Star Polymers - ACS Publications - American Chemical Society

Review pubs.acs.org/CR

Star Polymers Jing M. Ren,† Thomas G. McKenzie,† Qiang Fu,† Edgar H. H. Wong,† Jiangtao Xu,‡ Zesheng An,§ Sivaprakash Shanmugam,‡ Thomas P. Davis,*,∥,⊥ Cyrille Boyer,*,‡ and Greg G. Qiao*,† †

Polymer Science Group, Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia ‡ Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine, School of Chemical Engineering, UNSW Australia, Sydney, New South Wales 2052, Australia § Institute of Nanochemistry and Nanobiology, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 2000444, People’s Republic of China ∥ ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia ⊥ Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom ABSTRACT: Recent advances in controlled/living polymerization techniques and highly efficient coupling chemistries have enabled the facile synthesis of complex polymer architectures with controlled dimensions and functionality. As an example, star polymers consist of many linear polymers fused at a central point with a large number of chain end functionalities. Owing to this exclusive structure, star polymers exhibit some remarkable characteristics and properties unattainable by simple linear polymers. Hence, they constitute a unique class of technologically important nanomaterials that have been utilized or are currently under audition for many applications in life sciences and nanotechnologies. This article first provides a comprehensive summary of synthetic strategies towards star polymers, then reviews the latest developments in the synthesis and characterization methods of star macromolecules, and lastly outlines emerging applications and current commercial use of star-shaped polymers. The aim of this work is to promote star polymer research, generate new avenues of scientific investigation, and provide contemporary perspectives on chemical innovation that may expedite the commercialization of new star nanomaterials. We envision in the nottoo-distant future star polymers will play an increasingly important role in materials science and nanotechnology in both academic and industrial settings.

CONTENTS 1. Introduction 2. Star Polymer Synthesis 2.1. Synthetic Approaches 2.1.1. Core-First Approach 2.1.2. Arm-First Approach 2.1.3. Grafting-onto Approach 2.2. Star Polymer Synthesis via Various Polymerization Methods 2.2.1. Ring-Opening Polymerization (ROP) of Cyclic Esters and Derivatives 2.2.2. Ring-Opening Polymerization (ROP) of N-Carboxyanhydride 2.2.3. Atom Transfer Radical Polymerization (ATRP) 2.2.4. Single Electron Transfer Living Radical Polymerization (SET-LRP) 2.2.5. Nitroxide-Mediated Living Radical Polymerization 2.2.6. Reversible Addition−Fragmentation Chain Transfer (RAFT) Radical Polymerization © 2016 American Chemical Society

2.2.7. Ring-Opening Metathesis Polymerization (ROMP) 3. Characterization 3.1. Traditional Characterization Techniques (GPC, NMR, DLS) 3.2. Two-Dimensional Chromatography 3.3. Spectroscopic Analysis of Star Polymers 3.4. Direct Imaging via Microscopy 3.5. Direct (Cross-Linked) Core Analysis 4. Properties and Applications 4.1. Rheology 4.2. Thermal Properties 4.3. Nanostructured Thin Films 4.4. Interfacial Stabilizing Agents 4.5. Star Polymers for Gene Delivery 4.6. Star Polymers for Drug Delivery 4.6.1. Drug Encapsulation 4.6.2. Drug Delivery 4.7. Star Polymers for Imaging

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Received: January 4, 2016 Published: June 14, 2016

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DOI: 10.1021/acs.chemrev.6b00008 Chem. Rev. 2016, 116, 6743−6836

Chemical Reviews 4.8. Nanoreactors/Catalysis 4.9. Current Industrial Applications 5. Conclusion and Future Perspectives Author Information Corresponding Authors Notes Biographies Acknowledgments References

Review

materials scientists seeking higher order architectures with unique properties due to their spatially defined (i.e., core− shell−periphery) yet compact three-dimensional structure. A diverse range of star polymer structures can be realized through controlled polymerization techniques, with key examples including miktoarm, block copolymer, network−core, and end-functionalized star polymers as illustrated in Figure 1. Different approaches toward the synthesis of star polymers exist and can be broadly categorized into three types: (i) the core-first, (ii) arm-first, and (iii) grafting-onto approaches. Each of these has a select set of advantages and disadvantages inherently attached, and so care must be taken when planning the desired properties or targeted application for the star polymer prior to deciding which approach to employ. Advances in controlled/living polymerization methods have greatly improved the accessibility to star polymers, with libraries of stars of different size and/or functionality now able to be prepared for detailed assessment of structure−property relationships. In particular, reversible deactivation radical polymerization (RDRP) (formerly referred to as controlled/ living radical polymerization (CLRP)) has revolutionized the synthesis of complex polymeric architectures, including star polymers, due to the improved control over end-group fidelity (i.e., “livingness”) and molecular weight distributions. Given the benefits of radical polymerizations over systems relying on an ionic mechanism (e.g., less strict reaction conditions, wider range of compatible functional groups, etc.) these techniques have become arguably the most used for the preparation of functional star polymers. Despite the significant progress in this area, adoption of RDRP techniques for industrial-scale synthesis of complex polymeric structures remains limited. This will need to be addressed if the proposed use of star polymers in high-value applications is to be realized. The means of synthesis and the potential applications of star polymers are, in the authors’ opinion, of equal value. Therefore, both will be discussed at length in the current review. Section 2 will begin by discussing more conceptually the different approaches toward the synthesis of star-shaped polymers, including why certain pathways may be more appropriate for a targeted application as well as common challenges encountered for each approach. This will then be expanded on in more detail by presenting the wide variety of different polymerization methods that have been employed for the synthesis of star polymers. This section will present key aspects of each polymerization technique including the range of polymerizable monomers, typical reaction conditions, particular difficulties or limitations, as well as state-of-the-art optimizations that have been developed to ensure high yields and finer control over the generated star structure. In section 3 the methods to characterize the physical and macromolecular properties of star polymers will be discussed, including key features such as the calculated number of arms (Narm), the molecular weight (MW), the molecular weight distribution (MWD), and the hydrodynamic size in solution. Each of these features has a strong influence on the properties of the synthesized star polymer, which will be highlighted in section 4 along with the potential applications of star polymers with different structures or functionalities. This review therefore aims to provide a comprehensive overview of the research concerning star polymers and to highlight works of particular interest mainly covering the period from 2009 up to the present day. The interested reader is directed to reviews by Qiao1 and Matyjaszewski2 for research

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1. INTRODUCTION Star polymers represent a broad class of branched macromolecular architectures with linear “arms” radiating from a central branching point, typically referred to as the “core”. These macromolecules can be further classified according to monomer composition, sequence distribution of the arm polymer, and chemical structure or molecular nature of the core (Figure 1). They represent one of the most simple deviations from one-dimensional linear polymers and have therefore been the subject of immense interest for chemists and

Figure 1. Illustration of various types of star polymers classified by (a) composition and sequence distribution of the arm polymer, (b) difference in arm species, (c) core structure, and (d) functional placement. 6744


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Figure 2. Schematic illustration of star polymer synthesis via the core-first approach.

Figure 3. Schematic illustration of three common strategies for star polymer synthesis via the arm-first route including (a) macroinitiator, (b) macromonomer, and (c) self-assembly cross-linking approaches.

published prior to 2009. Due to the extensive breadth of available synthetic strategies, the use of ionic polymerization for the synthesis of star polymers is not included in this review. Over the period following our previous review on the subject,1

we observe that the development of star polymers has been closely linked to the advance in polymerization techniques that display increasing synthetic precision (i.e., monomer/block sequencing, high end-group fidelity, low dispersity, etc.). In 6745


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tailored initiator design adds complication to the overall synthesis, as such miktoarm stars with great arm numbers are especially difficult to obtain via this approach. Nevertheless, star block copolymers can be made with ease through chain extension initiated by the “living” chain ends that are “inherited” from the previous polymerization (Figure 2). A further drawback of the core-first approach is that arm polymers of the synthesized stars cannot be directly characterized, so indirect methods including end-group analysis, determination of branching parameters, and isolation of the arm polymers after cleavage must be employed to determine the arm MWs (section 4).1 When controlled radical polymerizations are performed for the core-first star synthesis, special precautions should be taken to prevent side reactions such as bimolecular termination and disproportionation. These side reactions may lead to star−star coupling and termination of the growing arm polymers, resulting in star products with wide MW distributions, as well as ill-defined structures including uneven and cyclic arms.24 2.1.2. Arm-First Approach. Different from the core-first approach, the arm-first approach forms star polymers by crosslinking linear polymers via a polymerization or coupling reaction (Figure 3) in a convergent fashion. Upon the basis of a cross-linking mechanism, arm-first star synthesis can be further categorized into three subclasses including the (i) macroinitiator (MI), (ii) macromonomer (MM), and (iii) selfassembly cross-linking (SC) routes. As the first synthetic step, i.e., arm formation, linear polymers with a terminal initiation site, with polymerizable chain ends, or having a short crosslinkable block segment are first prepared (in the cases of MI, MM, and SC routes, respectively). Controlled/living polymerization techniques capable of preparing linear functional polymers with precise microstructural control have been proven ideal for the arm synthesis. The linear polymers are subsequently linked together via either polymerization or coupling chemistry to yield star polymers, and this synthetic step is referred to as the star-formation step. For the MI route, star polymers are formed via the polymerization of a di(or higher)-functional monomer (i.e., the cross-linker) initiated by the arm polymer (i.e., the arm macroinitiator) (Figure 3a). Star polymers are made in a similar fashion via the MM route, the cross-linking polymerization, however, is initiated by a small molecule initiator, and the arm polymers participate in the polymerization as macromonomer (Figure 3b). Rather than polymerization, coupling chemistries are often utilized as the cross-linking reaction in star synthesis via the SC method. Star polymers are produced by connecting the arm copolymers through the cross-linkable block via the reaction of the pendent groups and a complementary di(or higher)-functional compound (Figure 3c). The arm copolymers are often designed to be able to preassemble into micelle structures prior to the cross-linking process.25 The benefits of the precoupling self-assembly are two-fold, (1) facilitating the efficient coupling among the core-isolated cross-linkable functionalities and (2) minimizing star−star intermolecular cross-linking, and the performed stars would obtain better structural control and narrow arm number distributions.26 Highly efficient reactions (e.g., thiol−yne,27 oxime ligation,28 and copper click chemistry29) are often exploited as the coupling chemistry, and this guarantees fast star formations in excellent yields. Additionally, functional cross-linkers were designed and employed, so that the cross-linked stars are able

particular, the use of externally regulated polymerizations has gained in popularity, with several examples demonstrating the synthesis of well-defined star polymers in systems under photo-3 and electrochemical4 control. Another area of promise is the use of water as the primary reaction medium for the synthesis of star polymers in either hetero-5−8 or homogeneous9 polymerization systems, eliminating the need for (relatively) expensive and environmentally unfriendly organic solvents. The continued improvements in robust, efficient, and orthogonal coupling chemistries10 have also allowed for a diverse range of postpolymerization modifications of star polymers, which is of importance for advanced applications of these polymers such as drug/gene delivery,11 or as nanoreactors for confined catalysis.12 The above-mentioned developments all contribute to a strong and healthy outlook for the continued interest in star polymers as unique and versatile nanomaterials, with their potential use in high-value applications seemingly limited only by the limits of imagination of the practicing polymer chemists.

2. STAR POLYMER SYNTHESIS 2.1. Synthetic Approaches

The synthesis of star polymers via controlled/living polymerization techniques follows three well-established strategies, which include the core-first, arm-first, and grafting-onto approaches. 2.1.1. Core-First Approach. The core-first approach employs a presynthesized multifunctional initiator (i.e., the core) to form star polymers by divergently growing linear polymers (i.e., the arms) (Figure 2). To obtain star polymers with well-defined structures (i.e., the same arm number and arm length), the initiating sites on the core should have equal reactivity and 100% initiation efficiency. Additionally, the polymerization methods used must have a rate of initiation much greater than that of the propagation and exhibit no or minimal chain termination reactions, so the degree of polymerization (DP) of each arm polymer (i.e., arm length) will be comparable. Since controlled/living polymerization techniques fulfill these mechanistic requirements, star polymers with a high level of control over structure, composition, and functionality have been prepared by these techniques via the core-first approach, employing various combinations of monomers and multifunctional initiators (section 2.2). The most attractive aspect of the core-first approach is its excellent yields, as pure star polymers can be conveniently isolated from the crude reaction containing unreacted monomers, ligands, and catalysts through simple means such as precipitation. However, the limitations of this approach include that the star products have low arm numbers (typically ranging from 3 to 8) and a much smaller core domain compared to stars prepared via the arm-first route (section 2.1.2). This is often because multifunctional compounds with small molecular sizes and low functionality are utilized as the core initiator, which restricts both the core dimension and the arm number of the resulting star polymer. To rectify this problem, functionalized hyperbranched 13,14 and dendritic polymers, 15,16 poly(saccharides),17,18 nanoparticles,19−21 and nanogels22 have been used as multifunctional initiators to afford star polymers with large core sizes and high arm numbers. Additionally, the core-first approach is not suitable for preparing miktoarm star polymers unless specially designed functional cores with orthogonal initiating functionalities are employed.23 This 6746


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Figure 4. Schematic illustration of star synthesis via the grafting-onto approach.

macromolecules is also known as star microgels, star-like microgels, star nanogels, core−shell star nanoparticles, and core cross-linked micelles.1 Another attractive feature of the arm-first approach is that miktoarm stars can be obtained with relative ease through the “in−out” or “multiarm” methods (Figure 3). The in−out method is exclusively applicable to stars synthesized via the MI and MM approaches, whereas the multiarm method can be applied to all arm-first syntheses. For the in−out method, the initiating functional groups enclosed in the cores of the preformed star polymers (prepared by the MI or MM approach) initiate another polymerization to grow a second generation of arms outward to yield miktoarm stars (Figure 3a and 3b). For the multiarm method, equal or more than two types of different arm polymers (i.e., macroinitiators, macromonomers, or cross-linkable block copolymers depending on the synthetic route) are made and cross-linked to afford miktoarm stars, as exemplified by the SC star synthesis illustrated in Figure 3c. 2.1.3. Grafting-onto Approach. Star polymers prepared via the grating-onto approach possess the highest level of structural control among all three star synthesis approaches, as the core and arm of the stars can be synthesized and characterized independently before the star formation. Star polymers are made by the coupling reaction of the core (i.e., usually a multifunctional coupling agent) and the arms (i.e., linear polymers with a complementary reactive terminus) (Figure 4). The arm polymers can be prepared through either polymerization initiated by functional initiators or postpolymerization end-group modification of presynthesized living linear polymers. The arm number of the star polymers prepared via the grating-onto approach is equal to the functionality of the core, provided that the coupling reaction is quantitative. Star polymers prepared via the grafting-onto approach usually have a low arm number (typically 4−8) and small core size, which are limited by the functionality and dimension of the coupling compounds available. Also, synthesis of stars with large arm numbers (>20) and high MW arms is exceedingly difficult as steric congestion around the core hinders the coupling reaction and leads to incomplete conjugation. Even when highly efficient coupling chemistries (e.g., click reactions) are used for the star synthesis, lengthy reaction times and an excess of arms are often required to compensate for the steric and entropic penalties to obtain stars with well-defined structure and equal arm numbers in good yields. Rigorous purifications are thus needed to isolate the stars from the unutilized linear arms. Like the arm-first approach, the grafting-

to dissociate and reconstruct upon the application of an external stimulus.26,28−31 As opposed to the core-first approach, the arm polymers can be synthesized and characterized prior to star formation via the arm-first approach, which means a high level of control over the arm structure can be obtained. However, star polymers prepared via this approach suffer from broader arm number distributions compared to those obtained via the core-first (section 2.1.1) and grafting-onto (section 2.1.3) approaches. The number of arms incorporated into the stars are influenced by a number of parameters, including the DP and composition of the arm precursors, the nature of the cross-linker, the crosslinker-to-arm ratio, and the timing of cross-linker addition (for one-pot syntheses).2,32 Furthermore, star synthesis via the armfirst approach often experiences low yields resulting from incomplete arm-to-star conversions. Rigorous purifications such as chromatography, precipitation, or dialysis protocols are needed to isolate pure star products. The causes of the low arm-to-star conversion vary depending on the nature of the polymerization methods used. For star synthesis through controlled radical polymerizations, disproportionation and bimolecular termination of the propagating (macro)radicals, which lead to the formation of “dead” chains, are responsible for the low arm conversion,33−35 whereas for ring-opening polymerization systems, inter- and intramolecular transesterifications result in unincorporated low-MW species.36 The arm-first approach may deliver star polymers with very high MW (in excess of one million in some cases) and large arm numbers (>100). Star polymers prepared via the arm-first approach share a noticeable feature: their cores consist of crosslinked network structures that lack mobility and have large molecular sizes (typically 30 wt % relative to the overall MW of the star macromolecule), in sharp contrast to the cores of stars prepared via the core-first and grafting-onto approaches, which often hold negligible MWs relative to the whole star. Derived from this exclusive structural feature were new functionalization opportunities for star polymers prepared via an arm-first approach. The large core domains provide high capacity for the storage of functional compounds via covalent attachments37 and/or supramolecular interactions.38 The neighboring arm polymers shield the functionalized cores from the surrounding environment; thus, the star polymers are able to provide the stored functional moieties with site-specific isolation for various applications in life science and materials technology.38−40 Star polymers prepared via the arm-first approach are often referred to as core cross-linked star (CCS) polymers, as this term highlights their unique core dimension and distinguishes them from other types of stars. In the literature, this class of 6747


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Figure 5. Schematic illustration of star synthesis via the core-first/grafting-onto hybrid approach.

cross-linking of functional linear polymers and yields unique CCS polymers with a statistical distribution of arm numbers. Polymerization of monomers from a multifunctional core via the core-first approach may afford star polymers with a precise number of arms and controlled arm length, given that controlled/living polymerizations were employed for the synthesis. The product stars hence have better structural control than stars prepared via the arm-first approach. Among all the synthetic strategies, the grafting-onto synthesis offers the best control, as the core and arm polymers can be independently synthesized and characterized prior to the coupling reaction. Barner-Kowollik and co-workers exploited this unique attribute to prepare unusual butadiene/acrylonitrile star polymers by conjugation of two block copolymers, i.e., of poly(acrylonitrile-co-butadiene) (NBR) and poly(styrene-coacrylonitrile) (SAN).47 The conjugation is achieved via a hetero-Diels−Alder (HDA) click reaction employing cyclopentadiene-capped NBRs with dienophile SAN copolymers, leading to the formation of four-arm miktoarm star polymers. However, when preparing stars with larger arm numbers (>20), the grafting-onto approach may give ill-defined stars with less than the targeted numbers of arms, as the existing arm polymers may hinder further grafting by shielding the “free” arm polymers from accessing the reactive sites. The hybrid synthesis that combines the core-first and grafting-onto route provides facile access to miktoarm star polymers but offers a low degree of control over product MWs and structures. When selecting the route of star synthesis, there are several important factors one should take into consideration. These include the nature (type, size, composition, and degree of structural control) and application of the targeted star polymers, purification technologies available, and polymerization methods accessible for the synthesis.1,2,48,49

onto approach offers a facile method to produce miktoarm star polymers by the application of different types of arm precursors having identical complementary chain ends, through which they can be joined onto the multifunctional coupling agent. For instance, an elegant approach was proposed by Barner-Kowollik and co-workers,41 where they prepare a three-pronged βcyclodextrin (CD) core and adamantyl-functionalized polymers prepared by RAFT polymerization. Supramolecular selfassembly between admantyl and CD was exploited for the formation of star-shaped architectures with a very high yield. A combination of different synthetic approaches may be utilized to access star polymers with high structural and functional complexities. As a notable example, the crossover of the core-first and grafting-onto syntheses has been demonstrated as a useful technique for building miktoarm star polymers.42−44 In this “hybrid” synthesis, where the multifunctional core having two (or more) sets of orthogonal functionalities serves as both the linking agent and the initiator, stars are made by grafting presynthesized arm polymers onto the core, followed by growing a second generation of arms via polymerization (initiated by the core-bounded initiating sites) or vice versa (Figure 5). The grafting-onto and polymerization reactions can sometimes be carried out in one pot depending on the reaction conditions. However, the hybrid synthetic route holds several drawbacks. First, the resulting star polymers have limited arm numbers and core dimensions similar to stars prepared via the core-first and grafting-onto approaches. The star synthesis involves multiple steps including preparation of the multifunctional core that demands significant amounts of effort. Furthermore, the steric congestion of pre-existing arm polymers around the core would hamper the polymerization or grafting of the second generation of arms. Consequently, the resulting stars would have ill-defined structures (i.e., uneven arm number and arm length) with broad MW distributions,45 and this poor control may result in difficulties in the isolation of pure star products. In a seminal paper, Barner-Kowollik and coworkers demonstrated that the nature of the core (i.e., the position of the functional groups) to attach the arms dictates the efficiency of grafting-onto processes.46 The authors showed that when rigid and large cores are used, such as fullerenes, “perfect” coupling efficiencies between the core and the arms could be achieved via a Cu(I) click reaction that are not possible in sterically more restricted core regimes. All synthetic strategies described above are well established and can be carried out through the application of controlled/ living polymerization techniques and efficient coupling chemistries. However, each synthetic route possesses certain advantages and shortcomings and is therefore more suitable for the synthesis of particular types of star polymers over others. The arm-first approach is a simple method that involves the

2.2. Star Polymer Synthesis via Various Polymerization Methods

2.2.1. Ring-Opening Polymerization (ROP) of Cyclic Esters and Derivatives. In the past decades, ring-opening polymerization (ROP) of cyclic (carbonate and phosphate) esters has received significant attention in developing materials matrix for drug delivery and tissue engineering applications, since the product polymers are often nontoxic with excellent biocompatibility and biodegradability.50−52 Other than potential biomedical use, high mechanical strength, and low to moderate melting temperature make ROP polymers, aliphatic polyesters, in particular, as ideal switching components for shape memory materials.53,54 In addition, the hydrophobicity and crystallinity of polyesters, which lends these materials the ability to self-organize in solution and solid states creating higher order macromolecular assemblies, has further expanded the application scope of these polymers.55 6748


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Common ROPs of cyclic esters and derivatives catalyzed by an organic acid/base or organometallic complex proceed at fast reaction rates via the activated monomer and/or coordination insertion mechanisms.56 Some of the organic catalyst-mediated ROPs are able to reach completion within a few minutes at room temperature.57,58 As a living polymerization technique, ROP affords product polymers with controlled microstructures and narrow MW distributions (dispersity (Đ) is typically less than 1.3). Compared to controlled radical polymerizations (e.g., atom transfer radical polymerization (ATRP) and reversible addition−fragmentation transfer (RAFT) polymerization) and living ionic polymerizations, ROP is inert to radical scavengers (e.g., O2) and has a higher degree of tolerance to protic impurities. Hence, it requires less stringent reaction conditions. Although the presence of protic contaminants (e.g., H2O) will not cause termination, protic species may act as initiators or induce side reactions such as inter- and intramolecular transesterifications at elevated reaction temperatures.50,59 Protic solvents and contaminants therefore should be avoided in ROP to ensure the polymerization products do not have ill-defined end-group functionalities and broad MW distributions. Conventional polyesters or polycarbonates prepared via ROP lack functionality along the main chain backbone, which has restricted the potential applications of this important class of degradable materials, stemming from a scarcity of functional monomers. More recently, cyclic monomers with pendent functionalities such as alkene, alkyne, halogen, protected acid, alcohol, thiol, and amines have been developed.60−64 (Co)polymerizations of these monomers have allowed access to an array of functionally and architecturally diverse polyesters (or polycarbonates) which can be readily transformed into materials with tailored properties upon postpolymerization modifications (M2.1−2.14, Figure 6). An additional merit of ROP is that some of the polymerizable monomers can be obtained from biomass, for example, lactide (M2.5) and trimethylene carbonate (M2.8) can be derived from corn starch65 and fatty acids,66respectively. Therefore, ROP can be considered as a “green” process capable of converting renewable feedstock into useful degradable materials (e.g., bioplastics), which may supersede polymers derived from fossil fuel sources in the future, thereby reducing the materials production-related carbon footprint and environmental impacts. The excellent control, robustness, versatility, and relative simplicity in reaction setup make ROP one of the most extensively used synthetic methods for functional polyesters with intricate and exquisite architectures. Polyester-based homo- and block copolymer star polymers have been prepared through ROP via both the arm-first and the core-first approaches, while miktoarm stars have been constructed through the application of ROP and click chemistry via a hybrid grafting-onto/grafting-from synthetic route. In the following sections, the latest development of star polymer synthesis via ROP will be critically evaluated. The discussions will focus on advances in the synthesis and application of starshaped polyesters in four particular areas, including (1) catalysis, (2) functionalization, (3) stereochemistry, and (4) supramolecular assemblies, which have recently drawn considerable attention. As this review only covers research works published since 2009, the readers can refer to other reports for reviews on the earlier works concerning star formation via ROP.1,67,68 Rather than offering an assemblage of summaries on all recent publications, this part of the review will

Figure 6. Common cyclic esters used for polyester-based star synthesis.

highlight seminal works, which may warrant exciting future discoveries and/or expedite development and commercialization of the polyester-based star polymers. 2.2.1.1. New Catalytic Systems for Star Synthesis via ROP. Star polymers are intrinsically stable nanoparticles with a multivalent functional structure which allows the attachment of biologically active agents. When made with biocompatible, biodegradable, and low-toxicity compositions (e.g., poly(phospho)esters or polycarbonates), they may serve as ideal materials for advanced biomedical applications including diagnostic imaging, tissue engineering, and targeted drug delivery. Traditionally, polyesters and polycarbonates with controlled structures such as stars were prepared via metal complex-mediated living ROP. However, these heavy metal catalysts are often toxic, and their residuals could potentially pose threats to the human body, and this raises concerns over the use of these product polymers in therapeutic and pharmaceutical applications. Fortunately, there are some organometallic catalysts with mild toxicity. Stannous octoate (Sn(Oct)2) (C2.1, Figure 7), for example, is the United States Food and Drug Administration (FDA)-approved additive for the production of commercially used biomedical polymers with a legal residual content of 20 ppm.69 However, Sn(Oct)2, like any other Lewis acids, is notoriously difficult to remove from the polyester or polycarbonate products due to the oxophilic nature, and the residual tin levels in linear polyester products often exceeds 1000 ppm.70,71 High catalyst loadings (usually 6749


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system is therefore particularly attractive to large-scale synthesis of biocompatible polymers, as the polymerization may take place in the absence of solvents, i.e., under “green” and industrially relevant conditions, and the product polymers would contain negligible amounts of metal zinc due to low catalyst loadings. Later, the same authors reported the synthesis of well-defined three-arm star polymer P(TMC)373 and copolymer P(TMC-b-L-lactide(LLA))374 through the Zn(II)mediated ROP via a core-first approach. Their studies demonstrated the synthetic versatility and potential application of the new catalytic system in producing biocompatible and biodegradable polymers for drug delivery and medical implant applications. Recent development in organocatalysis has introduced various organic compound-based catalytic systems for ROP of cyclic (phospho)esters and carbonates with incredible control and simple operations (C2.3−2.7, Figure 7).57 Research works pioneered by Hedrick and Waymouth have demonstrated that organic catalysts have surpassed conventional organometallic complexes (Sn, Al, Ti, etc.) in several performance indicators and set the new gold standard for ROPs.58 The organic catalystmediated ROP (OROP) can be carried out under mild conditions (usually at room temperature), with reaction rates comparable to or even faster than the organometallic catalytic systems operating at elevated temperatures. A high selectivity of the organic catalysts for polymerization propagation over transesterification of open-chain ester polymers and the low reaction temperatures that suppress the transesterifications bestow product polymers with very narrow MW distributions.75 Unlike metal catalysts, organocatalysts are nonoxophilic and thus can be more readily removed from the oxygen-rich polymer products. The benefits of facile catalyst removal are two-fold. First, it would minimize problematic transesterifications of product polymers during purification or storage. Also, harmful toxicity imparted by the catalyst can be greatly reduced or eliminated, which is essential to the synthesis of polymers for biological applications. As being chemically stable, inexpensive, and commercially available, organocatalysts are accessible to researchers of all experience and skill levels. Despite the widespread use of organic catalyst-mediated ROP in synthesis of telechelic poly(phospho)esters or polycarbonates, the application of organocatalysis in star synthesis via ROP has not been demonstrated until more recently. Coady et al. successfully synthesized an array of poly(L-lactide) (PLA)-based star polymers via the core-first approach using (−)-sparteine/N′-(3,5-bis(trifluoromethyl)phenyl)-N-cyclohexyl-thiourea (TU) (C2.3) as catalyst.76 PLLA stars with high MWs (Mn up to 87.6 kDa) and arm numbers (up to 64) were obtained by employing β-cyclodextrin (β-CD, I2.1), hyperbranched polymer (Boltorn H20, I2.2), and dendrimers with a large number of nucleophiles, i.e., 2,2bis(hydroxymethyl)propionic acid (bis-MPA, I2.3) and poly(propyleneimine) (PPI, I2.4) dendrimers, as the core initiators, Figure 8. The initiation efficiencies of the multifunctional core were determined to be quantitative (99%), and the TUcatalyzed ROPs proceeded without termination and no (or minimal) unwanted transesterifications. All star products had well-defined structures with exceedingly low Đ values (typically around 1.05). OROP chain extension from the preformed star polymers was possible to give well-defined star block copolymers. To demonstrate this, star polymers with poly(Llactide)-b-poly(trimethylene carbonate) (PLLA-b-PTMC) copolymer arms were made through the OROP of TMC using

Figure 7. Common ROP catalysts utilized for polyester-based star synthesis.

one equivalent to the initiator) were often needed for the polymerization due to the low catalylic activity of Sn(Oct)2, and this together with inefficient catalyst removal result in high contamination of the product polymers. In addition, ROP mediated by Lewis acids such as Sn(Oct)2 follows a coordination insertion mechanism, which demands elevated temperatures to achieve a fast reaction rate. Elevated reaction temperatures are however disfavored, especially for industrialscale processes where energy conservation is particularly important from a cost and an environmental perspective. Besides, high reaction temperatures exacerbate side reactions such as intra- and intermolecular transesterifications catalyzed by the Lewis acid catalysts, leading to the formation of impurities and broadening of the product MW distributions. In the past decades, tremendous research efforts have therefore been made in the quest for more robust and efficient ROP catalysts that are capable of catalyzing the polymerization under mild conditions and giving no or minimal side-reaction products. The ideal catalyst is preferably nontoxic or can be efficiently removed postpolymerization via simple means (e.g., precipitation or solvent extraction) so the product materials are free of toxic remnants. This is particularly important for synthesis of polymers with complex macromolecular architectures (e.g., stars) for biomedical use, since the catalyst loadings per macromolecule required for their synthesis are usually much greater than that of the linear counterparts. Also, polymers with intricate structural arrangements (e.g., the core− shell branched structure of stars) are apt to entrap small compounds, making catalyst removal even more difficult. More recently, Guillaume et al. demonstrated the application of Zn(II)-based organometallic complex [(BDI)Zn(N(SiMe3)2)] (BDI = CH(CMeNC6H3-2,6-iPr2)2) (C2.2) for the highly efficient, solvent-free ROP of trimethylene carbonate (TMC, M2.8).72 Compared to Sn(Oct)2, C2.2 is more biologically friendly as zinc ion participate in the human metabolic pathway, and ROPs promoted by C2.2 may proceed under milder reaction conditions (60 °C vs >100 °C for Sn(Oct)2-mediated ROPs) with faster reaction rates (completion within minutes vs hours for a typical ROP catalyzed by C2.1). Catalytic amounts of zinc as low as 20 ppm is able to obtain linear PTMC with a MW of 237 kDa (equivalent to ca. 2300 repeating units) in less than 2 h at 100 °C. The reported 6750


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Figure 8. Functional core initiators for polyester-based star synthesis.

the PLLA star polymers as macroinitiators. The ability to form star block copolymer is an essential feature for synthesizing advanced delivery vehicles. The block star synthesis could be carried out in two ways: polymerization from a macroinitiator or via sequential addition of monomers in a one-pot two-step synthesis. The chain extension OROP of TMC catalyzed by TU was found to be much slower than the earlier OROP of LA with the same monomer to initiator ratio [M: I = 20] (reaction time: 30 min vs 24 h for stars prepared from third-generation (G-3) bis-MPA dendrimer). When TU was replaced by 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), a more efficient

catalyst for OROP of TMC, the same chain extension can be completed in 2 h. The study has shown that with a judicious choice of catalyst, monomer, and initiator, OROP may provide facile access to star polymers with supreme structural control and tunable functionalities via a core-first approach. Soon after, OROP was also proved to be highly advantageous to the armfirst star (i.e., CCS) synthesis. A more recent example of corefirst star synthesis via OROP was demonstrated by Guo et al., who prepared well-defined three- and five-arm star polymers (Đ < 1.3) via O-benzenedisulfonimide (C2.7, Figure 7) catalyzed ROP of TMC using trimethylolpropane and pentaerythritol as 6751


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Figure 9. Schematic illustration for the synthesis of polyester-based CCS polymers via the organic catalyst-mediated ring-opening polymerizations. Reproduced with permission from ref 36. Copyright 2012 American Chemical Society.

room-temperature formation of well-defined degradable CCS polymers (Figure 9). Miller et al. prepared the polyester-based CCS polymers using δ-valerolactone (δ-VL, M2.2), 4,4′bioxepanyl-7,7′-dione (BOD, M2.6), and an organic base (i.e.,1,5,7-triaza-bicyclo[4.4.0]dec-5-ene, TBD, C2.5) as the monomer, cross-linker, and catalyst, respectively, while Qiao et al. synthesized stars of similar degradable and biocompatible composition using ε-caprolactone (ε-CL, M2.3), BOD (M2.6), and an organic acid (i.e., methanesulfonic acid, C2.6) as the monomer, cross-linker, and catalyst, respectively. CCS polymers with high molecular weights (>300 kDa) and narrow MW distributions (Đ < 1.3) were obtainable in both reports. The rates of star polymer formation for the organic systems were found to be at least twice as fast as the controls (star synthesis catalyzed by Sn(Oct)2), even though the control reactions were performed at 110 °C. The slower star formation ensued from inefficient catalysis of the tin(II) complex, which is attributable to its oxophilicity and large molecular size. During star synthesis, the tin(II) complex C2.1, unlike the organic counterparts, can be trapped in the cross-linked oxygen-rich core of the synthesized stars and unable to catalyze the crosslinking of unbounded arm polymers. Consequently, CCS synthesis via the tin(II)-mediated ROP often requires lengthy reaction times to achieve moderate arm-to-star conversions (typically ∼60%). The study by Miller et al. has shown that the residual tin(II) content in CCS polyester produced via the Sn(Oct)2-catalyzed ROP is 1800 ppm, 90 times the FDAapproved limit of 20 ppm.69The result verifies the entrapment of Sn(II) complex in the CCS polymer matrix, causing difficulties in catalyst removal. In contrast, less oxophilic organic catalysts can be effectively eliminated via simple solvent extraction or precipitation methods.76 Notably, Qiao et al. observed arm-to-star conversion in the CCS synthesis does not reach completion (100%), even via OROP at prolonged reaction times. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectroscopic analysis found the “unconverted” low-MW species consisted of a mixture of cyclic and telechelic polyesters. The overall CCS formation mechanism was proposed based upon the results (Figure 10). It was then concluded that the intra- and intermolecular transesterifications that took place during the star synthesis preclude the quantitative yields, corroborating the earlier finding that low yields of the tin(II)-mediated star synthesis was a direct result of more pronounced transesterifications at a higher reaction temperature. The results have also pointed out that robust catalysts with a high selectivity for polymerization

the polyol initiators, respectively, at a mild reaction temperature (35 °C).77 The CCS polymer synthesis via ROP through the arm-first approach was first established by Wiltshire and Qiao.78 Their early work described the first synthesis of a fully degradable CCS polymer, prepared from ε-caprolactone (M2.3) and 4.4′bioxepanyl-7.7′-dione (M2.6) as the monomer and cross-linker, respectively. Since all monomers and cross-linkers in the CCS polymer are interconnected via ester linkages, the star can be completely hydrolyzed under acidic or basic conditions into discrete molecular segments. By ingeniously integrating the ATRP technique (which is capable of preparing various functional polymers with a nondegradable carbon−carbon backbone) into the synthetic framework, the authors later demonstrated the synthesis of a remarkable array of selectively degradable CCS polymers, which include stars with partially degradable arms, fully degradable arms, and fully degradable cores.79,80 The convergence of low-demanding conditions, synthetic versatility, and functionalization selectivity makes this novel framework highly attractive toward the synthesis of degradable materials with tunable properties for various applications, particularly in the areas of tissue engineering and drug delivery. However, a major pitfall of this degradable CCS synthesis is low arm-to-star conversions, which lead to poor yields of pure star products after rigorous purifications. This has impeded the further development and potential commercialization of the degradable CCS polymers despite their wide application potential. The reported CCS synthesis employed organometallic complexes (Sn(Oct)2, C2.1) as catalyst, and the reaction requires elevated temperatures (ranging from 65−110 °C) to achieve a satisfactory rate of star formation.81 The inter- and intramolecular transesterifications, which can be severely aggravated at high reaction temperatures, were first speculated and later proved to be responsible for the low arm-to-star conversions. The intramolecular transesterification leads to cyclization of the arm macroinitiators to afford non-crosslinkable (“dead”) cyclic polymer chains without a nucleophilic initiating site (e.g., a hydroxyl terminus), and these polymers can no longer participate in star formation. The intermolecular transesterification causes coupling among stars, leading to polymer products with high MW impurities and broad MW distributions. Vigorous purifications were therefore needed to eliminate these side-reaction products, resulting in poor yields. By using robust and highly efficient organic catalysts, the research groups of Miller69 and Qiao36 simultaneously demonstrated the rapid, scalable, high-yield (>90%), and 6752


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functionalities into specific locations within the macromolecules. Generally, for star polymers, functional moieties can be installed in the core, along the arms, and at the periphery in three ways: (i) use of (multi)functional initiator (Figure 11a− c), (ii) polymerization of functional monomers or cross-linkers (Figure 11d−f), and (iii) postpolymerization modification (Figure 11g). Both core- and end-functionalized star polymers can be accessible through the use of functional initiators. Corefunctionalized stars can be produced via a core-first approach, where the polymerization is initiated by a multifunctional compound carrying the desired functionality and multiple initiation sites (Figure 11a). Also, by employing a dualfunctional initiator, core-functionalized CCS polymer can be obtained through a slightly more complicated synthetic route. The employed initiator needs to be asymmetric in functionality and possess both the targeted and the initiating functionalities. Copolymerization of macromonomers and cross-linkers in the presence of the difunctional initiator allows not only the synthesis of a CCS polymer but also the installation of a large number of the desirable functionalities into the core of the star (Figure 11b). A variation of the arm-first approach that uses a difunctional initiator to first prepare an arm macroinitiator may lead to end-functionalized CCS polymers (Figure 11c), as the subsequent cross-linking of the arm polymers occurs from the initiating chain ends and leaves the other functional termini exposed at the periphery of the resultant CCS polymer. Arm-functionalized star polymers can be derived from polymerizing functional monomers through both the corefirst and the arm-first routes. In the core-first synthesis, the direct polymerization of the functional monomer initiated by a multifunctional initiator would result in arm-functionalized star polymers (Figure 11d), whereas for the arm-first synthesis, the functional monomer was first polymerized to construct the arm macroinitiator, prior to the star formation step, where the polymerization of cross-linker was initiated to yield armfunctionalized CCS polymers (Figure 11e). If the functional monomer was copolymerized with cross-linker during star formation, a core-functionalized CCS polymer would result instead (Figure 11f). A similar core-functionalized CCS polymer can be achieved through the polymerization of a cross-linker carrying the same functionality as the functional monomer. However, the cross-linking and functional densities of the two resultant CCS polymers would be different, and consequently, the physicochemical properties of these stars may differ. Postpolymerization modification represents a more synthetically involved route toward functionalized star polymers, and it requires the attachment of desired functional groups to complementary functionalities present in the preformed stars (Figure 11g). Such circuitous synthetic strategy is considered beneficial when controlled polymerizations involving the functional initiator or monomer become restricted such that well-defined functionalized star polymers are unobtainable through the above-mentioned methods (Figure 11a−f). Such a situation may arise when coordination/reaction of the monomer with the catalyst, initiator, or propagating chains occurs during the polymerization. Additionally, monomers with bulky functional pendent groups may suffer from poor conversions due to polymerization−depolymerization equilibrium resulting from steric constraints and entropic penalties. Postpolymerization modification then constitutes a viable, more

Figure 10. Schematic illustration for the proposed mechanism of the formation of polyester-based CCS polymers via ring-opening polymerization. Reproduced with permission from ref 36. Copyright 2012 American Chemical Society.

relative to transesterification of the produced polyesters are the key to maximizing the yield of the CCS polymers. The OROP combined with the arm-first and core-first approaches have led to a library of star polyesters with structural and functional diversity. These innovative synthetic methods offer rapid, room-temperature, and high-yield star synthesis and excellent control over the MW and structure of the product polymers. As a low-cost and synthetically less demanding process, OROP may potentially offer researchers of all experience and skill levels facile access to star polymers of biocompatible and biodegradable compositions, aiding in materials development and technological innovations in both academic and industrial settings. 2.2.1.2. Functionalized Star Polymers Prepared via ROP. Material properties of polymers are determined by the molecular architecture, composition (or functionality), and functional group placement within the macromolecules. As described in the preceding sections, star polymers of biocompatible and biodegradable compositions with controlled dimensions (size, arm length, arm number, etc.) can be obtained through ROP. Given the high functional group tolerance, ROP is capable of introducing a diverse pool of 6753


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Figure 11. Schematics illustrating the preparation of functionalized star polymers. (a) Core-functionalized star prepared via the core-first approach, (b) core-functionalized star prepared via the arm-first “macromonomer” approach, and (c) end-functionalized star prepared via the arm-first approach using a functional initiator. (d) Arm-functionalized star prepared via the core-first approach, (e) arm-functionalized star prepared via the arm-first approach, and (f) core-functionalized star prepared via the arm-first approach using functional monomer (or cross-linker). (g) Core-, arm-, and end-functionalized stars synthesized via postpolymerization functionalization.

efficient, albeit less straightforward method for the preparation of core-, arm-, or end-functionalized stars, depending on the functional placement of the preformed star polymers (Figure 11g). Core-Functionalized Stars Prepared via ROP. Synthesis of core-functionalized star polymers have been well established through ROP via a core-first approach in the past by employing functional compounds with three (or more) nucleophilic (hydroxy or amine) functional sites as the initiator. For example, poly(caprolactone) (PCL) star polymers with core encapsulation capability have been made from pentahydroxy-

functionalized coranulene (I2.5, Figure 8), which can interact and complex with C60 through π−π interactions.82 The excellent solubility of PCL arm segments in most organic solvents allows the star to provide enhanced solubility and processability to fullerene materials. Organic−inorganic hybrid star polymers were synthesized via the ROP of ε-CL (M2.3) in the presence of an octahydroxy-functionalized polyhedral oligomeric silsesquioxane (POSS). The POSS-PCL star polymer served as switching components of high-performance shape memory (SM) materials, which possess remarkable cycles-averaged (N: 2−5) shape fixities (strain stress recover6754


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abilities ranging from 98% to ca. 100%). Since the POSS core serves as both cross-linking junction and the hard segment, the POSS content critically affects the shape fixity, recoverability, and stress storage capacity of the SM materials.83 Star polymers with noncovalently bonded core structures demonstrate exclusive properties. For example, the noncovalent bonds are often labile and may break in response to external stimuli such as pH or temperature, bestowing the stars with the stimuli-responsive disassembly capability. Synthesis of polyester-based star polymers with noncovalently bonded core structures has been demonstrated by Fraser et al. based upon transition metal complexes, including iron, ruthenium, and europium with hydroxy-substituted dibenzoylmethane (dbm, I2.8)84 or bipyridine (bpy, I2.7) ligands.43,85 Two different approaches were utilized to make the organometallic star polymers: (i) growing polymers from the ligand to give the macroligand, followed by chelation,86 and (ii) using the metal complex to directly initiate the polymerization to afford star polymers.87 Although polyester-based star polymers with different arm compositions (e.g., homopolymer, block copolymer, and miktoarm stars) were obtainable via the former method, the latter approach proved to be more efficient and gives homogeneous star products. However, ROP using organometallic complex as initiator in the presence of Lewis acid catalysts (e.g., Sn(Oct)2) might lead to a slow reaction rate and ill control due to the competing ligand−catalyst interaction. Recently, Chen et al. reported the iron tris(1-[4-(2-hydroxylethoxyl)-phenyl]-3-phenyl-propane1,3-dione (Fe(dbmOH)3, I2.8) complex initiated ROP of LA (M2.5) in the absence of additional catalysts (Figure 12a).87 This study found that Fe(dbmOH)3 complex played multiple roles in the polymerization, which acts as a catalyst, the protecting group for the enol moiety in dbmOH, and a trifunctional initiator. As a result, the Fe(dbmOH)3-mediated ROP of LA was fast and highly efficient, and it afforded welldefined triarm metal complex star polymers in excellent purity and yield (Figure 12b and 12c). Given the functional features of Fe(dbm)3 complex (including chromophores, pH-responsive linker, and potential bioactive agents in cancer therapy) and the biocompatibility and biodegradability of PLA, the resultant metal complex star (i.e., Fe(dbm-PLA)3) may be further explored as stimuli-responsive luminescent materials for drug delivery and medical imaging applications. Demetalation of the star via acid treatment may liberate dbm end-functionalized linear PLA as a dual-emissive polymer, which exhibits both fluorescence and rare room-temperature phosphorescence in the solid state. Despite the fact that luminescent materials hold great potential in electronic and biomedical applications, luminophore-containing polymers often share the inherent weakness of being highly emissive in dilute solutions but experience quenching of emission upon aggregation (i.e., the aggregation caused quenching (ACQ) effect), which limits the application scope of these macromolecules. To provide access to new luminescent, biocompatible, and biodegradable materials without the ACQ effect, Zhao et al. recently developed a synthetic protocol toward functionally and architecturally diverse polyesters (or polycarbonates) with aggregation-induced emission (AIE) characteristics.88 Various functional four-arm star polymers were synthesized via ROPs of rac-β-butyrolactone (M2.1), ε-CL (M2.1), rac-LA (M2.5), and allyl- or propargylfunctionalized trimethylene carbonates (M2.9 and M2.10, respectively) using tetrahydroxyl-functionalized tetraphenyle-

Figure 12. (a) Schematic illustration for the synthesis of Fe(dbmPLA)3 three-arm star polymer. (b) Gel permeation chromatography (GPC) overlay of Fe(dbmPLA)3 and the corresponding dbmPLA macroligand obtained after demetalation by acid treatment. (c) 3D GPC plot of Fe(dbmPLA)3 from a UV−vis diode-array detector. Reproduced with permission from ref 87. Copyright 2010 American Chemical Society.

thene/salan lutetium complex as the initiator/catalyst (TPA4O-[Lu], I2.9, Figure 13a). Propeller-like small molecules such as tetraphenylethene exhibit excellent AIE properties but often have poor solubility characteristics, high melting temperatures, and hence low processability. Incorporating AIE molecules into polymer segments (e.g., the core of a star polymer) would significantly improve their processability. For example, the AIE functional polymers can be cast into thin solid films or devices by spin coating under simple conditions (Figure 13b), whereas small AIE molecules may require more costly and energydemanding techniques (e.g., vacuum sublimation and vapor deposition) for device and thin film fabrication. Zhao and coworkers also demonstrated that click functionalities (i.e., CC 6755


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Figure 13. (a) Schematic illustration for the synthesis of four-armed, star-shaped AIE-active biocompatible polymers using salan lutetium alkoxide complexes TPE-4O-[Lu]. (b) Photographs of (i) AIE-active PLA-coated glass substrate taken under room light and UV illumination, and (ii) starshaped luminogenic biocompatible polymers under room light and UV illumination. Reproduced with permission from ref 88. Copyright 2014 American Chemical Society.

and CC bonds) can be conveniently installed into the arm segments of the stars via (co)polymerization of functional monomers with pendent allyl or propargyl moieties. Thus, the stars may serve as universal scaffolds for the modular synthesis of advanced functional polymers with biocompatibility, biodegradability, and AIE properties for medical imaging and electronic materials. Shell/Corona-Functionalized Stars Prepared via ROP. Polyester- and polycarbonate-based star polymers are considered as excellent delivery vehicles in advanced polymer therapeutics because of their tunable molecular size, biocompatibility, and biodegradability and the ability to

encapsulate therapeutic agents through hydrophobic interactions. However, poor aqueous solubility precludes the use of these stars in drug delivery and other related biomedical applications, as precipitation of star polymers would immediately follow after intravenous administration, and this would not only prohibit effective transportation of therapeutics to diseased tissues but also cause artery blockage endangering the patient’s life. Additionally, a harsh physiological environment (e.g., low pH, oxidative, or enzymatic) will result in degradation of the star polymers and cause premature release of drug payloads, curtailing the therapeutic efficacy. Hence, functionalization of these stars is necessary to install a protective 6756


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Figure 14. Schematic representation of the synthetic approach to PCL-b-PEGMA block copolymer stars with 4- and 6-PEGMA arms. Reproduced with permission from ref 89. Copyright 2009 American Chemical Society.

content was not influenced by the size of the hydrophilic corona. It was anticipated that in vivo biodegradation of the PCL segments would regulate the rate of drug release while liberating the PEG moieties as small macromolecular segments, facilitating the postdelivery clearance of the nanoparticle. Careful control over the length of the PEG and PCL segments would prevent the aggregation of the star polymers and afford unimolecular nanocarriers with controlled sizes in aqueous media. Adopting a similar synthetic strategy, Liu et al. successfully prepared a PCL-b-PEG star polymer as a novel anticancer theranostic vehicle (Figure 15).91 The star polymer was prepared from a hyperbranched macroinitiator (i.e., fractionated Boltorn H40) rather than small multifuctional compounds, so the resultant nanoparticle would have a large molecular size (within the size regime ranging from 20 to 100 nm) to minimize recognition by reticuloendothelial systems and maximize the blood circulation times. The ATRP initiated from the PCL star macroinitiator not only installs the hydrophilic PEG shell layer but also introduces “clickable” azide functionalities onto the periphery of the star polymers by copolymerizing oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA475) with 3-azidopropyl methacrylate (AzPMA). The azide functionalities subsequently allowed for efficient attachment of alkyne functional cancer cell-targeting functionality (i.e., folate derivative) and T1-type MRI contrast agent (i.e., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid (DOTA)-Gd) via Cu(I) click chemistry. The in vitro and in vivo studies concluded that the drugloaded star polymer may serve as a potent theranostic platform, as the star existed as a structurally stable unimolecular micelle with extended blood circulation duration, and demonstrated

hydrophilic outer layer (i.e., shell), which can provide water solubility and in vivo stability for the star polyesters. This can be achieved through a second polymerization step using RDRPs techniques (such as ATRP89 and RAFT90) since RDRPs allows the direct polymerization of a large pool of hydrophilic functional monomers. For star polymers prepared via the core-first approach, shell installation can be attained divergently through the polymerization (chain extension) of a functional monomer (Figure 11d). Schubert et al. reported the synthesis of 4- and 6-arm block copolymer stars consisting of a PCL inner domain and poly(ethylene glycol) (PEG) shell through a combination of ROP and ATRP (Figure 14).89 Before the ATRP chain extension, acylation between the terminal hydroxyl groups of the preformed PCL star polymers and 2-bromoisobutyryl bromide was performed to introduce the bromoisobutyryl groups as the ATRP initiating sites. Using a dibromo functional compound as the branching agent during the acylation step, the preformed PCL star polymers can be converted into block copolymers stars with double the number of PEG segmental arms (raised from 4 and 6 to 8 and 12, respectively). Besides providing solubility of the star polymer in aqueous solution, the PEG shell may endow the star enhanced stability, longer plasma half-life, and reduced in vivo immunogenicity. Therefore, this procedure that combined ROP and ATRP may provide facile access to tunable functional nanocarriers for various delivery needs. In the same study, the PCL inner domain of the star was demonstrated to be capable of encapsulating hydrophobic compounds (4-(naphthalene-1yldiazenyl)benzene-1,3-diamine as a model drug). The size of the domain can modulate drug loading capacity (drug loadings: 20 and 30 per star for PCL-b-PEG stars with estimated PCL domain MWs of 6.2 and 10.9 kDa, respectively), and the drug 6757


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Figure 15. Schematic illustration of the synthetic route employed for the preparation of the amphiphilic multiarm star block copolymer, H40-PCL-bP(OEGMA-Gd-FA). Reproduced with permission from ref 91. Copyright 2011 Elsevier.

methacrylate (TMS-PgMA) using 2-hydroxy-ethyl 2′-methyl2′-bromopropionate as the initiator. The arm polymers (with a high number of alkyne functionalities) were then cross-linked via tandem ROP of BOD to afford a CCS polymer with up to 450 alkyne functional units. By taking full advantage of the robust, efficient, and versatile nature of the click chemistry, it was later demonstrated that this star polymer can be conveniently transformed into a library of highly coronafunctionalized CCS polymer with brush-like arms by grafting the star with different azido functional compounds (Figure 17a).93 For example, fluorescently tagged, saccharide-based, and amphiphilic CCS polymers were successfully prepared with a large number of grafted functionalities ranging from 45 to 450 units. Not only has this report established a “scaffold” approach for the synthesis of highly functionalized star polymers for specific application needs but also it has found that the grafting efficiency of functional compounds onto a CCS polymer is not solely related to their molecular size (Figure 17b). Other factors including molecular structure, the compatibility with the CCS polymer, and synergistic driving forces, such as the potential formation of inclusion complexes, would influence the grafting efficiency. This research thus provided valuable information for high-density functionalization of three-dimensional nanostructures. In addition to the modular synthesis of functional stars, another application of polyester-based degradable star polymer with high peripheral functionality is the template synthesis of

both cancer cell-targeting and high-contrast MRI imaging capabilities. The in vitro drug encapsulation and release study showed the unimolecular micelle is capable of encapsulating paclitaxel, a well-known hydrophobic anticancer drug, with a loading content of 6.67 w/w% and exhibiting controlled release of up to 80% loaded drug over a time period of ca. 120 h. In vitro MRI experiments in rats demonstrated considerably enhanced T1 relaxivity (18.14 s−1 mM−1) for unimolecular micelles compared to 3.12 s−1 mM−1 for a small molecule counterpart, alkynyl-DOTA-Gd. More importantly, the unimolecular micelles-based MRI contrast agents were not excreted by the glomerular filtration mechanism within the kidney in sharp contrast to those exhibited by conventional small molecular MRI contrast agents. As demonstrated in the previous study by Liu et al., the introduction of chemical handles (such as clickable groups) into the corona of the star polymer allows for the attachment of tailorable functional moieties for different application needs (e.g., targeting and imaging agents for theranostics). Intuitively, a high number of the chemical handles would offer a greater potential to manipulate the physical and chemical properties of the star polymers to meet the application requirements. More recently, the Qiao group reported the synthesis of a degradable CCS polymer with a great number of peripheral “clickable” alkyne functionalities via an arm-first approach (Figure 16).81,92 The arm of the star polymer was prepared via the sequential ROP and ATRP of ε-CL and trimethylsilyl-protected propargyl 6758


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Figure 16. Synthetic illustration for the synthetic route employed for the preparation of highly corona-functionalized CCS polymers via sequential ROP, ATRP, and copper-catalyzed azide−alkyne cycloaddition (CuAAC) click chemistry. Reproduced with permission from ref 81. Copyright 2011 American Chemical Society.

diameter of the hollow sphere and the shell thickness, are controllable by simply varying the MWs of the PCL and poly(azide) blocks, respectively. Additionally, the cross-linking density of the shell was adjustable according to the duration of UV exposure. Lin and co-workers anticipated that such hollow nanoparticles may lead to the development of novel drug delivery vehicles with controlled drug release profile, tunable by

organic nanocapsules. Lin et al. reported the synthesis of a star copolymer with arms consisting of a degradable PCL inner and photo-cross-linkable poly(azide) outer block. The star polymers were synthesized by successive ROP and RAFT polymerizations via a core-first approach (Figure 18a).90 After the UVtriggered shell cross-linking and hydrolysis of the PCL domain, a hollow-polymer nanoparticle was then successfully formed. It is noteworthy that the dimensions of the nanoparticles, i.e., the 6759


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Figure 17. (a) Structures of azido-substituted compounds C1−7 and terminal azido-functionalized polymers P1−4 employed for click functionalization of alkyne functional star polymers. (b) Graph of the click functionalization efficiency of the azido-substituted compounds versus the estimated molecular size of those compounds. Reproduced with permission from ref 81. Copyright 2011 American Chemical Society.

preparing a carboxylic acid chain end-functionalized PLLA star polymer via the ROP of L-LA (M2.5) using hexahydroxylfunctionalized tris(phenyl)ethane as the core initiator and converting the hydroxyl chain ends of the stars into carboxylic acid groups by reacting with succinic anhydride. Next, 1-, 2-, and 3-generation (G-1−3) poly(amidamine) (PAMAM) dendrons, which have a primary amine at the dendron root and benzyl ester-protected carboxyl group at the periphery, were coupled onto the PLLA star via amide coupling to afford

varying the thickness or cross-linking density of the shell layer, as well as the extent of UV exposure. Other than the direct polymerization of functional monomers, another approach to install a highly functionalized corona is to conjugate the preformed star polymer with multifunctional compounds through the chain-end functionalities via a postpolymerization modification method (Figure 11g). Cao and Zhu prepared a series of amphiphilic dendrimerlike star polymers (DLSPs) through such an approach94 by first 6760


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Figure 18. Schematic illustrations for (a) the synthetic strategy for unimolecular polymeric core−shell nanoparticle and hollow nanocapsule and (b) the proposed mechanisms for the dye encapsulation and release of the core−shell nanoparticle. Reproduced with permission from ref 90. Copyright 2014 American Chemical Society.

DLSPs with 24, 48, and 96 protected carboxyl end functionalities (Figure 19). Deprotection of the benzyl esters resulted in stars with a large number of peripheral carboxylic acid functionalities, and further modifications through the carboxylic acid groups afforded triethylene glycol and amine periphery-functionalized star polymers. All functionalized DLSPs demonstrated good water solubility (ranging from 10 to 25 mg mL−1) and existed as unimolecular micelles (with minimal aggregations) in aqueous solution. The high peripheral functionality, excellent water solubility, potential drug encapsulation capability, and biodegradability of the PLLA domain would make these star polymers excellent candidates for delivery nanocarriers. 2.2.1.3. Stereochemistry of ROP Star Polymers. Similar to simple organic compounds, the spatial orientation of monomer units within a macromolecule (i.e., stereochemistry or tacticity) may impart profound effects on the polymer properties in both solution and solid states. PLA is, among many others, the most well-known polymer prepared via ROP that displays stereo-

chemical properties. The stereoregularity not only affects its physicochemical properties but also enables PLA to form unique supramolecular assemblies. For example, isotactic PLAs (either D- or L-form) show higher melting and degradation temperatures (Tm and Td, respectively) than the atactic analogues with the same MW. Physically blending the macromolecular isomers of D- and L-PLAs would give a higher order supramolecular assembly of high crystallinity through stereocomplex formation. This product material exhibits a substantially different crystal structure with a higher Tm (ca. 230 °C) than those of the homochiral crystals of each individual assembling component (ca. 180 °C).72 Apart from stereoregular control, topology manipulation provides an alternative means to modulate the material properties of polymers. For instance, when built into a star structure, PLA shows lower Tm, Tg, and crystallization temperature (Tc) than the linear polymer of a similar MW. Additionally, PLA stars exhibit lower hydrodynamic volume and higher viscosity than the linear counterparts in solution.67 6761


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Figure 19. Schematic illustration for the synthesis of various PLLA core and PAMA shell, highly corona-functionalized dendrimer-like star polymers (DLSP)s. Reproduced with permission from ref 94. Copyright 2011 American Chemical Society.

(C2.1) and/or (2) varying the racemic (D- vs L-LA) ratio in the monomer feed (Figure 20). The polymerization that was initiated from dipentaerythritol using different combinations of monomer feeds and catalysts afforded 6-arm stars with atactic, heterotactic, and isotactic (racor L-PLA) PLA arms. The stereocontrol placed dramatic effects on the physical properties of these polymers. For example, isotactic rac-(a racemic mixture of D- and L-forms) and L-LA polymer stars exhibit remarkable stability toward hydrolytic degradation compared to the atactic and heterotactic analogues, since long sequences of isotactic blocks produce crystalline domains, which inhibit diffusion of the hydrolyzing solution.

With a dual control over the stereochemistry and topology of the macromolecule, the synthesis of stereoregular star polyesters may provide exciting opportunities for developing new functional polymers with desirable properties for applications in conventional materials and emerging nanotechnologies. Cameron and Shaver succeeded in synthesizing a family of PLA star polymers with various tacticities.95 This was achieved through (1) the application of aluminum salen complexes, potent catalysts for synthesis of stereoregular polyesters, in conjunction with a nonstereoselective catalyst tin(II) complex 6762


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Figure 20. Schematic illustration of (a) tacticity control by aluminum and tin complexes in the polymerization of rac-lactide and (b) the synthesis of 6-arm PLA star polymer via a core-first approach using dipentaerythritol as the initiator. Reproduced with permission from ref 95. Copyright 2012 Wiley-VCH.

(ca. 10 kDa) with narrow MW distributions (Đ ≈ 1.1) and an identical PLLA/PDLA block ratio of 1:1 but different arm numbers (Narm = 2, 3, 4, 5, and 6). The differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies revealed the solvent-cast films of the PLA linear stereoblock polymer and stereomiktoarm stars preferentially formed stereocomplex crystals with Tm greater than that of the samples prepared from the linear and star homopolymer PLAs. Additionally, an increase in arm number of the star was found to cause a decrease in the Tm and crystallinity of the stereocomplex crystal. This is most likely due to the increase in chain ends and branching points in the polymers which leads to higher crystalline imperfections. Interestingly, the stereomiktoarm star-shaped PLAs with symmetric architectures (i.e., PLLA-b-PDLA, (PLLA) 2 -b-(PDLA) 2 , and (PLLA) 3 -b(PDLA)3) were found to exhibit a higher Tm and crystallinity than those with asymmetric star-shaped architectures, (PLLA)2b-PDLA, (PLLA)3-b-PDLA, and (PLLA)3-b-(PDLA)2 (Figure 21b and 21c), indicating the structure symmetry of the stereomiktoarm stars affects the degree of stereocomplex formation. Other than tacticity and structural symmetry, the spatial directionality of the arms may also affect the thermal and physical properties of a star polymer. Bisht et al. explored the synthesis of nonoptically active star polymers with spatially

Utilizing rac-LA, it is possible to prepare isotactic PLA stars with stereoblock arms. The polymer star arms bearing strong RRRR and SSSS character may potentially create stereocomplex behavior through intermolecular dipole−dipole interactions in bulk phase. Therefore, the isotactic rac-star demonstrated enhanced thermal properties, including higher resistance to melt and thermal degradation (i.e., high Tm and Td) than the isotactic L-star polymer. By varying the ratio of isomers (L- vs D-LA) in the monomer feed and using Sn(Oct)2 as the catalyst, a series of star polymers with various levels of isotacticity can be made. In general, an increase in the level of isotacticity (i.e., an increased isotacticity bias) leads to an increase in the Tg and Td of the resulting PLA star polymers. A high isotacticity bias (>70%) is needed to induce materials transition from amorphous to a more regular semicrystalline, thereby rendering the polymer enhanced resistance to hydrolysis. More recently, Satoh et al. successfully prepared an array of star polymers consisting of both PLLA and poly(D-lactide) (PDLA) linear arm polymers, i.e., stereomiktoarm star polymers.96 The stereomiktoarm PLA star polymers were prepared through the organic catalyst-mediated ROP of D- or LLA followed by click chemistry via a convergent approach (Figure 21a). This series of stereomiktoarm star polymers ((PLLA)x-b-(PDLA)y; x and y = 1, 2, and 3) had the same MW 6763


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Figure 21. (a) Schematic illustration for the synthetic routes employed for the PLA stereomiktoarm star polymers. Graphs illustrate the dependence of (b) the melting temperature (Tm,sc) and (c) the crystallinity (Xsc) of the stereocomplex on the arm number of the linear stereoblock and PLA stereomiktoarm star polymers. Open circles (○) and filled circles (●) indicate the symmetric and asymmetric star-shaped architectures, respectively. Reproduced with permission from ref 96. Copyright 2013 American Chemical Society.

directional PCL arms via a core-first approach.97,98 The conformation constraints imposed on this synthesized star originate from the rigid, bowl-shaped resorcin[4]arene core initiator (I2.10, Figure 22). As a direct consequence of the spatial directionality, enhanced interactions between the arms of the stars were expected in higher order polymer structure. The directional PCL stars hence demonstrated higher thermal stability (Tm and Td) and crystallinity than their linear counterparts. The

complete opposite was observed for regular PCL star polymers, which generally exhibit lower melting points and crystallinity compared to linear PCLs with similar MWs, due to a combined effect of branching and restricted arm mobility.98 These studies outlined above highlighted enormous possibilities in developing biocompatible and degradable materials with new characteristic properties through engineering the tacticity, branching directionality, as well as geometric symmetry of these macromolecules. In addition to tailoring the MW, chemical composition, and architecture of the macromolecules, tacticity control provides another powerful instrument for modulating material properties of the ROP star polymers for different application needs. 2.2.1.4. Supramolecular Self-Assembly of ROP Star Polymers. Supramolecular interactions (including hydrogen bonding, metal coordination, hydrophobic, and π−π interactions) have evolved as a vital mechanism for assembling the intricate and exquisite higher order biomacromolecular constructs (e.g., DNA, liposome, and proteins), which mediate essential bioprocesses in living organisms. Inspired by nature’s craftsmanship, scientists have been striving to deliver innovative high-order synthetic polymers with novel functions and properties. Polymeric micelles prepared from linear block copolymers via hydrophobic interactions in solution are a notable example of such materials. They constitute a platform technology useful to a diverse number of applications including template synthesis, targeted drug delivery, molecular separation, and catalysis. Similar high-order polymer assemblies have also

Figure 22. Schematic illustration for the synthesis of directional PCL star polymers based on tetrahydroxy resorcinarene initiator I2.10. Reproduced with permission from ref 97. Copyright 2009 Royal Chemical Society. 6764


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Figure 23. Synthesis of ABC miktoarm star polymers μ(PEG-PS-PCL) using CuAAC click reactions in sequence, followed by ring-opening polymerization (ROP). Reproduced with permission from ref 45. Copyright 2010 American Chemical Society.

and mitochondrial functional repair by transporting nimodipine and coenzyme Q10 to microglia and mitochondria, respectively. Kakkar et al. also found that micelles and drug-loaded micelles prepared from AB2 miktoarm stars (e.g., PCL-(PEG)2) have smaller sizes and greater stability (upon freeze drying) compared to those obtained from the linear block copolymer counterparts with the same MW and compositions (i.e., PCL-bPEG) (Table 1). These results again underlined the effect of polymer topology on the physical properties and morphology of the resultant supramolecular assembly.99

been found in the solid state, which include lamellar solids and thin films, and crystal structures of polymer stereocomplexes (vide infra) and polyrotaxanes. In recent times, supramolecular assemblies fabricated from miktoarm or block copolymer star polymers were successfully prepared and demonstrated unique morphologies and properties, e.g., multicompartment and stimuli-responsive micelles that are not easily accessible through linear block copolymers.99 Due to the rising needs of advanced materials in medical and pharmaceutical applications, polymer supramolecular assemblies constructed from star polymers of biocompatible and biodegradable compositions, polyester-based star polymers produced via ROP in particular have gained significant research attention over recent years. Similar to unimolecular micelles prepared from amphiphilic star polymers, micelles made from polyester-based miktoarm stars are excellent candidates for nanodevices for in vivo delivery of therapeutics.100 Strong hydrophobic interactions among the polyester arms (e.g., PCL) allow the miktoarm stars to form stable micelles with low critical micelle concentrations (CMCs). The polyester domains of the resulting micelles readily solubilize hydrophobic drug molecules or other therapeutic agents and protect them against enzymatic degradation. Additionally, the in vivo hydrolysis of the core domain may affect the discharge of payloads, thereby offering control over the therapeutic release. Kakkar et al. recently reported the synthesis of a series of AB2 and ABC miktoarm star polymers using a combination of click chemistry and ROP.45,101,102 The miktoarm star synthesis begins with a molecular building block with two protected alkyne and one hydroxyl functionalities (I2.11, Figure 23). By using different types of silyl protecting groups, the two alkyne functionalities can be made “orthogonal”. This is particularly advantageous for ABC-type miktoarm star synthesis, as two compositionally different polymers can be linked together via sequential click reactions, followed by ROP to afford the triarm star polymer.45 Kakkar and co-workers successfully prepared PCL-(PEG)2101 and PCL-PEG-TPPBr (TPPBr = triphenylphosphonium bromide)100 miktoarm star polymers adopting the same synthetic strategy. By judiciously tailoring the arm lengths, the AB2 and ABC miktoarm star polymers are able to self-assemble into spherical micelles with low CMCs and superior colloidal stability in aqueous solution. These micelles potentially serve as therapeutic delivery systems for neuroinflammation treatment

Table 1. Effect of Freeze Drying on the Size of PEG-b-PCL and PEG/PCL Miktoarm Star Micelles and the Corresponding Nimodipine (NIM) Loaded Micelles in the Presence of 5% (w/v) Sucrose and Trehalosea RH after freeze drying b

micelles PEG2000-PCL5800 (blank) PEG2000-PCL5800 (NIM loaded) PEG7752-PCL5800 (blank) PEG7752-PCL5800 (NIM loaded) a b

RH before freeze

5% trehalose

5% sucrose

16.3 ± 0.2 18.4 ± 0.8

27.6 ± 0.5 31.5 ± 0.5

31.5 ± 0.6 33.5 ± 0.9

9.4 ± 0.1 9.4 ± 0.0

25 ± 1.2 24 ± 2.1

31.2 ± 0.4 29.6 ± 1.7

Reproduced with permission from ref 101. Copyright 2010 Elsevier. RH: hydrodynamic radius (nm), mean of six measurements ± SD.

Unlike the aforementioned stars with soft coil arms, miktoarm stars containing both soft coil and rigid rod arms have been less explored in the past. More recently, Kakuchi et al. established a novel synthetic protocol toward AB2 and AB3 rod−coil miktoarm star polymers to expand the synthetic methodology toward this class of macromolecules, and the authors also reported their unique self-assembly phenomena in both solution and solid states.103,104 The miktoarm star polymers are composed of rigid poly(n-hexyl isocyanate) (PHIC) and soft aliphatic polyester PLLA (or PCL), serving as the A and B segments, respectively. Synthesis of the AB2 and AB3 stars was achieved through the click coupling of the azido chain end-functional PHIC (PHIC-N3) with ethynyl-functionalized alcohols yielding di- or trihydroxyl end-functionalized PHICs (PHIC-(OH)2 and PHIC-(OH)3), followed by the ROP of LA (or CL) using PHIC-(OH)2 and PHIC-(OH)3 as the macroinitiators, respectively. Self-assembly studies found 6765


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Figure 24. Hydrodynamic radius (Dh) measured by DLS of PHIC-b-PLLA1−3 and PHIC-b-PCL1−3 in DMF (1.0 mg mL−1 at 25 °C). (a) f PHIC = 0.54−0.59 (PHIC-b-PLLA: Mn,NMR = 19 200 Da, PHIC-b-PLLA2: Mn,NMR = 20 700 Da, and PHIC-b-PLLA3: Mn,NMR = 19 700 Da), and (b) f PHIC = 0.50−0.53 (PHIC-b-PCL: Mn,NMR = 20 900 Da, PHIC-b-PCL2: Mn,NMR = 22 200 Da, and PHIC-b-PCL3: Mn,NMR = 20 600 Da). (c) Schematic illustration for the proposed aggregation behavior of PHIC-b-PLLA1−3 and PHIC-b-PCL1−3 in DMF. Reproduced with permission from ref 104. Copyright 2014 Royal Chemical Society.

Figure 25. Schematic illustration of the complex vertically orientated lamellar structure prepared from a series of miktoarm star polymers PHIC− PCLm (m = 1−3; Mn,NMR(PHIC) = 11 300−11 400 Da and Mn,NMR(PCL) = 4800−5300 Da). Reproduced with permission from ref 103. Copyright 2014 American Chemical Society.

the AB2 and AB3 miktoarm star polymers (i.e., PHIC-(PCL or PLLA) 2 and PHIC-(PCL or PLLA)3 ) as well as the corresponding linear analogue (i.e., PHIC-PCL (or PLLA)) forms spherical micelles in DMF. The sizes of micelles prepared

from copolymers of the same compositions and MWs decrease with increasing arm number of the polyester chains (i.e., PCL or PLLA) due to the excluded volume effect of the polyester domain (Figure 24). The CMCs of the micelles increase with 6766


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Figure 26. Schematic illustration for the synthesis of four-arm PCL-b-POEGMA475-b-PMEO2MA and PCL-b-PMEO2MA-b-POEGMA475 star polymers using pentaerythritol as core initiator. Reproduced with permission from ref 106. Copyright 2011 Wiley-VCH.

property variations in response to changes in microenvironment (e.g., UV radiation, variation in pH, temperature, or redox potential), have obtained significant attention in life science and pharmaceutical fields. The research and development of these “smart” polymer assemblies may bring about a new generation of biomedical nanodevices with enhanced performance and minimized side effects.100 Matyjaszewski et al. recently prepared a novel water-soluble, thermoresponsive micelle through self-assembly of an amphiphilic four-arm triblock copolymer star.106 This star polymer was prepared by the ROP of ε-CL and sequential ATRPs using pentaerythritol as the core initiator (Figure 26). The arm polymers therefore consist of three distinct polymer blocks, including a hydrophobic, biocompatible, and biodegradable PCL, water-soluble OEGMA475, and thermoresponsive poly(di(ethylene oxide) methyl ether methacrylate) (PMEO2MA) (LCST = 20 °C) segments. Poly(oligo(ethylene oxide)methacrylate)s (POEGMAs) such as PMEO2MA are a unique class of thermoresponsive polymers with low critical solution temperatures (LCSTs), which vary with the length of the oligo(ethylene oxide) side chain. Similar to linear PEG, good water solubility, biocompatibility, and anti-immunogenicity make POEGMAs excellent building blocks for temperatureresponsive materials for biological applications. By modulating the block length and block sequence of the hydrophilic polymer segments in the stars (i.e., POEGMA475 and PMEO2MA, Figure 26), the polymers could self-assemble into different spherical micelles with specific modes of temperature-induced aggregation. For example, the micelles formed by the star (PCL83-b(POEGMA475)20-b-PMEO2MA105)4 with PMEO2MA at the periphery undergo reversible sol−gel transitions between room temperature (22 °C) and human body temperature (37 °C) as a result of the temperature-triggered reversible intermicellar aggregation (Figure 27). These micelles may be developed into an injectable dual-delivery system for both hydrophobic and hydrophilic therapeutic agents. In another report by Feng et al., temperature-responsive intramicellar aggregation was designed to modulate the release

increasing arm number of the polyester chains, and this result is in good agreement with the earlier report by Kakkar and coworkers. The same research group later studied the film morphologies of PHIC-(PCL)x miktoarm star polymers using synchrotron grazing incidence X-ray scattering (GIXS) measurements and quantitative data analysis.103 The results showed the miktoarm star polymer films formed vertically oriented lamellar structures, regardless of the arm number and arm length of the stars. Surprisingly, conventional cylindrical packing motifs commonly observed in the film prepared from the linear diblock copolymers of comparable volume fractions were completely absent. Interestingly, within the individual PHIC and PCL domains, distinctive morphological features were observed. The PHIC domain consisted of a mixture of horizontal and vertical multibilayer structures, whereas the PCL phase formed fringed micelle-like crystals and/or highly imperfect folded crystals (Figure 25). The formation of such unique hierarchical structures in thin films was driven by the multibilayer formation characteristic of the highly rigid PHIC segment and in part by the crystallization and the resulting morphologies of the soft PCL moieties. Similar to miktoarm stars, self-assembly of amphiphilic block copolymer stars (i.e., star polymers with block copolymer arms) may also afford interesting supramolecular constructs, which have been extensively investigated in the past. However, studies on polymer assembly using more complex star block architectures had not been reported until recently. Shen et al. prepared well-defined amphiphilic star-block copolymers consisting of eight PCL-b-PAA-b-PCL (PAA = poly(acrylic acid)) arms. These ABA star-triblock copolymers were prepared by a combination of ROP, ATRP, and click chemistry.105 Unfortunately, contrary to the authors’ expectations, self-assembly of this triblock copolymer star in aqueous solution did not lead to any unique new morphology but spherical micelles. In the past few years, biocompatible, biodegradable, and stimuli-responsive micelles, which may exhibit structural or 6767


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of 6, 7, and 8 glucose units, respectively. The unusual geometric structure that resembles a hollow truncated cone with a hydrophobic internal cavity and hydrophilic outer surface allows CDs to be threaded onto a macromolecule to give polyrotaxanes. The driving forces for the polyrotaxane formation (i.e., the inclusion complexation (IC)) include the intermolecular hydrogen bonding between adjacent CDs as well as geometric compatibility and hydrophobic interactions between CDs and the included polymers. Linear aliphatic polyesters with biocompatibility and biodegradability, such as PCL, poly(ethylene adipate) (PEA), poly(trimethyleneadipate) (PTA), and poly(1,4-butylene adipate) (PBAP), were capable of forming polyrotaxanes with CDs. Since CDs are not only biocompatible and biodegradable but also hydrophilic with good water solubility, the polyester/CD polyrotaxanes have great application potential in many healthcare and life science materials. In the past, star-shaped polyester/CD polyrotaxanes along with other polyrotaxanes with complex architectures have been investigated. The aim of these studies was not only to evaluate the effect of topology on inclusion complexation for academic curiosity but also to develop novel functional materials for delivery and therapeutic applications. Recent reports on the polyester/CD star polyrotaxanes include the following: Dong et al. prepared a water-dispersible star-shaped poly(pseudo)rotaxane through inclusion complexation of a four-arm PCL star polymer with a porphyrin core and α-CDs for potential applications in photodynamic therapy;111 Han and Zheng reported the synthesis of an α-CD/PCL-based six-arm star polyrotaxane with a macrocyclic oligomeric silsesquioxane (MOSS) core as new organic−inorganic hybrid materials;112 Ren et al. prepared a four-arm star block copolymer, i.e., (PLLA-b-PEG)4, via ROP and N,N’-dicyclohexylcarbodiimide (DCC) coupling chemistry. They found that α-CDs can be selectively threaded onto the PEG block or both the PLLA and the PEG blocks depending on reactions conditions to yield partially and fully threaded star polyrotaxanes, respectively;113 Yilmaz et al. synthesized a six-arm polyrotaxane through inclusion complexation of β-CD and a star polymer, which contains cholesterol end-capped PCL arms emanating from a phosphanzene core.114 Bioactive compound (e.g., cholesterol) functionalized star polyrotaxanes are expected to have promising applications in drug delivery systems and tissue engineering scaffolds. These studies have unequivocally confirmed the material properties of the star macromolecules that have been significantly altered through the IC. The IC suppresses the melting and crystallization of the star-shaped polyesters, and the resultant supramolecular assemblies assume new crystalline structure in bulk phase, with X-ray diffraction properties substantially different from that of the star precursors. More importantly, the threaded CDs provide the star host with a hydrophilic exterior and hence better dispersibility in aqueous solution. Such functional features have significantly extended the application scope of polyesterbased star or other nanoparticles in the fields of bioengineering, nanomedicine, and medical imaging. All of the previously reported star polyrotaxanes were prepared from star polymers synthesized via the core-first approach. More recently, Qiao et al. reported the first synthesis of CCS polyrotaxane through supramolecular self-assembly of a PCL-based CCS scaffold and α-CD (Figure 29).115 Different from conventional star polyrotaxanes, the CCS polyrotaxane has a cross-linked network core structure and a

Figure 27. Photographs show temperature-induced sol−gel transitions of [PCL83-b-P(OEGMA475)20-b-P(MEO2MA)105]4. Concentration: 10 wt %. Reproduced with permission from ref 106. Copyright 2011 Wiley.

profile of encapsulated payloads.107 A thermoresponsive micelle with an LCST of ca. 61 °C was prepared based on a four-arm amphiphilic star-diblock copolymer (PCL-b-POEGMA300)4, Mn (OEGMA) = 300 g mol−1). The amphiphilic star was synthesized from a tetrahydroxyl functional porphyrin through ROP and ATRP via a core-first approach. An in vitro drug release study showed that at room temperature the hydrated POEGMA corona of the micelle stabilizes the hydrophobic PCL core in PBS solution, allowing a slow diffusion of the loaded drug molecules. At a temperature above the LCST, the corona is deformed due to intramicellar aggregation of the POEGMA components. Consequently, the rate of drug release was accelerated ca. 4fold at 30 h (Figure 28). With modification to lower LCST, this micelle system may serve as a potent delivery vehicle for anticancer therapeutics in hyperthermia therapy.

Figure 28. Drug release profile of camptothecin (CPT) encapsulated the micelle self-assembled from (PCL-b-POEGMA300)4 (Mn,NMR ((PCL-b-POEGMA300)4) = 81 300 Da, f PCL = 0.20) star at 25 and 62 °C. Reproduced with permission from ref 107. Copyright 2011 Wiley-VCH.

Polyrotaxanes are a unique class of polymer assemblies with necklace- or channel-type supramolecular structures, which consist of a linear polymer threading through discrete cyclic oligomers via inclusion complex formation. Since the first report by Harada et al., a plethora of studies on the synthesis and characterization of new polyrotaxanes has subsequently been published. 108,109 Among many existing types of polyrotaxanes, the cyclodextrin (CD)-based ones are the most common.110 CDs are cyclic oligosaccharides composed of D-glucose units that are joined by α-1,4-glucosidic linkages. Common subtypes of CDs include α-, β-, and γ-CDs comprised 6768


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Figure 29. Schematic illustration for the synthesis of the CCS polyrotaxane: (i) ring-opening polymerization; (ii) star formation via ring-opening polymerization; (iii) inclusion complex formation; (iv) click end-capping reaction. Reproduced with permission from ref 115. Copyright 2012 WileyVCH.

larger arm number (Narm = 15 compared to Narm ≤ 8 of the conventional star polyrotaxanes). Capitalizing on mild reaction conditions and functional group tolerance of OROP, the PCL star was synthesized with alkyne “clickable” chain ends in high yield (95%). After inclusion complexation with α-CD, the click reaction between the alkyne group and a bulky azido anthracene derivative permanently locked α-CDs onto the PCL arms while rendering the star polyrotaxane with photoluminescent properties through the anthracene moieties. Likewise, other functionality can be conveniently installed onto the CCS polyrotaxane by taking advantage of the versatility of the click reaction. The inclusion ratio (i.e., the α-CD:CL ratio) of the CCS polyrotaxane was determined to be ca. 0.7 via 1H NMR spectroscopic analysis, less than the theoretical 1:1 stoichiometry observed in linear α-CD/PCL polyrotaxane.116 The low α-CD:CL ratio is a direct result of steric congestion at the core caused by a high arm polymer density. Therefore, threading of α-CD onto the arms along the radial direction toward the core becomes increasingly difficult and less thermodynamically favorable. Inclusion ratios lower than the theoretical value (ranging from 0.5−0.98) were also observed for other star-shaped polyrotaxanes,111−113 reflecting the toll of

the architecture on inclusion efficiency. The facile and versatile synthesis reported by Qiao et al. that combines OROP, α-CD/ PCL inclusion complexation, and click reaction delivered a new paradigm of polyrotaxanes with intricate architecture and functional properties. This study along with other latest developments in star polyrotaxanes would create new research avenues in supramolecular chemistry and warrant novel functional materials for therapeutic delivery and tissue engineering applications. 2.2.2. Ring-Opening Polymerization (ROP) of NCarboxyanhydride. Since the first reported account of Ncarboxyanhydride ring-opening polymerization (NCA-ROP) by Deming in 1997,117 the application of NCA-ROP to synthesize star polymers has been steadily increasing over the past few years. While other controlled polymerization techniques are still commonly used in the preparation of synthetic complex polymer architectures, the demand for biocompatible and biodegradable polymers that are more relevant for clinical bioapplications have driven researchers to explore alternative synthetic methods. NCA-ROP, a controlled chain-growth polymerization technique, which relies on the use of amino acids as building blocks, fulfills such criteria as the formed 6769


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Figure 30. Synthesis of various PLL stars using different generations of PPI dendrimers for siRNA delivery applications. Synthesis involved the NCA-ROP of ZLL NCA monomer with a PPI dendrimer, followed by deprotection with HBr in trifluoroacetic acid (TFA) solution. Reproduced with permission from ref 125. Copyright 2014 Royal Chemical Society.

the fundamental mechanism and kinetics pertaining to the star formation process itself. In the remainder of this section, we will highlight and discuss some of the main papers on star polymers prepared via NCA-ROP, most notably focusing on their structure−property relationship in relation to their respective applications. Heise and co-workers prepared various poly(L-glutamic acid) (PLGA) star polymers from dendritic polypropyleneimine (PPI) dendritic initiators (generations 2−5; 8−64 terminal primary amines) via a core-first approach and studied the encapsulation properties of these star polymers with a fluorescent molecule (rhodamine B).120 The size, arm length, and MW of the star-shaped polypeptides were configured by simply varying the dendrimer generation and monomer feed ratio. It was noted that maximum MW was attained within 6 h of reaction time for all star polymers generated, which were narrowly dispersed (Đ < 1.2), and the largest star obtained has a total of 2300 glutamic acid (GA) units using a fifth-generation dendrimer initiator. The authors made a key point in stating that high-MW polypeptides are made possible in the form of star polymers that are otherwise unobtainable for analogous linear architectures. Crucially in this work, they demonstrated that an 8-arm star polypeptide with a total of 296 GA units has higher loading capacity (ca. 3 times) compared to a linear PLGA having a similar amount of GA units (252), signifying

polypeptides bear close structural resemblance to naturally occurring peptides and proteins that are already present in the human body. Furthermore, the availability of natural and synthetic amino acids with different functional groups allows for facile incorporation of specific functionalities into polypeptide materials. Although polypeptides prepared via NCA-ROP lack specific amino acid sequence control compared to those prepared via solid-phase peptide synthesis, the NCAROP approach enables the preparation of high molecular weight (>100 repeat units) amino acid polymers that are synthetically challenging to prepare using other strategies. It is exactly for these reasons that many research groups are beginning to develop keen interests in applying NCA-ROP for star polymer synthesis. Given that this review only focuses on the developments of star polymers after 2009, the reader is referred to comprehensive reviews by Kricheldorf118 and Hadjichristidis et al.119on NCA-ROP-derived star polymers and other architectures for studies conducted before 2009. The majority of the work in this area since 2009 mainly explores the various functionalities of star polypeptides such as their cargo encapsulation and release profiles, lectin binding capabilities, and fluorescent and self-assembly behavior and how these properties correlate with the star structure (e.g., peptide chain length, number of arms). These studies were less focused on 6770


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Figure 31. (a) Illustration of complexes formed between PEGylated-PHis star polymers with insulin and loaded into PLGA microspheres. (b) Synthetic scheme for the preparation of PEG-conjugated PHis star polypeptides. Reproduced with permission from ref 128. Copyright 2012 Elsevier.

phenylalanine NCA (targeting 5 repeat units per arm), followed by a second NCA-ROP reaction with either ε-benzyloxycarbonyl-L-lysine (ZLL) NCA or γ-benzyl-L-glutamate (BLGA) NCA (targeting 20 repeat units per arm). Although the molecular weight distributions (MWDs) of the stars were considered monomodal by the authors, the Đ values were between 1.5 and 1.6. It is highly possible that the broad MWDs were caused by the formation of ill-defined polypeptide through initiation via the secondary and tertiary amines of the PEI core or by impurities in the reaction mixture. The star polypeptides were then coupled with PEG by reacting the amino groups on the peripheries of the arms with monomethoxy PEG containing 4-nitrophenyl carbonate end groups. Finally, the peptide

the advantage of the star architecture over loading capacity. Furthermore, they demonstrated that the number of rhodamine encapsulated per star increased with increasing peptide arm length. Additionally, the PLGA stars were shown to be enzyme degradable where the encapsulated rhodamine B was released in the presence of an enzyme capable of hydrolytic cleavage of PLGA such as thermolysin. In a separate study, Liu and coworkers synthesized two star-shaped peptide block copolymers using a branched polyethylene imine (PEI) (MW ≈ 1.8 kDa) with ca. 15 primary amine groups as the initiator core and studied the encapsulation properties of these star polymers with various small hydrophobic and hydrophilic guest molecules.121 The star polymers were synthesized by first polymerizing L6771


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Figure 32. Synthesis of glycosylated star polymers by coupling of glucosamine to PLGA stars in the presence of DMTMM. Reproduced with permission from ref 130. Copyright 2015 Wiley-VCH.

transformation efficiencies were 34% and 60%. While the guanidinated stars exhibited lower toxicity compared to the nonguanidinated versions, the former have relatively lower binding strength with DNA because of the delocalization of polymer charge. In a separate report, Na and co-workers synthesized various multiarm poly(L-histidine) (PHis) from 1benzyl-N-carbobenzoxy-L-histidine (BLHis) NCA using a PEI core (Mw ≈ 600 Da) that were subsequently coupled with PEG containing N-hydroxysuccinimide active ester end group (Figure 31).128 The PEGylated PHis stars formed complexes (30−60 nm in size) with insulin, which were loaded into poly(lactide-co-glycolide) microspheres and evaluated as potential long-term, sustained insulin delivery formulation via in vivo studies. Liu and co-workers also synthesized polycationic peptide stars that consist of a PEI core, PLL arms, and PEG outer shell as potential nanocarriers of insulin.129 Glycosylated components are important in biological processes as they regulate vital functions including cellular recognition and signaling. In another recent work from Heise’s group, a library of PLGA star polymers was synthesized from different generations of PPI dendrimers and postmodified efficiently with glucosamine by employing the coupling reagent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (Figure 32).130 A high degree of glycosylation was attained in almost all cases (even up to 96% and 73% for 8-arm and highly dense 64-arm PLGA stars, respectively), highlighting the efficiency of this coupling strategy. Sugar conjugation to star polymers proceeded in near quantitative fashion when targeting 25% and 50% degree of substitution. However, incomplete glycosylation became more apparent when targeting 100% degree of substitution as the number of arms and arm length increased. This is because the carboxylic acid groups closest to the core are less accessible and more sterically hindered than those located closer to the periphery, and in other words, the density of sugar moieties is most likely to be concentrated at the outermost regions of the arms. We believe this to be an important observation for the postmodification of the arms of star polymers in general, which most likely holds true for other coupling strategies and molecules. The synthesized glycopolypeptides were compared in terms of their binding strength with a model lectin, concanavalin A (ConA). It was demonstrated that PLGA stars with higher amounts of substituted sugar have better binding affinities with ConA. Although there was no distinguishable difference in binding affinities among the star polymers, the binding affinity of linear analogues was poorer in comparison to the stars, highlighting the importance of

protecting groups were removed to yield PLGA and poly(Llysine) (PLL)-derived star block copolypeptides with siteisolated hydrophobic and hydrophilic shells. Similar polypeptide stars were prepared by the same group in a follow-up study, albeit without the hydrophilic peptide shell.122 The authors determined in more detail the loading capacity of various hydrophobic guest molecules with respect to the different chain lengths of the hydrophobic peptide arms. For all the star polymers made with different types of hydrophobic amino acid NCAs (e.g., ZLL, BLGA, L-leucine, L-phenylalanine, and Ltryptophan), the loading capacity of pyrene, oil red, and doxorubicin (DOX) increased (by ca. 1.2−3 times depending on the type of the guest molecule) when the number of repeat units of the hydrophobic peptide doubled, similar to what was observed in the report by Heise et al.120 Following this, they reported the synthesis of PLL-based star block copolymers as pH-responsive nanocarriers for anionic drugs.123 The stars were composed of a PEI core, PLL inner shell, and PEG outer shell. The model drug diclofenac sodium was successfully encapsulated at physiological pH and demonstrated sustained release at high or low pH values (10−11 or 2−3). Along the lines of small molecule encapsulation, Yu and Liu et al. prepared a 7-arm PLGA star from an aminated β-CD initiator that was later complexed with cis-dichlorodiammine platinum(II) drugs, formed inclusion complex with adamantly functionalized PEG via host−guest chemistry, and last self-assembled into supramolecular micelles.124 In 2013, Heise and Cryan et al. reported the synthesis of a series of PLL star polymers using different generations of PPI dendrimers for gene delivery applications (Figure 30).125 Specifically, monodisperse stars with 8, 16, 32, and 64 PLL arms, with each arm has ca. 40 amino acid residues, were made and complexed with plasmid DNA pGL3 and small interfering RNA (siRNA) for transfection studies. They found that stars with lower number of arms were most promising as gene delivery vectors based on the formed polyplexes size (100, depending on the approach taken, with well-defined Narm generally only accessible with a lower number of initiating sites (e.g., small molecules, dendrimers). Naturally occurring biomolecules can also be efficiently converted into multifunctional initiators for ATRP, leading to the formation of star structures with bioderived cores. For ATRP, the initiating moiety consists of an activated alkyl halide (i.e., C−X), and this functionality is commonly introduced via esterification of a hydroxyl group with an alkyl halide-containing acid chloride or acid bromide. This makes modification of various saccharides particularly attractive due their abundance of pendant hydroxyl groups, and indeed, star polymers synthesized using ATRP and a core-first approach have been realized using glucose-,182−184 sucrose-,185 and cyclodextrin (CD)-derived152,159,186−191 multifunctional initiators. ß-CD is of particular interest, as it possesses a rigid toroidal conformation with 7 primary hydroxyl groups on the external facet and 14 secondary hydroxyl groups on the internal

initiator molar ratio (5:1 to 35:1). In addition, CCS polypeptides with PBLGA arms were also prepared via the same approach and subsequently modified with hydrazine, which readily displaces the benzyl protecting groups to yield pendant hydrazide groups. In another report by the same group, PLL stars bearing peripheral allyl functionalities were made via the arm-first approach using N-(trimethylsilyl)allylamine as the initiator.142 The allyl-functionalized PLL stars were modified with thiolated PEG-folic acid conjugate via thiol−ene chemistry for subsequent cancer cell targeting studies. Tested with a model breast cancer cell line (MDAMB-231), higher cell internalization was observed with the folic acid-conjugated PLL stars compared to those without the targeting moiety, demonstrating the potential of these star polymers for drug delivery applications (Figure 38). Two later independent reports on the formation of CCS polymers via NCA-ROP were demonstrated by Xing et al.143and Ding et al.144 Coincidentally, in both of these studies amine-terminated PEG macroinitiators (MW ≈ 2 and 5 kDa, respectively) were employed in the NCA-ROP of Cys NCA together with BLGA NCA or L-phenylalanine NCA as comonomers, Table 2. Equimolar amounts of Cys and BLGA NCA at a total monomer-to-macroinitiator molar ratio of 4.8:1 was used by Xing et al. to form CCS with PEG arms radiating from a polypeptide core. The size of the CCS was ca. 160 nm in diameter, as determined by DLS measurements. The loading of indomethacin and release in the presence of glutathione (GSH) were also demonstrated. Meanwhile, Ding et al. employed Lphenylalanine NCA as a comonomer (at ca. 4−7 times higher in molar concentration than the cross-linker Cys NCA) and at different total monomer-to-macroinitiator molar ratio (25:1− 42:1) to yield CCS with tunable sizes (170−230 nm). Doxorubicin was loaded into the star polymers, and it was found that the drug was released at a slightly faster rate for stars containing a lesser amount of amino acid in the core. Interestingly, the CCS prepared in these two separate studies revealed similar cargo release rates at the same GSH concentration of 10 mM. 2.2.3. Atom Transfer Radical Polymerization (ATRP). Atom transfer radical polymerization (ATRP) is a form of transition metal-mediated controlled/living radical polymerization that has been employed extensively since its inception in the mid to late 1990s,145−148 allowing for the synthesis of a wide variety of functional polymers with controlled molecular weights and low dispersities.149 Access to numerous polymer topologies via ATRP was recognized early on, and the synthesis of brush, comb, and star polymers, among others, has been demonstrated for a range of monomers under a variety of 6776


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the synthesis of 21-arm poly(N-isopropylacrylamide) (PNIPAM) stars via ATRP, where conversion of each hydroxyl group on the ß-CD precursor into moieties capable of initiating the ATRP reaction (i.e., initiating sites) was achieved using 2chloropropionyl chloride.195 Following polymerization to form the arms, the end groups were converted into additional ß-CD functionalities, and their ability to form host−guest inclusion complexes with hydrophobic species was investigated and manipulated using the thermoresponsive PNIPAM to modulate the inclusion properties. Using a similar approach, Schmidt et al. converted saccharose into a multifunctional initiator and synthesized a series of 8-arm stars with either random or blocklike chain sequences along each arm.185 The star products with block copolymer arms (namely, poly(α-gamma butyrolactone methacrylate)-b-poly(methyl adamantly methacrylate) (PGBLMA-b-PMAMA) and PGBLMA-b-(PMAMA-co-poly(hydroxyl adamantly methacrylate) (PHAMA))) showed low dispersities (Đ < 1.2) and excellent performance as a photoresist material for lithographic applications compared to the random star copolymer or a reference linear terpolymer of similar chemical makeup.185 Importantly, the block copolymer arms synthesized in this study were formed via an in situ chain extension following full consumption of the first monomer, allowing for a convenient one-pot pathway. Fluorophores and natural dyes can also be used as multifunctional ATRP initiators for star synthesis,157,196 providing the additional benefit of being able to image the resultant star products directly using fluorescence microscopy techniques. Synthetic initiators are also commonly employed for star synthesis via the core-first approach, with the advantage that certain elements of the initiator design can be fine tuned (e.g., arm number, orthogonal functionalities, etc.) and desirable features can be included (e.g., degradability197). Modification of dipentaerythritol to form a hexafunctional ATRP initiator was used by Zhu et al. for the synthesis of a 6-arm star with a triblock arm structure composed of a pH-responsive poly(2(diethylamino)ethyl methacrylate) (PDEMA) block, a hydrophobic poly(methyl methacrylate) (PMMA) block, and a hydrophilic POEGMA block, sequenced from the core to the periphery in the order core-(PDEMA-b-PMMA-b-POEGMA).198 These stars were shown to self-assemble into multiple morphologies depending on the pH, with micelles observed at pH 2.0, vesicles at pH 7.4, and multicompartment micelles at pH 10.5 (Figure 39). A model hydrophobic drug, celecoxib, was used to demonstrate the pH dependence of both the loading capacity and the drug release rate, indicating the potential of such structures for drug delivery applications.198 Cucurbit[n]urils (typically, n = 5, 6, 7, 8, 10) are synthetic macrocyclic compounds with a structure similar to that of ßCD. They are of interest due to their ability to form inclusion complexes with hydrophobic and cationic species.199 A modified cucurbit[6]uril with six ATRP initiating groups was employed by Su et al. for the synthesis of a six-arm star with PNIPAM arms and the molecular recognition ability of the cyclic core investigated.200 A more complex synthetic initiator, called a “molecular spoked wheel” (MSW), was used by Matyjasewski et al. to synthesize a series of six-arm “star-like” macromoleulces, where each arm was further modified to contain pendant initiation sites for the growth of brush-like polymers using a “grafting-from” method (Figure 40).201 These extremely large star structures could be visualized directly by AFM, with the chain length (i.e., DP) of both the main arm backbone and the brush side chains, observed to significantly

Table 2. Structures of the Various NCA Monomers Employed for the Synthesis of Star Polymers via NCA-ROP

facet. This has made it a good starting material for the synthesis of star polymers with up to 21 arms via the core-first approach.24,153,192,193 Moreover, using asymmetric functionalization strategies, the inner and outer hydroxyl groups can be modified orthogonally,156,158,194 allowing for the synthesis of miktoarm star structures with ß-CD cores. Tian et al. reported 6777


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Figure 39. Proposed self-assembly mechanisms of star-(PDEMA-b-PMMA-b-POEGMA)6 at pH 10.5, 7.4, and 2.0. Reproduced with permission from ref 198. Copyright 2015 Royal Chemical Society.

Figure 40. Core-first synthesis of star-brush polymers with hexafunctional “spoked wheel” ATRP initiator via double “grafting-from” approach. Reproduced with permission from ref 201. Copyright 2014 American Chemical Society.

affect key structural features such as flexibility and rigidity. These architectures were thus termed “octopus-like” or “starfish-like” in nature, depending on their degree of structural flexibility. To increase the Narm in the core-first approach, initiators of higher functionality are required. Dendrimers are threedimensional, highly branched polymeric architectures with attractive features including their nanoscopic size, narrow dispersity, well-defined molecular structure, hydrophobic cavity on their interior for potential encapsulation/loading, and availability of multiple functional groups at the periphery.202 Several examples exist in the literature regarding the modification of dendrimer periphery to yield sites capable of initiating ATRP reactions; however, the synthesis of high-order dendritic structures is often complicated and expensive. An alternative approach is the use of hyperbranched polymers as the platform from which stars are grown.152,203,204 The resulting star-like structures are often termed “hyperstar polymers”, which aptly describes their genesis, as well as the resulting architecture. Hyperbranched polyglycerols (HPGs), formed via the anionic ring-opening polymerization of glycidol,205 are one of the most commonly employed

precursors for the synthesis of hyperstar polymers via ATRP, due to the abundance of hydroxyl groups amenable to transformation into initiating sites.206 For example, Lederer et al. reported on the synthesis of a HPG-core star polymer with PMMA arms using ATRP.207 The initial HPG precursor was calculated to have 107 hydroxyl groups; however, by controlling the degree of esterification with 2-isobutyryl bromide, a series of HPG-Brx initiators was formed (where x is the degree of functionalization), providing access to stars with different Narm values. Other hyperbranched polymers have been employed, including those that provide aromatic and aliphatic core domains.208 In 2012, Gao et al. described an elegant approach toward hyperstar polymers with high molecular weights and low dispersities using a one-pot ATRP of an inimer (initiator− monomer).209 Crucially, a microemulsion polymerization was employed to compartmentalize the growing hyperbranched polymer and minimize interpolymer reactions. This was necessary as poorly defined structures had been commonly observed for homogeneous reactions of inimers. The synthesized hyperbranched polymer is therefore well defined and contains multiple initiating sites which can be utilized for 6778


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Figure 41. Hyperbranched MIs formed by emulsion ATRP used for the synthesis of hyperstar polymers. Degradation of star architecture can be achieved by use of degradable, disulfide-containing inimer precursor. Reproduced with permission from ref 209. Copyright 2012 American Chemical Society.

Figure 42. Core-first approach using cross-linked micro/nanogels as multifunctional initiators. Reproduced with permission from ref 223. Copyright 2010 American Chemical Society.

disulfide linker was introduced between the POSS and the initiating sites to allow for cleavage of the polymeric arms under reducing conditions. Moreover, the use of poly(2(dimethylamino)ethyl methacrylate) (PDMAEMA) as the arm structure allowed for efficient binding of siRNA for gene delivery following cationization of the pendant tertiary amine centers.212 Other inorganic cores used for core-first star synthesis include metal complexes (e.g., Ir217), metal− porphyrins (e.g., Zn,180,218,219 Sn,107,220 and Pd221), and other metal−oxide structures (e.g., Ti oxo clusters93,222). Many of these metal-centered star polymers are of interest because of the photocatalytic abilities of the core,219 with benefits derived from the polymeric arms including increased solubility characteristics and improved recoverability, as well as potential modulation of the photoactivity or fluorescence intensity when the use of stimuli-responsive polymers is employed.180,220 Star polymers can also be accessed by a modified core-first approach, whereby polymerization of a divinyl species (i.e., cross-linker) is employed to form a polymeric micro/nanogel, with initiating functionalities retained embedded in the network structure. 22 Subsequent polymerization of a monovinyl monomer generates stars with micro/nanogel cores and a

subsequent chain extension with a second monomer (in this case, tert-butyl acrylate (tBA) or OEGMA) to yield the hyperstar product (Figure 41). Additionally, inimers with redox-cleavable units were also synthesized, and the degradation of the hyperstar via addition of tributyl phosphine ((nBu)3P) was monitored via DLS, with degradation observed to occur in less than 10 min. The degraded species were shown to have a number-averaged molecular weight (Mn) of 13 200 Da and Đ of 1.32, indicating complete degradation of the star architecture.209 Polyhedral oligomeric silsesquioxanes (POSS) have found extensive use as an inorganic initiator for star synthesis via ATRP.167,169−171,210−216 A typical POSS compound is a silicabased three-dimensional nano-object with a cage-like structure, with pendent functional groups on each vertex (typically octafunctional, although hexa-, deca-, and dodecafunctional POSS compounds also exist). These pendent functional groups can be transformed into initiating sites for ATRP. Following polymerization, the star structures are described as inorganic− organic hybrids with polymeric arms and POSS-derived cores.212,213 Xu et al. reported on the synthesis of biodegradable POSS-derived star polymers for gene delivery, whereby a 6779


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of MI species. The authors demonstrated this effect by using three methods of reducing agent doping: the addition of all of the required reducing agents at the start of the reaction, the continuous addition of reducing agent in controlled quantity throughout the course of the reaction, and the timed release of reducing agent throughout the reaction. The quantity increased with star formation (thus increasing the rate). Indeed, the latter method was found to achieve the best results, with a MI-to-star conversion of over 98%, a high molecular weight (Mw,MALLS = 252 kDa), and a very low dispersity (Đ = 1.16) (Figure 43).33

number of linear radiating arms. Conveniently, both steps (i.e., core and arm synthesis) can be performed using ATRP.223,224 For example, Matyjaszewski et al. performed the cross-linking of ethylene glycol diacrylate (EGDA) via ATRP in dilute conditions to generate a polymeric microgel, which was subsequently used as a multifunctional macroinitiator for the polymerization of n-butyl acrylate (BA) to generate stars with a cross-linked PEGDA core, radiating PBA arms, and terminal carbon−halogen moieties (i.e., initiating sites) at the star periphery.223 These were then further chain extended with a disulfide-containing methacrylate cross-linker to form a network gel via interstar cross-linking (Figure 42). The disulfide linkage could then be cleaved under reducing conditions to generate fully soluble individual stars containing terminal thiol functionality, with subsequent oxidation shown to reform the gel network.223 Matyjasweski and collaborators also conducted Monte Carlo simulations for the synthesis of stars via this technique with the effect of various parameters (e.g., initial cross-linker and initiator concentration, timing of monomer addition, etc.) on the structure of the formed star product investigated in detail.225 Interestingly, they reported that the structure of stars formed via this technique differs in some respects from those formed via an arm-first approach where chain extension with a cross-linkable species is employed, despite obvious structural similarities (vide infra). 2.2.3.2. Arm-First Approach. The synthesis of star polymers via the arm-first approach using ATRP generally involves the preparation of a living linear macroinitiator (MI) followed by a chain-extension polymerization with a divinyl (or higher) species, referred to as the “cross-linker”.1 This generates starshaped architectures with a wide range of linear radiating arms (typically 10−100) and a densely cross-linked core. When using controlled radical polymerization techniques for the synthesis of CCS polymers, the potential of these structures has been markedly held back by the imperfect star conversions (i.e., MIto-star conversion) typically observed, as well as the need to isolate the MI prior to addition of the cross-linker. Recently, these challenges have received increasing attention, and as such many major advances and improvements on the synthesis of CCS polymers have been reported. The imperfect MI-to-star conversion typically associated with the formation of CCS polymers can be due to a number of factors but are most typically ascribed to the loss of chain end functionality (i.e., “livingness”) of the MI species prior to (or during) cross-linking, as well as steric congestion around the core limiting the addition of further MIs when a suboptimal ratio of cross-linker-to-MI is used. The use of activators regenerated by electron transfer (ARGET) ATRP was shown by Matyjasewski et al. to greatly improve the formation CCS polymers compared with traditional ATRP, with much improved star yields (≥95% vs 84%), higher molecular weights, lower dispersities, and more arms per star observed.33 To achieve this result, the activator/deactivator ratio (i.e., Cu(I)X/ Cu(II)X2) must be finely controlled. It was reasoned that due to the persistent radical effect (PRE) the radical concentration is highest at the beginning of the reaction and lowers throughout the course of polymerization. Given that termination reactions (which lead to reduced star conversion) are proportional to the instantaneous radical concentration, it was hypothesized that by timing the addition of reducing agent for ARGET-ATRP the rate of radical generation could be manipulated to be low at the early stage of star formation and gradually increase with time to allow for full incorporation

Figure 43. Comparison of final CCS polymer products synthesized via traditional ATRP (entries 1 and 2) and those synthesized via ARGETATRP (entries 4−6), where PMDETA refers to N,N,N′,N′,N″pentamethyldiethylenetriamine, TPMA refers to tris(2-pyridylmethyl)amine, “CF” is the continuous flow method, while “TF” is the timed flow method for reducing agent addition. Reproduced with permission from ref 33. Copyright 2010 American Chemical Society.

This work truly demonstrates that the synthesis of CCS polymers via the arm-first approach is only limited by the suboptimal conditions that are routinely employed and suggests that further optimization may lead to a generalized solution to the problems previously encountered such as low MI-to-star conversions and broad star dispersities. In 2011 Matyjasewski and co-workers demonstrated the use of an electrochemical cell for on-demand manipulation of the Cu(I)X/Cu(II)X2 ratio simply by tuning the applied potential, employing an extremely low amount of initially added catalyst species.226 This technique could provide enhanced control over the polymerization externally, resulting in the suppression of termination events and thus furnishing polymers with a higher degree of end-group functionality. When the system was applied to the synthesis of star polymers via the arm-first approach, high MI-to-star conversions were observed (up to 95%) and the stars were narrowly dispersed (Đ ≈ 1.3).4 Using a multistep chronoamperometry technique the applied potential was gradually increased throughout the course of the crosslinking reaction, directly affecting the reaction rate due to a changing Cu(I)X/Cu(II)X2 ratio. By manipulating the reaction rate (via the applied potential) such that it began slowly and then increased as the star conversion increased, a reduction of star−star coupling and other termination events could provide access to higher molecular weight stars with higher MI-to-star conversions,4 in accordance with the results of the ARGETATRP study.33 Although this is a general principle, the ease with which the rate can be tuned in this system given that it is controlled by an external stimulus (i.e., applied potential), rather than a chemical stimulus (i.e., reducing agent), makes this approach particularly amenable to optimization using this approach (i.e., in situ rate manipulation). Termination events in radical polymerization are nonlinearly proportional to the concentration of active radicals in solution. 6780


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Figure 44. Synthesis of core- and periphery-functionalized CCS polymers via the arm-first “macromonomer” approach. Reproduced with permission from ref 229. Copyright 2010 American Chemical Society.

As an alternative to manipulating the activator/deactivator ratio to minimize these events and thus increase the arm-to-star conversion, the use of macromonomers (MMs) instead of MIs, i.e., linear polymers that contain a single polymerizable unit at either the α or ω chain end (but not both), was introduced.227,228 Using this method, the radical concentration is determined by the amount of low molar mass initiator added to initiate the cross-linking step and hence can be controlled experimentally. This approach has been used for the synthesis of a variety of well-defined CCS polymers,228 with chemical groups such as fluorescent dyes for imaging229 or cationic moieties for complexing with siRNA,230,231 incorporated into the core through the use of functional comonomers during the cross-linking step. Matyjasweski et al. also demonstrated the synthesis of stars with tailored functional groups at the star periphery using this technique by employing a telechelic MM with a short peptide sequence at the α terminus and a polymerizable moiety at the ω terminus (Figure 44).229,232 This is a highly versatile approach that has perhaps been underutilized to date and thus may require further exploration. Although copper is predominantly used as the catalyst species for ATRP reactions, other transition metals can also be employedmost notably ruthenium (Ru)for the synthesis of well-controlled polymers of low dispersity. For the arm-first synthesis of CCS polymers using a MI approach, a significant improvement in arm-to-star conversion was reported by Qiao and Kamigaito et al. by using a Ru-catalyzed ATRP system.34 The Ru catalyst, Ru(Ind)Cl(PPH3)2, and a tertiary amine cocatalyst233 were used to synthesize highly living PMMA MIs, which were subsequently reacted with ethylene glycol dimethacrylate (EGDMA) (i.e., cross-linker) to form CCS polymers. The MI-to-star conversion was found to decrease linearly with increasing MI chain length (i.e., molecular weight), with quantitative MI-to-star conversions observed for the lowest molecular weight MI used (>99%, MI Mn = 8000 Da) within 24 h.34 When compared to a traditional Cumediated ATRP catalyst system (Cu(I)Cl/2,2′-bipyridine) a 10−20% increase in MI-to-star conversion was observed for all MI molecular weights investigated (Figure 45). It should be pointed out that in this work the MIs were isolated at low to moderate monomer conversions prior to their use in the crosslinking step to ensure their “livingness”. The group of Sawamoto have reported on a wide range of functional CCS polymers with tailored chemistries using Rucatalyzed ATRP via the arm-first approach.233 Recently, they demonstrated the synthesis of fluorinated-core CCS polymers

Figure 45. CCS polymer conversion versus macroinitiator Mn for the Cu-catalyzed ATRP (◆) and Ru-catalyzed ATRP (●) systems. Reproduced with permission from ref 34. Copyright 2011 Wiley-VCH.

by employing a fluorinated comonomer during the crosslinking step.234 The resulting star products show high potential for the capture and release of perfluorinated compounds for water purification applications.177−179,235 For CCS polymers synthesized via ATRP, core functionality can also be introduced after star formation either by chain extension of the corelocalized ATRP initiating groups with a functional monomer236 or by chemical ligation of functional species via other techniques (e.g., click reactions). Terashima and Sawamoto et al. also described the synthesis of a CCS polymer in which an active Ru catalyst was embedded in the core through copolymerization with a ligand-derived monomer during the cross-linking step.174 Remarkably, this star displayed high catalytic efficiency for a range of polymerization reactions and chemical transformations and was described as a molecular microreactor.39,175,176 In another work by the same group, the synthesis of CCS polymers with arms that could be cleaved at their interface with the core was described by introducing an acetal linkage between the linear polymer (PEG) and the ATRP initiating group (Figure 46).237 Interestingly, following cleavage of the arms via hydrolysis of the acetal linkages, the resulting microgel (that had previously been the star core) showed good solubility in typical organic solvents, contrary to prior expectations.237 2.2.3.3. Grafting-onto Approach. The grafting-onto approach involves the synthesis of monofunctional linear polymers which can then be covalently (or noncova6781


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Figure 46. GPC chromatograms of (a) arm-cleavable CCS polymer prepared via cross-linking reaction of PEG-acetal-Cl with EGDMA and (b) EGDMA microgel obtained by arm cleavage of CCS with trifluoroacetic acid. Reproduced with permission from ref 237. Copyright 2014 American Chemical Society.

Figure 47. (a) Molecular structures of the amphiphilic copolymer(s) investigated for self-folding; (b) generalized scheme for “single-chain folding” and subsequent cross-linking to generate the star product. Reproduced with permission from ref 151. Copyright 2015 Nature Publishing Group.

lently238−240) attached to a (multi)functional species that acts as a branching point and therefore becomes the star core.44 Due to the steric hindrance associated with coupling reactions of high molecular weight polymeric species these reactions often require highly efficient and modular chemistries, and thus, reactions that adhere to the click principles have found widespread use in preparing and/or modifying81,241−243 star polymers via this approach.244−246 ATRP has been used extensively as the technique to make linear polymer precursors

prior to star formation because of the availability of various facile end-group transformation chemistries.247 Perhaps most obvious is the conversion of the terminal halogen into an azide group by nucleophilic substitution with sodium azide (NaN3), as the CuAAC reaction is one of the most commonly employed click reactions.248 Alternatively, reactive groups can be incorporated into the linear polymer through use of a functional ATRP initiator. This provides linear precursors with α-functionality rather than ω-functionality for the 6782


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Figure 48. Synthesis of 5 arm-star pentablock copolymers via SET-LRP with a pentafunctionalized core. Reproduced with permission from ref 273. Copyright 2012 Royal Chemical Society.

ATRP with ring-opening polymerization (ROP),107,249−257 anionic-ROP (AROP),258 Pd-catalyzed ethylene living polymerization, 259,260 enhanced spin capturing polymerization (ESCP), 2 6 1 ring-opening metathesis polymerization (ROMP),262 and reversible addition−fragmentation chain transfer (RAFT) polymerizaiton263 have been demonstrated in the literature for the construction of star polymers. This can provide access to stars with arms (or cores) composed of polymers not accessible via ATRP, such as conducting/ conjugated polymers or degradable polyesters such as PCL. 2.2.4. Single Electron Transfer Living Radical Polymerization (SET-LRP). The concept of single-electron transfer-living radical polymerization (SET-LRP) was first introduced by Percec et al. in 2006.264 Amid the controversy surrounding the actual mechanism behind SET-LRP, the only certainty is that under a specific set of reaction conditions, i.e., the polymerization takes place in polar solvents (e.g., DMSO) and distinctively in the presence of Cu(0) species and N-ligands (e.g., Me6TREN), well-defined and high molecular weight polymers from functional monomers containing electronwithdrawing groups (e.g., acrylates) can be synthesized efficiently at room temperature and at relatively short time scales.265 Regardless of the true mechanistic pathway of SETLRP, several groups have applied this set of reaction conditions advantageously to the synthesis of star polymers. Prior to 2009, the synthesis of 4-arm star polymers via the core-first approach

subsequent coupling reaction. When this approach is used for the synthesis of star polymers the resulting star arms retain their active halogen group (i.e., the ω-functionality of the linear precursor) at the star periphery. This is particularly useful for the synthesis of star-block copolymers, where such “star macroinitiators” can be employed for subsequent ATRP chain-extension reactions. 2.2.3.4. Self-Folding (Single Molecule) Star Polymers. The controlled collapse of polymer chains in solution has become an emerging field in polymer science of late, with the process referred to as “self-folding” and the resultant structures termed “single chain nanoparticles” (SCNP). Terashima et al. recently reported on the self-folding of an amphiphilic random copolymer synthesized via Ru-catalyzed ATRP containing brush-like hydrophilic segments and polymerizable hydrophobic units to form a star-like SCNP.151 When in the collapsed state a radical initiator or an active Ru catalyst was added to covalently cross-link the core and thus stabilize the structures indefinitely (Figure 47).151 These novel self-folded star polymers offer a new pathway toward the design and manipulation of star structures, with precise control over the hydrophobic cavity thought to be of potential for performing chemical transformations inside a molecular nanoreactor. 2.2.3.5. Combinations of ATRP with Other Techniques for Star Synthesis. Other star polymers have been accessed by combining two or more different polymerization techniques in order to generate stars of higher complexity. Combinations of 6783


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range of highly structured star polymers with unprecedented control via the core- and arm-first approaches. Boyer et al. reported the synthesis of various 5-arm star (pseudo)pentablock copolymers in one pot via the optimized SET-LRP method using a pentafunctionalized sugar initiator as the core, where every reaction step was taken to (near)quantitative monomer conversion (Figure 48).273 Polymerizations were conducted in DMSO using Cu wire (as the active Cu(0) species), Me6TREN ligand, and Cu(II)Br2 at different ratios of Cu(II) to bromoester initiating groups ([Cu(II)]: [−Br] = 0.04:1, 0.08:1, and 0.16:1). During the polymerization of methyl acrylate (MA) at the lowest [Cu(II)]:[−Br] ratio of 0.04:1, multimodal MWD with a prominent high-MW peak caused by star−star coupling was observed, while successive chain extensions led to an increase in dispersity (Đ > 1.5) (Figure 49a). Increasing the amount of Cu(II) resulted in a significant improvement in control over the MWD, with stars having Đ values lower than 1.1 even after five chain-extension steps (Figure 49b and 49c). End-group analysis of the pseudopentablock PMA star at the end of the 5-step process revealed that ca. 94% of the living end roups remained intact at the highest [Cu(II)]:[−Br] ratio, whereas 99% in a onepot fashion (Figure 51a).35 The efficiency of this approach was demonstrated by the synthesis of linear PMA MI with ca. 90 repeat units at high monomer conversion (ca. 85%) in 2 h, followed by the addition of a cross-linkable vinyl monomer (i.e., ethylene glycol diacrylate (EGDA)) to initiate the star formation. In less than 16 h, well-defined PMA CCS with Đ < 1.4 and a tunable number of arms (7−40) depending on the cross-linker-to-MI molar ratio (ranging from 5:1 to 15:1) were obtained (Figure 51b). However, star−star coupling was observed when a shorter PMA MI (ca. 50 repeat units) was used to form stars, as evidenced by the higher Đ value (1.9). This phenomenon remains unavoidable like in every other CCS formation strategy due to the inability of shorter arms to shield the growing core from core-to-core cross-linking reactions. Regardless, star conversions were high for all cases (>92%). It is worth noting that the ratio of [Cu(II)]:[−Br] employed was 0.05:1. In a subsequent paper, poly(2-hydroxyethyl acrylate) (PHEA) CCS was synthesized using the same approach and postmodified with 4-(phenylazo)benzoic acid via carbodiimide coupling chemistry.277 The maximum amount of azobenzene moieties that can be conjugated was 20 mol % with respect to the hydroxyl groups on the star polymer. The azobenzenefunctionalized stars formed photoreversible inclusion complexes with α-CD due to the cis−trans isomerism of azobenzene. Another study by the Qiao group entailed the synthesis of two CCS polymers that contain ABABAB-type hexablock arms with alternating hydrophilic−hydrophobic (i.e., PHEA-PMA and PHEA-PtBA) segments via the one-pot SETLRP approach.278 The number of repeat units per block was ca. 10. Additionally, the synthesis of a CCS polymer with ABCDEF-type arms was demonstrated. The main point of their study was to illustrate that the arm-first approach ensures the multiblock sequence of the macroinitiator is carried through to the star structure with no arm defects based on the rationale that only living chains can participate in star formation, irrespective of any dead polymers present in the macroinitiator sample (Figure 52). Basic self-assembly studies of the ABABAB-type CCS polymers indicated the formation of supramolecular structures in 90% MeOH solution, whereas the linear analogues did not display any self-assembly behavior. Another major development in SET-LRP is the rapid formation of well-defined linear homo- and multiblock polymers from acrylate and acrylamide derivatives in water.279,276,280 Developed by the Haddleton group, this method entails the predisproportionation of copper(I) bromide/N-ligand complex (to generate Cu(0) species in situ) prior to the addition of initiator and monomer.279 They demonstrated that this predisproportionation step is crucial to

Figure 49. Molecular weight distributions of PMA star polymers synthesized through successive SET-LRP chain extension using different [Cu(II)]:[−Br] ratios of (a) 0.04:1, (b) 0.08:1, and (c) 0.16:1. Reproduced with permission from ref 273. Copyright 2012 Royal Chemical Society.

ether acrylate and the mannose-functionalized acrylate (Figure 50). The purpose of the synthesis of these star glycopolymers was to determine their ability to inhibit binding between human transmembrane lectin (DC-SIGN) with envelope glycoprotein (gp120) found on the surface of HIV-1 envelope. Interfering with the binding between the host lectins and virus has become an important avenue for anti-HIV applications. Surface plasmon resonance analysis revealed that the binding affinity of star glycopolymers increased with longer sugar arm length and in 6785


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Figure 50. Synthesis of 16-arm star glycopolymer by SET-LRP via the core-first approach. Reproduced with permission from ref 278. Copyright 2010 American Chemical Society.

Figure 51. (a) Formation of PMA CCS via SET-LRP in one pot. (b) GPC differential refractive index chromatograms of PMA CCS prepared at different macroinitiator-to-cross-linker molar ratios. Reproduced with permission from ref 35. Copyright 2013 Royal Chemical Society.

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Figure 52. Illustration depicting that the arm-first SET-LRP technique ensures the star structure to have the desired multiblock sequence for every arm. Reproduced with permission from ref 278. Copyright 2016 Wiley-VCH.

will discuss the few reports that employ NMP in the synthesis of star polymers from 2009 onward. Kuo and co-workers reported the synthesis of a series of 8arm star block copolymers via core-first NMP from a POSS nanoparticle.287 The POSS core initiator was first made by quantitatively incorporating 8 alkoxyamine groups onto the corners of a POSS cube through hydrosilylation of an allylfunctionalized 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) alkoxyamine in the presence of Karstedt’s agent. The POSS core initiator was employed in the NMP of styrene in bulk at 120 °C, where up to 80% monomer conversion was attained in 17 h to produce PS stars with ca. 80 repeat units per arm. Interestingly, no star−star coupling was observed at such a moderately high monomer conversion, and the stars were monodispersed throughout the polymerization (Đ < 1.1). To confirm the integrity of the arms, the POSS core was decomposed by hydrofluoric acid treatment, yielding linear PS chains that match their theoretical MW. For chain extension experiments with 4-vinylpyridine and 4-acetoxystyrene, PS stars with ca. 40 repeat units per arm were used. The diblock copolymer stars maintained low Đ values (

Star Polymers - ACS Publications - American Chemical Society

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