. Efficient Cell Reprogramming Using Bioengineered Surfaces. Adv. Healthcare Mater. 2012, 1, 177−182. (602) Cifuentes, A.; Borros, S. Comparison of Two Different Plasma Surface-Modification Techniques for the Covalent Immobilization of Protein Monolayers. Langmuir 2013, 29, 6645−6651. (603) Duque, L.; Menges, B.; Borros, S.; Förch, R. Immobilization of Biomolecules to Plasma Polymerized Pentafluorophenyl Methacrylate. Biomacromolecules 2010, 11, 2818−2823. BI



Chemical Reviews

Review

(622) Pirri, G.; Damin, F.; Chiari, M.; Bontempi, E.; Depero, L. E. Characterization of A Polymeric Adsorbed Coating for DNA Microarray Glass Slides. Anal. Chem. 2004, 76, 1352−1358. (623) Galbiati, S.; Damin, F.; Di Carlo, G.; Ferrari, M.; Cremonesi, L.; Chiari, M. Development of New Substrates for High-Sensitive Genotyping of Minority Mutated Alleles. Electrophoresis 2008, 29, 4714−4722. (624) Spuhler, P. S.; Sola, L.; Zhang, X.; Monroe, M. R.; Greenspun, J. T.; Chiari, M.; Ü nlü, M. S. Precisely Controlled Smart Polymer Scaffold for Nanoscale Manipulation of Biomolecules. Anal. Chem. 2012, 84, 10593−10599. (625) Suriano, R.; Levi, M.; Pirri, G.; Damin, F.; Chiari, M.; Turri, S. Surface Behavior and Molecular Recognition in DNA Microarrays from N,N-Dimethylacrylamide Terpolymers with Activated Esters as Linking Groups. Macromol. Biosci. 2006, 6, 719−729. (626) Di Carlo, G.; Damin, F.; Armelao, L.; Maccato, C.; Unlu, S.; Spuhler, P. S.; Chiari, M. Synthesis and Conformational Characterization of Functional Di-Block Copolymer Brushes for Microarray Technology. Appl. Surf. Sci. 2012, 258, 3750−3756. (627) Starling, J.; da Silva, C. M.; Silva Dantas, M. S.; de Fátima, Â .; Oréfice, R. L. N-Acryloxysuccinimide: Synthesis, Characterization, and Incorporation in Dental Adhesives. Int. J. Adhes. Adhes. 2011, 31, 767− 774. (628) Oliviero, G.; Bergese, P.; Canavese, G.; Chiari, M.; Colombi, P.; Cretich, M.; Damin, F.; Fiorilli, S.; Marasso, S. L.; Ricciardi, C.; et al. A Biofunctional Polymeric Coating for Microcantilever Molecular Recognition. Anal. Chim. Acta 2008, 630, 161−167. (629) Fu, H.; Hong, X.; Wan, A.; Batteas, J. D.; Bergbreiter, D. E. Parallel Effects of Cations on PNIPAM Graft Wettability and PNIPAM Solubility. ACS Appl. Mater. Interfaces 2010, 2, 452−458. (630) Liao, K.-S.; Fu, H.; Wan, A.; Batteas, J. D.; Bergbreiter, D. E. Designing Surfaces with Wettability That Varies in Response to Solute Identity and Concentration. Langmuir 2009, 25, 26−28. (631) Tanaka, H.; Hanasaki, M.; Isojima, T.; Takeuchi, H.; Shiroya, T.; Kawaguchi, H. Enhancement of Sensitivity of SPR Protein Microarray Using a Novel 3D Protein Immobilization. Colloids Surf., B 2009, 70, 259−265. (632) Ignatova, M.; Voccia, S.; Gabriel, S.; Gilbert, B.; Cossement, D.; Jérôme, R.; Jérôme, C. Stainless Steel Grafting of Hyperbranched Polymer Brushes with an Antibacterial Activity: Synthesis, Characterization, and Properties. Langmuir 2009, 25, 891−902. (633) Kessler, D.; Theato, P. Reactive Surface Coatings Based on Polysilsesquioxanes: Defined Adjustment of Surface Wettability. Langmuir 2009, 25, 14200−14206. (634) Kessler, D.; Jochum, F. D.; Choi, J.; Char, K.; Theato, P. Reactive Surface Coatings Based on Polysilsesquioxanes: Universal Method toward Light-Responsive Surfaces. ACS Appl. Mater. Interfaces 2011, 3, 124−128. (635) Kessler, D.; Roth, P. J.; Theato, P. Reactive Surface Coatings Based on Polysilsesquioxanes: Controlled Functionalization for Specific Protein Immobilization. Langmuir 2009, 25, 10068−10076. (636) Wan, X.; Wang, D.; Liu, S. Fluorescent pH-Sensing Organic/ Inorganic Hybrid Mesoporous Silica Nanoparticles with Tunable Redox-Responsive Release Capability. Langmuir 2010, 26, 15574− 15579. (637) Tahir, M. N.; Eberhardt, M.; Theato, P.; Faiß, S.; Janshoff, A.; Gorelik, T.; Kolb, U.; Tremel, W. Reactive Polymers: AVersatile Toolbox for the Immobilization of Functional Molecules on TiO2 Nanoparticles. Angew. Chem., Int. Ed. 2006, 45, 908−912. (638) Tahir, M. N.; Zink, N.; Eberhardt, M.; Therese, H. A.; Kolb, U.; Theato, P.; Tremel, W. Overcoming the Insolubility of Molybdenum Disulfide Nanoparticles through a High Degree of Sidewall Functionalization Using Polymeric Chelating Ligands. Angew. Chem., Int. Ed. 2006, 45, 4809−4815. (639) Finetti, C.; Colombo, M.; Prosperi, D.; Alessio, G.; Morasso, C.; Sola, L.; Chiari, M. One-Pot Phase Transfer and Surface Modification of CdSe-ZnS Quantum Dots Using a Synthetic Functional Copolymer. Chem. Commun. 2014, 50, 240−242.

(640) Gibson, M. I.; Danial, M.; Klok, H.-A. Sequentially Modified, Polymer-Stabilized Gold Nanoparticle Libraries: Convergent Synthesis and Aggregation Behavior. ACS Comb. Sci. 2011, 13, 286−297. (641) Gibson, M. I.; Paripovic, D.; Klok, H. A. Size-Dependent LCST Transitions of Polymer-Coated Gold Nanoparticles: Cooperative Aggregation and Surface Assembly. Adv. Mater. 2010, 22, 4721− 4725. (642) Cifuentes-Rius, A.; Ramos-Perez, V.; Borrós, S. Tailoring Carbon Nanotubes Properties for Gene Delivery Applications. Plasma Processes Polym. 2014, 11, 704−713. (643) Bauerle, P.; Hiller, M.; Scheib, S.; Sokolowski, M.; Umbach, E. Post-Polymerization Functionalization of Conducting Polymers: Novel Poly(alkylthiophene)s Substituted with Easily Replaceable Activated Ester Groups. Adv. Mater. 1996, 8, 214−218. (644) Kim, H.-C.; Lee, S.-K.; Lee, S. W.; Jeong, S. W. A Reactive Polythiophene for Protein Immobilization. Polym. Adv. Technol. 2009, 20, 298−302. (645) Kang, S. K.; Kim, J.-H.; An, J.; Lee, E. K.; Cha, J.; Lim, G.; Park, Y. S.; Chung, D. J. Synthesis of Polythiophene Derivatives and Their Application for Electrochemical DNA Sensor. Polym. J. 2004, 36, 937−942.

BJ


Activated Ester Containing Polymers: Opportunities and Challenges

Recommend Documents