Living Radical

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Functional Interfaces Constructed by Controlled/ Living Radical Polymerization for Analytical Chemistry Huai-song Wang, Min Song, and Tai-Jun Hang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b10465 • Publication Date (Web): 19 Jan 2016 Downloaded from http://pubs.acs.org on January 24, 2016

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ACS Applied Materials & Interfaces

Functional Interfaces Constructed by Controlled/Living Radical Polymerization for Analytical Chemistry Huai-Song Wang*, Min Song and Tai-Jun Hang* Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China. Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China.

ABSTRACT: The high-value applications of functional polymers in analytical science generally require welldefined interfaces, including precisely synthesized molecular architectures and compositions. Controlled/living radical polymerization (CRP) has been developed as a versatile and powerful tool for the preparation of polymers with narrow molecular weight distributions and predetermined molecular weights. Among the CRP system, atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) are well used to develop new materials for analytical science, such as surface-modified core-shell particles, monoliths, MIP micro- or nano-spheres, fluorescent nanoparticles and multifunctional materials. In this review, we summarize the emerging functional interfaces constructed by RAFT and ATRP for applications in analytical science. Various polymers with precisely controlled architectures including homopolymers, block copolymers, molecular imprinted copolymers and grafted copolymers were synthesized by CRP methods for molecular separation, retention or sensing. We expect that the CRP methods will become the most popular technique for preparing functional polymers that can be broadly applied in analytical chemistry.

KEYWORDS: controlled/living radical polymerization, analytical chemistry, separation materials, molecularly imprinted polymers, fluorescent or colorimetric sensors

1. INTRODUCTION Designing and constructing functional polymers have been witnessed as one of the most effective routes to develop new materials for analytical science applications such as chromatographic separation, solid-phase extraction, fluorescent or colorimetric sensing, and so on. Many highvaluable applications demand the synthesis of these supermolecules with well-controlled molecular structures and topologies. Generally, free radical polymerization has been used as an effective polymerization approach for both the commercial and lab-scale production of supermolecules because of its applicability to various monomers, mild polymerization conditions, and tolerance to many different solvents and impurities, but it is a poor-controlled polymerization process because of the fast propagation and inevitable radical termination reactions.1-3 Controlled/living radical polymerization (CRP) has revolutionized and revitalized the field of synthetic polymer chemistry over the past decade years. The CRP methods show great ability to 1

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give satisfactory results in terms of degree of polymerization and control the polymer architecture. Therefore, the versatility of CRPs has made the CRP-based techniques the most popular ones in the preparation of various advanced functional polymers. For analytical chemistry, various polymers with controlled architectures including homopolymers, block copolymers, molecular imprinted copolymers and grafted copolymers were synthesized by CRPs for molecular separation or sensing. In this review, we present a detailed overview of the recently developed advanced functional interfaces by CRP approaches for the analytical science applications.

2. FUNDAMENTALS OF CONTROLLED/LIVING RADICAL POLYMERIZATION (CRP) The definition of controlled/living polymerization is a polymerization reaction, where the polymerizations take place in a living way and the side reactions (such as termination and transfer reactions) are negligible during the polymerization processes, and the polymerization degrees of the resulting polymers increase linearly with the monomer conversions.1,4 In recent years, the most extensively investigated CRPs include atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT) polymerization and iniferter-induced “living” radical polymerization.5-7 These CRPs all rely on the concept that the reactive growing radical species is transiently and reversely converted into the dormant state via the formation of the covalent terminal. The dominant applied CRP methods are ATRP and RAFT, which were mainly introduced in this review. 2.1 Atom transfer radical polymerization (ATRP) Among the CRPs, ATRP is the most extensively studied synthetic technique owing to its specific features including the easy availability of many kinds of initiators, wide range of accessible monomers, and mild reaction conditions. ATRP is a catalytic process and can be mediated by a number of redox-active transition metal complexes (Scheme 1). The mechanism of ATRP involves the transfer of a halogen atom (X) from the dormant species, [e.g., alkyl halides (R-X) or polymers containing “living” halide end-groups (Pn-X)] to a low-oxidation-state metal catalyst (MtzL, Mt represents the transition metal species, L is a ligand) yielding a free radical (R· or Pn·) and higher-oxidation-state metal complex with coordinated halide ligand (Mtz+1L) (Scheme 1).2,8,9 In the ATRP technique, initiator must have a halogen (X = Br or Cl) and a functional group that can stabilize the formed radical (e.g. carbonyl, cyano or phenyl). The catalyst metal complex (MtzL) establishes a reversible equilibrium between growing radicals (Pn·) and dormant species (Pn-X). Generally, there were some drawbacks of ATRP technique: the halide serving as initiator is poisonous and reduced metal catalyst is too sensitive to oxygen. Novel methods of fine tuning initiation and activation for ATRP have been developed including reverse ATRP (RATRP), activator generated by electron transfer (AGET) ATRP10,11 and initiators for continuous activator 2


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regeneration (ICAR) ATRP9,12,13 (Scheme 1). Particularly, RATRP is a convenient method for circumventing oxidation problems of ATRP. It employs higher-oxidation-state metal catalyst (Mtz+1L) which is far more tolerant of exposure to oxygen.5-7 The initiator (I-X) and lowoxidation-state metal catalyst (MtzL) are generated in situ from conventional radical initiator and the higher oxidation state deactivator (Mtz+1L). The initial polymerization components for RATRP can be easily prepared, stored, and shipped for commercial use.

Scheme 1. Mechanism of ATRP methods.

2.2 Reversible addition-fragmentation chain transfer (RAFT) polymerization RAFT polymerization is another versatile living radical technique, which has been shown to be quite effective in solution and bulk polymerization systems.14-16 The RAFT polymerization comprises an addition-fragmentation equilibria by making use of thiocarbonylthio compounds (chain transfer agents) to control radical polymerization progress.17-19 The polymerization was initiated by a conventional free radical initiator, where the homolytic bond cleavage leads to two reactive primary free radicals (I· or Pn·) (Scheme 2). The key of the controlled/living nature of the RAFT progress is the equilibrium between the polymeric radicals (Pn·), the dormant species (3) and the bipolymeric intermediate radicals (4). RAFT polymerization can be used to synthesize well-defined polymers for numerous monomers (almost all monomers suitable for the conventional free radical polymerization) under mild reaction conditions. And, it can also be employed in all modes of free radical polymerization such as solution, emulsion, and suspension polymerizations.1,14,20

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Scheme 2. Mechanism of RAFT polymerization. Reproduced with permission of the American Chemical Society from ref.20

2.3 Monomers for CRP technique The great challenge for creation of functional polymers is to develop well-defined molecular weight, high stereoregularity and controlled monomer sequence. The CRP techniques, especially the ATRP and RAFT, have led to significant developments in the artificial polymers for various polymeric materials including chromatographic stationary phases, solid-phase extraction materials, and fluorescent or colorimetric materials for analytical science. A variety of functional monomers including polar and nonpolar, conjugated and unconjugated monomers (such as styrenes, methacrylates, acrylonitrile, acrylates, acrylamides, vinyl esters, vinyl amides, dienes, etc.) have been employed in the CRP techniques.9,21,22 Table 1 lists the structures and full names of some monomers discussed in this review.

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Table 1. Examples of functional monomers used in CRP for analytical chemistry. No .

Structure

Monomer name

Abbreviatio n

CRP employe d

Applications

1

Cellulose 2,3-bis(3,5dimethyl phenyl carbamate)-6-acrylate

MON-1

ATRP

Chiral stationary phase for HPLC23

2

1-Vinylimidazole

MON-2

ATRP

Stationary phase for HILIC24

3

2-hydroxyl-3-[4(hydroxymethyl)-1H1,2,3-triazol-1-yl]propyl 2-methylacrylate

HTMA

ATRP

Stationary phase for HILIC25

4

N-isopropylacrylamide

IPAAm

ATRP

5

3-Sulfopropyl methacrylate potassium

SPM

ATRP

6

Ethylene glycol dimethacrylate

EGDMA

ATRP and RAFT

7

Glycidyl methacrylate

GMA

ATRP and RAFT

8

Divinylbenzene

DVB

ATRP

9

Butyl methacrylate

BMA

ATRP

10

N,N-dimethyl-Nmethacryloyloxyethyl-N(3-sulfopropyl) ammonium betaine

MON-3

ATRP

11

Hydroxyethyl methacrylate

HEMA

ATRP and RAFT

12

2-(2methoxyethoxy)ethyl methacrylate

MEO2MA

ATRP

13

Methacrylic acid

MAA

RAFT

Thermoresponsive stationary phase for HPLC26-31 Cationexchange stationary phase for HPLC32 Stationary phase for HPLC32-36 Restricted access stationary phase for HPLC32,34-36 Stationary phase for HPLC34,37 Stationary phase for HPLC31 Membrane for protein binding, stationary phase for HPLC 38-40 RAM for HPLC33,41 Thermoresponsive monolith for HPLC42 MIPs for selective adsorption43,4 4

14

N,N'methylenebis(acrylamide ) 5

MBA


RAFT

MIPs for selective adsorption44


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MIPs for selective adsorption45 MIPs for selective adsorption46 Thermo- and pHresponsive surfaces46 Thermoresponsive stationary phase for HPLC28 MIPs for selective adsorption47 MIPs for selective adsorption47 MIPs for chiral separation48

15

4-Vinylpyridine

4-VP

ATRP

16

4-((4-Methacryloyloxy)phenylazo)benzoic acid

MPABA

RAFT

17

2-(Dimethylamino)ethyl methacrylate

DMAEMA

RAFT

18

N-tert-butylacrylamide

tBAAm

ATRP

19

Acrylamide

Aam

ATRP

20

Ethylene glycol methacrylate phosphate

EGMP

ATRP

21

2,6bis(acrylamido)pyridine

BAAPy

RAFT

22

--

APBA-PA

ATRP

Fabricating fluorescent sensor49

23

N,N-Dimethylacrylamide

DMA

RAFT

Fabricating fluorescent sensor50

3. SEPARATION MATERIALS FOR CHROMATOGRAPHY Polymer-related functional materials can easily be derivatized, and possess both high porosity and surface area. These merits have facilitated the polymeric materials as ideal stationary phases for chromatography. The polymeric stationary phases have been proved to be very suitable for liquid chromatography (or high performance liquid chromatography, HPLC) and a number of polymerbased stationary phases for HPLC were reported.51,52 Surface modifying silica supports with organic polymers is the mostly selected method. Because of the high surface area and ease of surface functionalization, silica supports have been utilized extensively as solid support for immobilizing polymers that contain unique functional groups. Furthermore, polymer monolith, with high cross-linked and rigid porous properties, is another well-used stationary-phase format for chromatographic analysis. For preparation of the polymeric stationary phases, CRP techniques can provide controllable polymer networks, desired compositions and molecular architectures, which will ensure the well selectivity of such stationary phases for chromatography. 3.1 Functional polymer modified on silica particle surfaces Porous silica is one of the most promising chromatographic support materials, and is commercially available for various separation modes (e.g. normal, reversed, ion exchange, affinity and size exclusion). The silica-polymer composite stationary phases combine the strength of silica with the selectivity and chemical inertness of polymer. By modification of silica with organic 6


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polymers, the column packing stability can also be achieved.51,53 Generally, the most common polymeric modification techniques are the “grafting from” and “grafting to” approaches.54,55 “Grafting from” a surface (such as surface-initiated polymerization) has been witnessed as a desirable method for achieving more evenly surface-distributed polymers and high grafting densities compared with “grafting to”.51 To date, surface-initiated polymerization on porous silica by CRP techniques exhibits great advantages, such as evenly distributed polymer layers, welldefined polymers grafted with high surface densities and controlled growth of polymer length. CRP initiators are usually chemically modified on the surface of silica supports, which are used as macroinitiators for the following “grafting from” polymerization. A list of CRP (ATRP and RAFT) macroinitiators used for preparing silica-polymer composite stationary phases is presented in Figure 1.

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Figure 1. Examples of surface-grafted functional CRP initiators on silica support.51

The mostly employed ATRP initiator for surface grafting polymers on porous silica is the macroinitiator Ini-1 (2-bromoisobutyrate-functionalized silica, Figure 1), which is prepared via reacting amino-functionalized silica with 2-bromoisobutyryl bromide. Yang and Choi prepared a chiral stationary phase (CSP) with cellulose derivatives by using Ini-1 as ATRP macroinitiator and MON-1 (Table 1) as monomer.23 Based on ATRP technique, the cellulose derivatives were modified on porous silica with two different methods: “grafting from” and “grafting to”. It was found that the chiral resolution ability of 10 racemates on the CSP prepared by the “grafting from” method was higher than that on the CSP prepared by the “grafting to” method. During the ATRP progress, the polymer chain length can be controlled by the ratio of monomer and initiator. Gong and co-workers prepared an imidazole-functionalized stationary phase for hydrophilic interaction chromatography (HILIC).24 Three types of such stationary phase with different chain lengths were obtained by altering the ratio of 1-vinylimidazole (MON-2, Table 1) 7



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to initiator from 25:1, 50:1 to 75:1. Accordingly, the retention times of the analytes (nucleobases/nucleosides) increased with the increase in the number of grafted imidazole groups on the stationary phase. Recently, ATRP technique has been increasing its importance in the development of intelligent polymers (especially the thermo-responsive polymers) which were grafted on the porous silica surface for the preparation of stationary phase for thermo-responsive chromatography. Surface initiated ATRP can provide the grafted polymers (or polymer brushes) with changeable polymer chain length and graft density. Poly(N-isopropylacrylamide) (PIPAAm) is the most remarkable thermo-responsive polymer, because PIPAAm exhibits a reversible phase transition in aqueous solutions depending on temperature at its lower critical solution temperature (LCST, 32 °C). Okano and co-workers have reported a series of thermo-responsive polymer-brush-grafted porous silica as chromatographic stationary phase based on the macroinitiator Ini-2 (Figure 1).26-30 For increasing the hydrophobicity of PIPAAm-grafted surfaces, hydrophobic comonomers [n-butyl methacrylate (BMA) and N-tert-butylacrylamide (tBAAm)] were introduced into the thermoresponsive surface by preparing block polymers. The block copolymers, poly(BMA-b-PIPAAm) 26

and poly(tBAAm-b-IPAAm]28, were grafted on the surface of silica support via a two-step

ATRP polymerization. High separation efficiency of hydrophobic steroids was obtained because of the strong interaction between the well-defined hydrophobicity-enhanced PIPAAm brush on silica surfaces and analytes. Temperature-responsive chromatography combined with ion-exchange property that using thermo-responsive ionic-copolymer-grafted stationary phases have also been investigated by Okano and co-workers for analyzing ionic biomolecules.27,29,30,56,57 By surface-initiated ATRP with macroinitiator Ini-2, poly[IPAAm-co-3-acrylamidopropyl trimethylammonium chloride (APTAC)

-co-tert-butylacrylamide

(dimethylamino)ethylmethacrylate

(tBAAm)],

(DMAEMA)-co-tert-butylacrylamide

poly[IPAAm-co-2(tBAAm)]

and

poly[IPAAm-co-acrylic acid (AAc)-co-tert-butylacrylamide (tBAAm)] were grafted onto a porous silica supports respectively to prepare thermo-responsive ionic chromatographic stationary phases (Figure 2). The copolymer-modified stationary phase can simply control the electrostatic interaction between ionic analytes and the copolymer by changing the column temperature. For example, on the column grafted with poly(IPAAm-co-APTAC-co-tBAAm), the elution behavior of adenosine nucleotides mixture containing AMP, ADP, and ATP exhibited a rectilinear retention time change with an inflection point at the LCST. It might because the grafted copolymer brushes collapse with increasing temperature, and the adenosine nucleotides cannot tend to diffuse into the collapsed copolymer brush. Thus, the retention time would decrease with increasing temperature. Furthermore, the acidic proteins (fibrinogen, human serum albumin, ovalbumin, etc.) can be adsorbed on the copolymer brushes with increasing temperature due to the stronger basic properties of the copolymer induced strong electrostatic interactions between quaternary amine

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groups and proteins. Such thermally modulated cationic chromatographic stationary phases exhibit great potential for separation of acidic biomolecule and purification of proteins.

Figure 2. Structures of polymer brush-grafted silica supports, and schematic illustration of thermally modulated biomolecule adsorption on the cationic copolymer brush, and chromatograms of adenosine nucleotides (a) (1: AMP; 2: ADP; 3: ATP) and protein (b) (fibrinogen) separated on HPLC, for which the packing material was poly(IPAAm-co-APTAC-co-tBAAm) brush-grafted silica support at various temperatures. Reproduced with permission of the American Chemical Society from ref.27

Considering of the “active” end group (alkyl halide initiator) presented in the resulting halogenterminated polymers, ATRP technique has also been employed in synthesis of multiple-functional materials by post-polymerization reactions. Dong and co-workers have reported various restricted access materials (RAMs) as HPLC stationary phases.32,34,58,59 The structure and separation mechanism of the RAMs are demonstrated in Figure 3. The RAMs are designed to allow the retention of analytes and restricting the access of macromolecules. The bi-functional structure of RAMs allows the direct injection of biological fluids during the HPLC analysis with high analytical efficiency.

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Figure 3. The structure and separation mechanism of RAMs.

Very recently, a strong-cation-exchange RAM was synthesized via surface-initiated ATRP by Dong and co-workers.32 Macroinitiator Ini-3 (Figure 1) was used for grafting poly(SPM-coEDMA) (Table 1) on the surface of porous silica. The synthesized Sil-poly(SPM-co-EDMA) was packed into a stainless steel chromatographic column (50 × 4.6 mm i.d.) and exhibited good cation retention and separation abilities toward Ca2+, Mg2+, K+, NH4+ and Na+. Then a postpolymerization was carried out using the terminal radically transferable atom (alkyl halide) on Silpoly(SPM-co-EDMA) as ATRP initiator for grafting the hydrophilic chemical barrier, poly(glycerol mono-methacrylate) [poly(GMMA)], which was obtained by hydrolysis of the epoxy groups of poly(GMA) (Table 1). As restricted access stationary phase, the prepared Silpoly(SPM-co-EDMA)-b-poly(GMMA) shows the strong cation exchange and protein exclusion properties in the HPLC analysis, and was further used for online extraction of melamine and cyromazine from milk samples. Additionally, poly(styrene-co-divinylbenzene) [poly(St-co-DVB)] was also grafted on the surface of silica for preparing the RAM [poly(St-co-DVB)-bpoly(GMMA)], which can be used in HPLC separation of aromatic/hydrophobic compounds in biological samples with direct injection method.34 Several researches have focused on novel initiators for ATRP to prepare more stable covalent bond between the surface of silica substrate and the carbon polymer chains. The macroinitiator Ini-4 (Figure 1), where the silanol groups were replaced with chlorine atoms, have been used to form initial Si-C bonds for anchoring polymeric chains to porous silica.60,61 The chlorine atom in Ini-4 is highly reactive and cleaves from the silicone easily using the standard ATRP catalysts. This initiation method can avoid the condensation of the ATRP initiator and result in hydrolytically stable Si-C bonds. The prepared materials can be potentially used as durable stationary phases for reversed-phase or hydrophilic interaction chromatography. Compared with ATRP, RAFT was less used for grafting polymers on the surface of silica as separation materials. It might because more rigorous reaction condition is needed for immobilizing the RAFT initiators on silica. RAFT agents with thiocarbonylthio groups usually 10


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should be freshly synthesized before immobilization. The mostly employed RAFT agents for surface-initiated polymerization were shown in Figure 1.43,62,63

3.2Modification of polymeric particle surfaces Although silica particle has been widely used as support for preparing chromatographic stationary phases, it was generally instable under alkaline conditions, and separation reproducibility decreases after repeated use of the silica-based stationary phases even at neutral condition. To overcome these drawbacks, polymeric particles with good chemical stability, strong mechanical strength and high mass transfer rate have been successfully used as separation materials either in preparative or analytical modes.34,64-66 The most commonly used polymeric supports are poly(GMA) or poly(EGDMA)-based monodisperse-porous particles.67,68 And the styrene (St)divinylbenzene (DVB) copolymers are also well used as separation materials.25,69 Qu and co-workers prepared a thermo-responsive high-peed protein chromatographic medium taking porous polystyrene (PS) microspheres as a base support.31 By surface-initiated ATRP, poly(IPAAm-co-BMA) brushes were successfully grafted on PS microspheres and the porous structure of PS was robustly maintained. As HPLC stationary phase, the poly(IPAAm-co-BMA) (Table 1) brushes can greatly reduce the nonspecific adsorption of proteins on PS microspheres. In order to give a straight insight on the hydrophobic/hydrophilic changes of microspheres surfaces, fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) adsorption experiment was carried out for the PS-poly(IPAAm-co-BMA) in different temperatures. The fluorescence intensity detected in PS-poly(IPAAm-co-BMA) is weaker at 25 °C than that at 40 °C. This indicates the non-specific adsorption of BSA on the PS-poly(IPAAm-co-BMA) can be controlled by the surrounding temperature. By simply changing the column temperature, three model proteins were separate at the mobile phase velocity up to 2167 cm·h-1. Ulbricht and co-workers recently reported a zwitterionic polymer functionalized porous membrane adsorber prepared by growing poly(MON-3) (Table 1) on poly(ethylene terephthalate) (PET) membrane via surface-initiated ATRP. It was found that the grafted poly(MON-3) exhibited an antipolyelectrolyte effect: the poly(MON-3) chains can be extended by adding chaotropic chloride and perchlorate salts to the solution and the flux through the membrane was accordingly reduced. Static adsorption showed that the IgG could be loaded to the membrane at medium salt concentration, and then 85-95 % of the bounded proteins can be eluted at either low or very high salt concentrations. Such stimuli-responsive pore system provides a novel technique for separation and purification of proteins. Other monodisperse polymeric microspheres, such as poly(3-chloro-2-hydroxypropyl methacrylate-co-EGDMA) [poly(HPMA-Cl-co-EGDMA)] and

poly(glycerol-1,3-diglycerolate

diacrylate-co-glycerol dimethacrylate) [poly(GDGDA-co-GDMA)], have been synthesized for grafting poly(MON-3) chains via ATRP for preparing ion exchange resins or chromatographic 11



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stationary phases.39,40 After slurry packed into a microbore column, the poly(MON-3) grafted poly(GDGDA-co-GDMA) was used as stationary medium for separation of organic acids, nucleosides and peptides by hydrophilic interaction chromatography (HILIC). This analysis is very important since the chromatographic separation of these analytes is generally difficult by reversed-phase chromatography.40 HILIC has shown great advantages in the separation of polar compounds with biological importance (i.e., amino acids, nucleosides, peptides, oligosaccharides, polar organic compounds and organic acids).70-74 The mobile phases of HILIC are dominantly containing water (or acidic/basic buffer),75-77 which requires more stable stationary phases compared with silica supports. The polymeric supports for preparing HILIC stationary phases have exhibited satisfactory performances for the separation of the polar compounds. The polymeric packings can be applied in broader pH range and more resistant against environmental conditions. 3.3 Polymer-based monolithic separation media Polymer-based monolith is a continuous unitary porous structure prepared by in situ polymerization or consolidation inside the column tubing.78 As chromatography stationary phase, the polymeric monolith has been successfully implemented in liquid chromatography and capillary electrochromatography due to their simple preparation procedure, good controllability over porous skeletons and surface chemistries.79 CRP methods can prepare the polymeric monolith with homogenous structure by a controlled polymerization process, and can functionalize the monolithic surfaces for desired chromatographic binding properties by grafting block polymers via post-polymerization reactions.80-84 We recently prepared a chiral monolithic stationary phase by RATRP technique, and then another post-polymerization reaction was initiated by direct ATRP to graft biocompatible poly(HEMA) (Table 1) on the surface of the monolith as a diffusion barrier for proteins.41 The mechanism for preparing the biocompatible chiral monolithic stationary phase was described as follows: the preparation of monolithic column (MC) by RATRP utilizes the conventional radical initiator [azobisisobutyronitrile (AIBN), I-I] to decompose to the radicals (I·) which can propagate by addition of monomers (m), and then be rapidly deactivated by higher-oxidation-state metal complexes [Cu(II)X2/L, X is the halide and L is the ligand]. Then the genarated low-oxidationstate metal complexes [Cu(I)X/L] and alkyl halide initiators (I-Pm-X) can react as the ATRP progress. For grafting poly(HEMA) on the surface of MC, direct ATRP technique was used to further initiate the terminal radically transferable atom (X) on I-Pm-X. During the synthesis of MC by RATRP, a mixture of monomer (m-Nitrophenyl methacrylate, NPMA), cross-linker (EGDMA) and initiator (AIBN) in the presence of porogenic solvents was introduced and sealed into a stainless steel column (150×4.6 mm, i.d.), and then a polymerization was triggered by keeping at a certain temperature. The ratio of monomer (m-Nitrophenyl methacrylate, NPMA)/initiator(AIBN)/CuBr2 was optimized to obtain MC with suitable structures. The m-nitrophenyl groups on the prepared MC can react with β-CD via an inclusion-acylation 12


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procedure. Such β-CD immobilized MC (CD-MC) can be used as chiral stationary phase for separating enantiomers by HPLC. For preparing biocompatible chiral MC, the alkyl halide groups on CD-MC were employed for grafting the hydrophilic polymer chains [poly(HEMA)], as a diffusion barrier for proteins, by direct ATRP. The result material (RA-CD-MC, Figure 4) was applied as HPLC column in the determination of chiral drugs in plasma with direct injection of biological samples. This multifunctional material can well facilitate the analytical efficiency in the biological sample chiral analysis.

Figure 4. RAMs for chiral separation. (A) Structure of RA-CD-MC; (B) protein exclusion mechanism of RA-CDMC; (C and D) Structure of poly-CD-RAM.

The ATRP (or RATRP) has also been employed for preparing ion-exchange or thermoresponsive monoliths.42,85,86 Hybrid cation-exchange monoliths, surface functionalized with sulfonic groups or carboxylic acid groups, have been synthesized by RATRP via a one-pot synthesis.85,86 These monoliths have well permeability and mechanical strength and were successfully used for separation the proteins (such as bovine serum albumin, lysozyme, human immune globulin, and papain) as HPLC stationary phases. The thermo-responsive monoliths were recently prepared by Qi and co-workers employing ATRP for grafting oligo(ethylene glycol)based polymer brushes on the surface of porous poly(EDMA) monolith.42 The copolymer, poly[MEO2MA-co-oligo(ethylene glycol) methacrylate (OEGMA)] (Table 1), has been reported to exhibit LCST values that can be tuned in the range of 26-90 °C by varying the co-monomer composition. The thermo-responsive copolymer-grafted monolith was synthesized by a two-step

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ATRP, and used as the thermo-responsive stationary phase for all-aqueous HPLC. The retention property of three test steroids can be adjusted by varying the column temperature. 3.4 Directly synthesized polymer beads Preparing monodisperse, highly cross-linked, and micrometer-sized spherical polymer particles has been attracted great attention in many analytical research areas such as chromatographic separation and molecularly imprinted solid-phase extraction. The polymeric microspheres can be directly prepared via the precipitation polymerization because of its easy operation and no need for any surfactant or stabilizer.87 However, the optimization of the drawbacks of traditional precipitation polymerization (such as time-consuming and low surface area) is normally required. Introducing RAFT agent into the precipitation polymerization system can impart living characteristics to polymer microspheres with surface-immobilized dithioester groups.88,89 Therefore, RAFT can provide a facile approach for one-pot synthesis of advanced functional polymer particles. Hydrophilic microparticles prepared via one-pot synthesis using RAFT technique have been reported in our previous work.33 The polymerization was initiated by hydrophilic macromolecular chain-transfer agent [poly(2-hydroxyethyl methacrylate), PHEMA], which contains a dithioester end group. The polymeric particles were prepared using β-CD (grafted with allyl groups) as functional monomer and EGDMA as cross-linker. The result particles (poly-CD-RAM, Figure 4) were slurry-packed into stainless steel columns (100×4.6 mm) and used as restricted access chiral stationary phase for direct analysis of biological samples by HPLC. The hydrophilic PHEMA on the RAM particles surface prevents proteins in the biological samples precipitating and adsorbing irreversibly on the particles. This multifunctional material can improve the analytical efficiency towards to chiral drugs in biological samples. 4. MOLECULARLY IMPRINTED POLYMERS (MIPs) MIPs as attractive polymeric materials have been widely designed for specific binding target molecules, and its applications have involved in many analytical research areas such as solidphase extraction (SPE), chromatographic separation and sensors.90-92 The MIPs are predominantly prepared by free-radical polymerization based on the copolymerization of functional and crosslinking monomers in the presence of molecular templates. Among them, CRP techniques allow the design of complex architectures and the modification of surface properties of the molecular imprinted materials.47 The MIPs prepared by CRP techniques can enhance molecular recognition properties because of homogeneous distribution of molecular binding sites in the final polymers with improved network morphologies. 4.1 Surface-grafted MIPs Porous inorganic materials (especially the silica) have been utilized extensively as solid supports for grafting MIP films because of their mechanical stability, high surface area, and ease of surface functionalization.93 The CRP technique allows the grafted polymer films with controllable 14


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thickness and structure. Therefore, preparation of surface imprinted core-shell particles have been reported by RAFT and ATRP via “grafting from” process. The molecular imprinting is a process to generate specific cavities, in which a template molecule interacts specifically via weak forces (such as hydrogen bonds, ionic, and electrostatic interaction, intermolecular force, etc.) with monomeric functional groups.94,95 Generally, organic (most often acrylic based) and inorganic (most often orthosilicate) monomers are employed as functional monomers to prepare the MIP receptors. Among the functional monomers, methacrylic acid (MAA, Table 1) is usually the first choice due to its ability to interact with templates as a hydrogen bond donor or acceptor, and form ion pairs.96-99 Sellergren group has made important contributions to the development of MIPs in separation science.100-103 Recently, they prepared a thin L-phenylalanine anilide (L-PA) imprinted poly(MAA-co-EDMA) layer on the surface of silica under controlled (RAFT) condition by using MAA as functional monomer.43,104,105 The resulting composite (SiPR, Figure 5A) was able to selectively retain the L-PA in relation to the thickness of the grafted poly(MAA-co-EDMA) layer. Furthermore, the silica supports were removed from SiPR by etching, and the obtained nanometer thin walled beads (PR) showed better recognition properties compared with SiPR (Figure 5B). It because the support removal can lead to an increase in surface area impacted the saturation capacity of the materials.

Figure 5. Thin walled imprinted polymer beads for selectively retain L-PA. (A) Removing the silica support from SiPA203: A1and A2 are the SEM images of SiPR and PR respectively. (B) Equilibrium binding isotherms of D(open symbols) and L-PA (solid symbols) for SiPR (red triangles) and PR (blue squares and green circles). Reproduced with permission of the American Chemical Society from ref.43

Zhang and co-workers synthesized a novel kind of lysozyme (Lys) surface-imprinted core-shell particles via RAFT strategy employing MAA and HEMA as functional monomers and MBA as cross-linker.44 The Lys imprinted particles with controllable imprinted shell was initiated by RAFT agent [4-cyano-4-(phenylcarbonothioylthio) pentanoic acid, CPCP] which has been absorbed on silica particles. Such core-shell particles showed obviously improved selectivity for 15



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protein recognition and exhibited great potential as straightforward method for developing artificial antibodies to capture proteins. On the surface of macroporous silica supports, nano-thin walled MIP layers were grafted via RAFT technique by Kadhirvel and co-workers.48 The BAAPy (Table 1) was used as functional monomer to prepare R-aminoglutethimide-imprinted layers, in which the BAAPy presents a donor-acceptor-donor array of hydrogen bond sites with aminoglutethimide. Therefore, the MIP layers show excellent selectivity toward the template (R-aminoglutethimide). The nano-thin-film MIP beads present enantiomeric separation factor for (R, S)-aminoglutethimide up to 11, while on previously reported CSPs, the separation factor is in the range of 1.016–1.520. The superparamagnetic Fe3O4 particle is another well used solid support for surface-grafting MIP films.106-108 The great virtue of these MIP-functionalized magnetic composites is the rapid magnetic response for selectively extract target molecules by an external magnetic field. The CRP technique can significantly facilitate the fabrication of nano-scale MIP layers on the surface of Fe3O4 particles.109-111 Zhao and co-workers have prepared several magnetic MIP nanoparticles by RAFT or ATRP for enrichment and detection of fluoroquinolones (FQs) in biological samples and animal products.112,113 These Fe3O4@MIP nanoparticles possess desired magnetic susceptibility, and exhibit high adsorption capacity and selectivity toward FQs. For example, the uniform ofloxacin (OFX) imprinted shell was constructed on the surface of Fe3O4@SiO2 (Figure 6A) by RAFT method. The acrylic acid (AA) and MAA were chosen as functional monomers for prepare the OFX imprinted MIP layers. After the optimization of reaction condition, the AA based MIP shows both highest binding ability and imprinted factor. Uniform MIP layer with an average thickness of 50 nm can be evenly grafted on the SiO2 shell benefiting from the characteristic superiority of RAFT reaction (Figure 6B). The Fe3O4@MIP nanoparticles possess high magnetization and can be rapidly and completely separated from the suspension by an external magnetic field within 10 s (Figure 6C). Thus, high selectivity toward FQs (ofloxacin, pefloxacin, enrofloxacin, norfloxacin, and gatifloxacin) was exhibited by competitive binding assay (Figure 6D). The Fe3O4@MIP nanoparticles were also successfully applied for the direct enrichment of the five FQs from human urine.

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Figure 6. OFX-imprinted magnetic nanoparticles for separation of FQs. (A) Schematic illustration of the structure of OFX-imprinted magnetic nanoparticle. (B) Transmission electron microscopy (TEM) images of Fe3O4@MIP. (C) VSM curves of (a) Fe3O4@MIP, (b) Fe3O4@SiO2, and (c) Fe3O4 nanoparticles (Inset: a solution of Fe3O4@MIP in the absence and the presence of a magnet). (D) Adsorption isotherm curves of OFX on Fe3O4@MIP and Fe3O4@NIP nanoparticles. Reproduced with permission of the American Chemical Society from ref.112

The mono-dispersed polymeric beads were also widely used for grafting MIP layers because of their characteristic large surface area to volume ratio and the promising surface properties for immobilizing CRP initiators. These polymeric supports include poly(GMA),45 poly(EGDMA-coMAA),114

poly(DVB),115

poly[EGDMA-co-4-vinylpyridine 116,117

polyethyleneterephthalate (PET).

(4-VP)]46

and

Zhao and co-workers prepared the macroporous core-shell

MIP particles for selective recognition of 2,4-dichlorophenoxyacetic acid (2,4-D), which has been used as herbicide and has shown potential damage to the vital organs of human (such as kidney and liver).45 The monodispersed macroporous poly(GMA) particles were synthesized and used as supporting matrix for preparing surface MIP particles (PGMA@MIP). The MIP layer was polymerized by surface-initiated ATRP employing 4-VP as functional monomer and EGDMA as cross-linker. The PGMA@MIP shows excellent permeability, binding capacity and adsorption kinetics owning to the recognition sites situated at the MIP layer. The MIP microsphere with multiple stimuli-responsive template binding properties was recently reported by Zhang and co-workers.46 The narrowly dispersed poly(EGDMA-co-4-VP) was prepared as “living” core polymer microsphere, which was immobilized with RAFT agent for the subsequent surface-initiated RAFT polymerization of poly(MPABA) (Table 1) in the presence of the template (propranolol). Such azo-containing core-shell MIP microsphere (CS-MIP) can release and uptake of propranolol by photoregulation. For improving its surface hydrophilicity and watercompatibility, the hydrophilic and responsive polymer brushes [poly(IPAAm-co-DMAEMA] (Table 1) were introduced on the surface of CS-MIP via a second round of RAFT (Figure 7). The copolymerization of IPAAm and DMAEMA provides hydrophilic polymers with both thermo17



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and pH-responsive properties. The grafted CS-MIP shows well specific template binding and high template selectivity in pure aqueous media. The UV light irradiation on the mixed aqueous solution of propranolol and grafted CS-MIP leads to obvious release and binding propranolol on the grafted CS-MIP (Figure 7C).

Figure 7. Multiple stimuli-responsive MIP microspheres. (A) Schematic illustration of the grafted CS-MIP. (B) SEM images of the “living” core polymer microspheres [poly(EGDMA-co-4-VP)] (B1) and the grafted CS-MIP (B2). (C) The grafted CS-MIP microspheres in a propranolol solution (0.05 mM) under the photo-switching conditions. Reproduced with permission of The Royal Society of Chemistry from ref.46

Additionally, several other inorganic materials, such as gold chip, graphite oxide (GO) particles and carbon nanotubes (CNTs), have been used as supports for surface grafting MIP layers for target molecular sensing.118-121 For example, the ametryn-imprinted sensing film has been fabricated on a gold chip by ATRP using MAA as functional monomer and EGDMA as crosslinking monomer.120 The release or rebinding ametryn on the MIP layer can affect the surface plasmon resonance (SPR) signal of the gold chip. This SPR wavenumber shift showed that the imprinted sensing film have impressive selectivity for ametryn compared to the non-imprinted film. The coated CNTs also have shown high adsorption capacity and fast mass transfer rate. Zeng and co-workers grafted the brucine imprinted poly(MAA-co-EGDMA) layer on multi-walled CNTs by RAFT precipitation polymerization.121 This material was supported on glassy carbon electrode for the electrochemical determination of brucine with high selectivity and sensitivity. 4.2 Polymeric MIP particles Polymeric particles generally possess significantly high surface-to-volume ratio, and thus have been applied to fabricate MIP particles for targeting small molecules, as well as larger organic compounds and biomacromolecules.122 In the earlier studies, the imprinted particles are usually obtained by grinding the imprinted polymer monoliths.123 This procedure leads to the particles of somewhat irregular shape and size, which can affect their molecular recognition ability especially when used as chromatographic packing materials. Precipitation polymerization provides a method 18


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for quickly and straightforward preparing uniform cross-linked spherical MIP particles in high yield and purity.124-127 By changing precipitation parameters, the size of synthesized MIP particles can be precisely tuned. RAFT has become the most powerful CRP method for precipitation polymerization of MIP particles by simply introducing suitable RAFT agents (normally thiocarbonylthio compounds) into conventional free radical polymerization systems.128-131 The group of Zhang has reported different kinds of MIP particles prepared by RAFT technique.132-135 Recently, they reported a series of MIP particles in sizes from nano- to micro-scale.136-140 The MIP particles with hydrophilic surfaces are prepared via one-pot RAFT precipitation polymerization by using hydrophilic macromolecular chain-transfer agents (macro-CTAs, Figure 8A). The hydrophilic polymer brushes on the MIP surfaces can significantly improve their water compatibility, and also can act as a protective layer to prevent proteins in the biological samples from accumulating on the MIP particle surface, and thus these hydrophilic MIPs show efficient recognition ability toward analytes in a real aqueous samples (including river water, pure milk, and bovine serum) (Figure 8B). For example, the hydrophilic 2,4-D imprinted nanoparticles (111-178 nm) were obtained by RAFT precipitation polymerization initiated by poly(HEMA) macro-CTA and a normal RAFT agent (cumyl dithiobenzoate, CDB) (Figure 8). The specific template binding of such grafted MIP nanoparticles are proved to be rather similar to that observed in methanol/water, pure water, river water, and diluted biological media, and can bind more of the template than the corresponding control polymers (CPs, Figure 8D). Furthermore, such hydrophilic MIP particles can also be used as restricted access material for online solid-phase extraction/HPLC for the analysis of sulfonylurea residues in soil samples.36

Figure 8. Hydrophilic MIP particles for molecular recognition. (A) Chemical structures of the hydrophilic MacroCTAs. (B) Illustration of specific recognition of analytes in the real, undiluted biological samples. (C) Characterization of MIP nanoparticles by SEM and dynamic light scattering (DLS). (D) Equilibrium binding of 19



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2,4-D (0.02 mM) to different amounts of the grafted MIP (filled symbols) and CP (open symbols). Reproduced with permission of Wiley-VCH from ref.138

In the MIP field, the use of ATRP has been limited because of its inherent incompatibility with acidic monomers, such as the most widely used functional monomer MAA. For overcoming this obstacle, considerable works have been devoted to develop new metal catalysts that can excellent control the polymerization of acidic monomers by ATRP.141-143 Very recently, the MIP nanoparticles, monoliths and thin films were synthesized via photoinitiated ATRP at room temperature.47 For compatible with acidic monomer (MAA), the polymerization employed fac[Ir(ppy)3] (ppy = 2-phenylpyridine) as ATRP photoredox catalyst (Figure 9A and B). The MIPs composed of MAA as functional monomer were produced by using testosterone and S-propranolol as model templates. Both of the imprinted polymers were very specific towards their corresponding analytes as evidenced by nearly no binding to the non-imprinted control polymers (NIPs) (Figure 9C). To assess the living character of the polymer chain-ends, poly(AAm) brushes were grafted from the halide-capped living ends (initiators) of the MIP nanoparticles. Then, the poly(AAm)-MIP nanoparticles were further functionalized by phosphorus-containing charged polymers [poly(EGMP)], which can provide biocompatibility,

improve cell attachment, and

enhance the mineralization processes.

Figure 9. MIP nanomaterials synthesized using photoinitiated ATRP. (A) MIP nanoparticles with chain-end initiator and further modification by grafting polymer brushes from nanoparticles. (B) Proposed mechanism of ATRP with iridium photoredox catalyst. (C) Equilibrium binding isotherms of [14C]testosterone with bulk MIP (filled triangle) and NIP (empty triangle) in toluene (bottom axis), and of [3H]propranolol with bulk MIP (filled circle) and NIP (empty circle) in acetonitrile (top axis). Reproduced with permission of Wiley-VCH from ref.47

Several other MIP materials, such as monolithic polymers, have been reported for molecular adsorption and on-line solid-phase extraction/HPLC analysis.35,144,145 However, compared with surface-grafted MIPs and MIP particles, the MIP monoliths were not widely used. It might because the monoliths are generally prepared in a molded column by in situ polymerization which 20


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requires strictly reaction conditions to ensure the narrow distribution within the network structures of the monoliths, and high-speed separation is usually impossible because of compression of MIP monoliths at high flow rates. CRP methods (especially RAFT) are perfectly suited for preparing homogeneous polymer networks, and they will become a popular choice for designing the favorite MIP products. 5. FLUORESCENT OR COLORIMETRIC SENSORS The development of fluorescent nanomaterials as fluorescent sensors has received considerable attention due to their inherent advantages, such as cost-effective, high sensitive, operational convenience, and especially their in situ imaging properties.146-148 Polymer based fluorescent sensing matrices may be designed by anchoring fluorescent moiety on the polymer backbone or by preparing block polymers, one of which contains fluorescent moiety.149 The CRP methods are very tolerant to many functional monomers, and they have been successfully used for preparing the fluorescent or colorimetric sensors in controlled progresses. 5.1 Organic/inorganic hybrid sensors As robust and bright light emitter, the semiconductor nanocrystals (quantum dots, QDs) have been adopted as a class of effective fluorescent sensors. Recently, the QDs have been incorporated into homopolymers or block copolymers for preparing QD-polymer hybrid sensors to integrate synergistic effects of both inorganic and organic components.150,151 The CdTe QDs embedded in glycopolymer vesicles for fluorescent lectin recognition have been designed by Shi and coworkers.152

The

star-shaped

poly(gluconamidoethylmethacrylate)

poly(ɛ-caprolactone)-b-poly(2-aminoethyl (SPCL-PAMA-PGAMA)

was

methacrylate-b-

synthesized

by

the

combination of ring opening polymerization and RAFTmethod. The QDs can be encapsulated in glycopolymer SPCL-PAMA-PGAMA vesicles, and the prepared Gly@QDs vesicles could specifically bind Concanavalin A (Con A). Such Gly@QDs vesicles provided a multifunctional platform for cell imaging with low cytotoxicity compared with the original QDs. Ellis and co-workers studied the anchoring of functional polymers to CdSe QD surfaces via surface-initiated RAFT polymerization for fluorescent detection of latent fingermarks.50 The fluorescent nanocomposites CdS/poly(DMA), CdS/poly(DMA-co-MMA) and CdS/poly(DMA-coSt) proved successful in developing latent fingermarks on non-porous aluminum foil substrates. These CdS/polymer nanocomposites retained their optical properties and showed broad fluorescence wavelengths making them ideal as visualized latent fingermarks. Compared with conventional fluorescent organic dyes, Lanthanide-doped upconversion nanoparticles (UCNPs) have exhibited superior performance as fluorescence probes for molecular imaging due to their high tissue penetration property. Qian and co-workers developed a robust method of preparing highly water-soluble core-shell UCNPs by surface-initiated ATRP of hydrophilic monomer, oligo(ethylene glycol) methacrylate (average Mn 360, OEGMA), on UCNP.153 As shown in Figure 10A and B, the prepared core-shell poly-OEGMA-UCNP (with an 21



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approximately 6.8 nm thick uniform polymer shell around the core) was further conjugated with ConA (CPO-UCNP) for cell surface glycan labeling. The CPO-UCNPs were successfully used to selective labele highly metastatic hepatocellular carcinoma cells (HCCHM3) in vitro (Figure 10C) and in vivo imaging of HCCHM3 inoculated mice.

Figure 10. Upconversion nanoparticles for selective cell imaging. (A) Schematic illustration of the poly-OEGMAUCNPs for in vivo imaging. (B) TEM images of poly-OEGMA-UCNPs at different magnifications. (C) UCL images of HCCHM3 cells incubated with CPO-UCNPs for 1 h. Reproduced with permission of the American Chemical Society from ref.153

The Ag@CdS core-shell nanoparticles wrapped with ferritin-MIP layers were presented by Madhuri and co-workers as optical-electrochemical dual probe for trace level recognition of ferritin.154 ARGET-ATRP was used to fabricate the MIP layers, which have shown high selectivity toward ferritin. Furthermore, the conduction band of CdS is at the potential of -1.0 V, whereas the Fermi level of Ag is at +0.15 V. Such large potential difference, between the conduction band of the CdS and the Fermi level of the Ag can facilitate the electron transfer between the CdS and the Ag, can result in enhanced optical properties of Ag@CdS nanoparticle. 5.2 Polymeric nanoparticle based fluorescent sensors Synthesis of polymeric materials with versatile structures is a growing area of interest due to their superior luminescent properties and multifunctional capability compared with conventional organic dyes. These advanced nanoprobes have potential applications as fluorescent sensors to investigate many fundamental processes in the life sciences. The CRP methods have also been introduced to the synthesis of the fluorescent nanoprobes.155-157 A series of fluorescent organic nanoparticles with the property of aggregation induced emission (AIE) have been reported by Wei and co-workers.158-162 As shown in Figure 11A and B, the AIE dyes were copolymerized with water-soluble monomers through RAFT polymerization. The obtained copolymers can be self-assembled into AIE-based fluorescent organic nanoparticles in pure aqueous solution due to their amphiphilic properties. To explore biomedical applications, their biocompatibility as well as the cell uptake properties were investigated. For example, The PhE-PEG nanoparticles (Figure 11C) were fabricated through RAFT polymerization using polymerizable AIE dye ( PhE ) and biomedical molecule (PEGMA) as monomers.161 The obvious 22


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AIE properties can be observed according to the fluorescence intensity of PhE-PEG in different solvents (Figure 11D). And, cell imaging applications of PhE-PEG nanoparticles show that strong fluorescence could be clearly observed after cell incubation. Such AIE materials will have great potential for various biomedical applications.163

Figure 11. AIE-based fluorescent nanoparticles for cell imaging. (A) The structures of AIE-based fluorescent organic nanoparticles. (B) Schematic showing the preparation of PhE-PEG nanoparticles and their cell imaging applications. (C) TEM image of PhE-PEG nanoparticles. (D) Fluorescence spectra of PhE-PEG (in methanol and water), the excitation wavelength was 488 nm. The inset shows photographs of PhE-PEG in methanol (left bottle) and in water (right bottle) under a UV lamp. (E) Confocal laser scanning microscopy (CLSM) of A549 cells incubated with 40 mg mL-1 of PhE-PEG for 3 h. Reproduced with permission of The Royal Society of Chemistry from ref.161

A number of pH responsive polymers, prepared by CRP methods, have been reported for bioanalysis.164-169 Generally, the pH of tumour cells, diseased tissues, endosomal and lysosomal compartments are different from the normal physiological pH (7.4). Fluorescent pH responsive polymers have received wide acceptability due to the precise signal detection. Recently, Nile Blue-based pH sensors have been prepared by Armes and co-workers for simultaneous far-red and near-infrared live bioimaging.166 ATRP was used to synthesize the diblock copolymers poly(2(methacryloyloxy)ethyl

phosphorylcholine-block-2-(diisopropylamino)ethyl

methacrylate)

(PMPC-PDPA), in which the biomimetic PMPC block can facilitate rapid cell uptake and the PDPA block was pH-responsive that enables vesicle self-assembly in aqueous solution (Figure 12A). After the Nile Blue Dyes (NB, NBM, and NBC) were labeled on PMPC-PDPA polymers, the prepared Dy-PMPC-PDPAs exhibited variable absorption and fluorescence emission 23



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depending on their local pH (Figure 12B and C). These fluorescent copolymers can be used for in vivo pH sensing. Furthermore, they are also useful for selective intracellular sensing of lysosomes and early endosomes via subtle changes in fluorescence emission (Figure 12D).

Figure 12. Nile Blue-based pH sensors for far-red and near-infrared live bioimaging. (A) The structures of Nile Blue-labeled PMPC-PDPA copolymers. (B) Fluorescence intensity vs pH for Nile Blue-labeled PMPC-PDPA copolymers. (C) Fluorescence emission intensity ratio (700/670 nm) vs pH for aqueous solutions of Nile Bluelabeled PMPC-PDPA copolymers. (D) Subcellular fluorescent staining of organelles in live cells by Nile Bluelabeled PMPC-PDPA copolymer (PMPC25-PDPA59-NBC0.08). Reproduced with permission of the American Chemical Society from ref.166

As fluorescent sensor, MIP materials have shown high efficiency toward the target

analytes.122,170 Zhang and co-workers prepared a kind of hydrophilic MIP nanoparticles, surface grafted with poly(HEMA), by using RAFT precipitation polymerization in the presence of a fluorescent monomer.171 The prepared tetracycline (Tc) imprinted nanoparticle was applied as optical chemosensor for direct drug quantification in real, undiluted biological samples. Significant fluorescence quenching can be observed when the MIP nanoparticles bind with Tc.

The fluorescent MIP nanoparticles proved to be an effective optical sensor for Tc quantification in the undiluted serums with a detection limit of 0.26 µM. Fluorescent polymer particales appear to be the most versatile fluorophores used in bioassays and cell imaging.172-174 Recent investigations have revealed that the precisely control of the polymer structure, morphology and functionalization methods is critical for fluorescence performance in practical biological applications. The CRP methods in the controlled synthesis of advanced functional polymers have shown great advantages, and may eventually become a popular choice for preparing many polymeric based fluorescent sensors. 6. CONCLUSIONS

24


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The merits of controlled/living radical polymerization have been well used for synthesizing polymers with the desired molecular weight and molecular architecture. So far, ATRP and RAFT are the most extensively studied CRP system. It because the initiating systems for ATRP and RAFT can be easily achieved and a large range of monomers (including acidic monomers) can be precisely polymerized. Thus, various functional materials, including surface-modified core-shell particles, monoliths, MIP micro- or nano-spheres, fluorescent nanoparticles and multifunctional materials have been continually polymerized by CRP system. These emerged functional materials have shown important roles in the field of analytical chemistry. Although a large number of novel functional materials have been prepared by CRP for applications in analytical science, the challenges still remain in the CRP system. Such as (1) special handling procedures are often required for ATRP to remove oxygen in the reaction mixture, (2) the transition metal complex (in ATRP method) must often be removed from the products, and the RAFT agents usually give odor problems, (3) for special analytical purposes (especially the bio-sensing and bio-separation), developing “smart”, safe and selective interfaces will be always needed. It requires the CRPs should be developed to be more controllable for polymerization of many functional monomers (e.g., single unit monomer insertion) to achieve desirable microstructural and morphological properties.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (T.-J. Hang); [email protected] (H.-S. Wang). Notes The authors declare no competing financial interest.

7. ACKNOWLEDGEMENTS

We thank the financial support from Jiangsu Provincial Natural Science Foundation (No. BK20150689 and No. BK 20151445), the Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance (No. DQCP2015QN01) and the Fundamental Research Funds for the Central Universities (Grant No. 2015PY010). We also thank Dr. Ya Ding for her

kind assistance in preparing our manuscript.

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