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Keywords:

  • click chemistry;
  • hybrid nanomaterials;
  • hydrogels;
  • hyperbranched;
  • nanomaterials;
  • nanoparticles;
  • protein conjugates;
  • protein-polymer conjugates;
  • reversible addition fragmentation chain transfer (RAFT);
  • star polymers;
  • vesicles

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Reversible addition fragmentation chain transfer (RAFT) polymerization is one of the most extensively studied controlled/living radical polymerization methods that has been used to prepare well-defined nanostructured polymeric materials. This review, with more 650 references illustrates the range of well-defined functional nanomaterials that can be accessed using RAFT chemistry. The detailed syntheses of macromolecules with predetermined molecular weights, designed molecular weight distributions, controlled topology, composition and functionality are presented. RAFT polymerization has been exploited to prepare complex molecular architectures, such as stars, blocks and gradient copolymers. The self-assembly of RAFT-polymer architectures has yielded complex nanomaterials or in combination with other nanostructures has generated hybrid multifunctional nanomaterials, such as polymer-functionalized nanotubes, graphenes, and inorganic nanoparticles. Finally nanostructured surfaces have been described using the self-organization of polymer films or by the utilization of polymer brushes. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

In 2003, we published a “RAFTing Downunder” Review covering the first 2–3 years of reversible addition fragmentation chain transfer (RAFT) Research at UNSW.1 In this follow-up, 7 years on, we will again focus on RAFT polymerization, oriented towards the construction of higher order structures—starting from single chains progressing to complex architectures, and finally building up towards hybrid nanoparticles. Whilst we plan to focus on our own work, especially more recent studies, we will also endeavor to place this in a broader context of international research in this area with emphasis on the publications that have had a significant influence on our own work. In the 10 years since we started working on RAFT technology, the research field has exploded and so much of the work encompassed in this review has seen major contributions from numerous groups and we have attempted to represent this work through an extensive list of references.

Over the course of 10 years of research, Centre for Advanced Macromolecular Design (CAMD) has had major research programs in a number of areas that we plan to cover only in a minimal fashion in this overview, in these cases other recent reviews have already summarized the output from these programs that have included fast-switching photochromic polymers,2 using RAFT to measure kt3 and the formation of honeycomb films from breath figures.4 In addition, research programs on pulsed-laser polymerization,5, 6 soft ionization mass spectrometry of polymers7–9 and cobalt catalytic chain transfer10, 11 that were initiated back in the mid-1990s have continued to contribute to CAMD output through to the present day. In very recent research, programs have also been established to study compartmentalization in heterogeneous polymerizations,12 and macromolecular design using thiol-ene13 and thiol-yne chemistry.14

The mechanism of MADIX/RAFT polymerization was established by Zard and coworkers15–20 and by Rizzardo and coworkers21–25 in the late 1990s, and whilst there still seems to be some intrigue over aspects of the mechanism under specific conditions,26–28 we contend that 99% of the story is known22, 29 and certainly enough to establish RAFT as a powerful synthetic technique for making a wide range of complex architectures including stars, combs, blocks and brushes.30 The CSIRO team has continued to monitor and report on the progress of RAFT technology through a series of reviews in the Australian Journal of Chemistry22–23, 31 and through the RAFT alliance.32 Recently, the “Handbook of RAFT Polymerization” published in 2008 provided a detailed overview of RAFT polymerization.30 Since 2008, RAFT polymerization has continued to attract lot of interest, justifying this present highlight article.

The well-defined complex macromolecules made by RAFT can be used to build nanostructures such as micelles, vesicles, and nanoparticles.33, 34 In addition, synthetic polymers can be combined with biomolecules or inorganic nanoparticles to address problems in medicine and bio- and nano-technology.35, 37 In some instances the RAFT functionality used to control polymerization can also be used efficiently for subsequent postpolymerization modification to generate complex structures.38–40 This present review will highlight a path from monomer incorporation into polymer chains using RAFT polymerization through to macromolecular assembly into nanostructures and is mainly focused on more recent research work. Finally, we conclude with an opinion on where RAFT related research is heading.

RAFT POLYMERIZATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Synthesis of Polymers Using Regular Monomers

RAFT has been used to polymerize a wide range of monomers, such as styrenic, (meth)acrylic, (meth)acrylamido,41–46 isoprene,47, 48 vinylic (e.g., vinyl acetate, vinyl pyridine, vinyl carbazole, vinyl pyrrolidone),49–57 and diallyl monomers, such as diallyldimethylammonium chloride.58, 59 As RAFT polymerization is adaptable to use in both organic and aqueous media,60 charged polymers (cationic,41 anionic,61, 62 or zwitterionic)63 can be successfully polymerized at room or high temperatures.64

Anionic monomers, such as sulfonate, carboxylic acid and phosphonic acid containing monomers, have all been polymerized using RAFT. Sulfonate65–68 and phosphonic acid69, 70 modified monomers have been polymerized in water, while carboxylic acid monomers have been polymerized in both water and organic media. Indeed, carboxylic acid monomers can present tunable hydrophilic/hydrophobic properties depending on the solution pH.71–73

Cationic monomers, such as pyridine, tertiary amine and phosphonium group containing monomers, exhibit pH sensitivity and have been used for the synthesis of smart materials, such as micelles.33, 62, 74

Zwitterionic monomers that is, sulfobetaine75–79 and phosphobetaine63, 80 have been successfully polymerized using RAFT polymerization. Zwitterionic monomers can imbue polymers with beneficial properties, such as antifouling behavior and bio-compatibility, as well as antimicrobial properties, and responsive behavior in aqueous solutions.81, 82 For example, 3-[N-(3-methacrylamidopropyl)-N,N-dimethyl] ammoniopropane sulfonate has an upper critical solution temperature (UCST) at ∼12 °C in water.75

RAFT polymerization was successfully employed to yield thermo-responsive polymers. The most famous polymer is poly(N-isopropyl acrylamide) (poly(NIPAAm)) having a lower critical solution temperature (LCST) around 32 °C.83 RAFT polymerization was successfully employed to control NIPAAm polymerization to obtain complex architectures.84–87 LCST can be tuned by copolymerization with acrylic acid to increase LCST88 or with tert-butyl acrylamide to decrease LCST.88 However, poly (N,N′-diethyl acrylamide) (PDEAAm), poly(N-(L)-(1-hydroxymethyl) propyl methacrylamide), and poly(N,N-dimethylethyl methacrylate) (poly(DMAEMA)) are also interesting polymers which present LCSTs around 26–35,89 30,89 and 50 °C,90 respectively (Table 1). More recently, PEG base polymers have been synthesized with a tunable LCST by copolymerization of oligo(ethylene glycol)-(meth)acrylate with diethylene glycol methyl ether-methacrylate and diethylene glycol ethyl ether-acrylate.91–93 Lutz et al. demonstrate that PEG base polymers present well-defined LCSTs.94

Synthesis of Functional Polymers From Specialized Functional Monomers

Several reactions were exploited to obtain functional polymers. Table 2 shows the most used reactions for modification of polymers to introduce functionality or to obtain more complex architectures.

Table 1. Examples of Thermo-Responsive Polymers Prepared by RAFT
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Table 2. Typical Reactions Used for Functionalization of Polymers
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Thiol Reactive Monomers

Pyridyl disulfide ethyl methacrylate (PDSM) has been successfully homopolymerized using RAFT polymerization with 4-Cyanopentanoic acid dithiobenzoate (CPAD) as the CTA (Scheme 1 and Table 3).95, 96 Excellent control of PDI and molecular weight was achieved in DMAc, as solvent and using AIBN, as the initiator at 70 °C. The presence of a pyridyl disulfide bond did not significantly affect the polymerization, that is, no significant transfer was observed during the polymerization of N-isopropylacrylamide (NIPAAm) or methyl methacrylates (MMA).97 The presence of pyridyl disulfide as a pendant group permits modification of the polymer using thiol compounds (Scheme 1), such as 2-mercaptopropionic acid, 2-mercaptoethanol or glutathione.95 In addition, the pyridyl disulfide functionality can be cleaved in the presence of TCEP to yield a free thiol able to react with maleimide compounds, such as doxorubicin modified maleimide96 or to PEG terminated methacrylate or allyl yielding a drug-polymer carrier or a graft copolymer. PDSM has also been copolymerized using RAFT in the presence of HPMA and OEG-MA yielding poly(PDSM-b-HPMA) and poly(PDSM-b-OEG-MA) diblock and statistical copolymers with a PDI inferior to 1.2.96 McCormick and coworkers98 have proposed an alternative approach to the synthesis of copolymers with pyridyl disulfide pendant groups by postmodification of amino pendant groups carried by poly(N-(2-hydroxypropyl)methacrylamide-co-N-(3-aminopropyl)methacrylamide (HPMA-co-APMA) copolymers with N-succinimidyl 3-(2-pyridyldithio)-propionate. The authors report an excellent reaction yield, and a subsequent conjugation with thiol terminated siRNA.

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Scheme 1. Chemical modification of pyridyl disulfide ethyl methacrylates (PDSM) polymers by thiol-ene (top) or pyridyl disulfide exchange chemistry (bottom).

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Table 3. Examples of Functional Monomers Used in RAFT Polymerization (note: R corresponds to H or CH3)
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Allyl pendant groups can be introduced into copolymer chains using a range of monomers as suggested by Wooley and coworkers99 for RAFT polymerization and by Hawker and coworkers100, 101 for ATRP, or by the polymerization of isoprene.47 CAMD researchers have exploited the copolymerization of allyl methacrylate and HPMA or the homopolymerization of 2-vinyloxyethyl methacrylate yielding diblock copolymers and hyperbranched polymers with PDIs lower than 1.2 and 2.0, respectively.102, 103 However, a slight increase of PDI was observed during the polymerization of allyl methacrylate - attributed to the slight copolymerization of allyl bonds at high conversion. Subsequently, allyl or vinyl groups were reacted with different thiol compounds, such as cysteamine, using thiol-ene reactions under UV irradiation in the presence of a photoinitiator. To avoid potential side reactions, such as cross-linking at high conversion, allyl end groups can also be introduced by postmodification. For example, Poly(HEA-b-DEG-A) copolymers have been synthesized using RAFT polymerization, with subsequent modification of the hydroxyl group with pentenoic acid. Finally, the pendant double bond was exploited to attach sugar moieties.104

Finally, the nucleophilic character of thiols can be exploited to perform nucleophilic substitution reactions, such as thio-bromo, thio-chloro, or thio-epoxy chemistries. Recently, these nucleophilic substitution reactions were promoted by Percec,105, 106 and subsequently exploited by CAMD researchers for the synthesis of hyperbranched polymers.107 More recently, thio-chloro chemistry using vinylbenzyl chloride,108 has been exploited to generate glycopolymers and graft copolymers at high yields.

Activated Ester Monomers

A wide range of activated ester monomers has been reported in the literature.109, 110 In this section, we highlight the most common and the most recent work on activated ester monomers. N-acryloxysuccinimide (NHS-A) yields a polymer bearing succinimidyl-activated ester pendant groups. NHS-A has been homo-polymerized and copolymerized in the presence of NIPAAm,46N,N-dimethyl acrylamide (DMA)111 and N-acryloylmorpholine (NAM)112 yielding water soluble statistical copolymers using RAFT polymerization with either a dithioester or trithiocarbonate. Moreover, at an azeotropic composition (60/40: NAM/NHS-A in mol %), polymer chains could be formed without composition drift, yielding a homogenous microstructure.113 RAFT copolymerization of NHS-A has been extended to other architectures, such as block copolymers in the presence of DMA, NAM and t-butyl acrylate (t-BA) to give hydrophilic block copolymer poly(DMA-b-NHS-A) and amphiphilic block copolymers poly[t-BA-b-(NHS-A-co-NAM)].113 McCormick and coworkers114 used NHS-A in the presence of a macro-RAFT agent bearing a PEO block to obtain poly(ethylene oxide)-b-poly(DMA-co-NHS-A) diblock polymers or poly(ethylene oxide)-b-poly(DMA-co-NHS-A)-b-poly(NIPAAm) triblock polymers. The versatility of these activated ester functional polymer precursors was demonstrated for several applications, such as the attachment of peptide, DNA, or fluorescent dye.115–117 The NHS-A units were also modified in the presence of ethylene diamine or N,N-dimethyl ethylene diamine to give RAFT-functional polymers bearing primary or secondary amine pendant groups. The methacrylate analogue to NHS-A, N-methacryloxysuccinimide (NHS-MA), has also been polymerized using RAFT, however, polymerization control proved difficult (a broad polydispersity was observed). In contrast, NHS-MA RAFT copolymerization in the presence of NIPAAm46, 118 or HPMA119 yielded better control, with a copolymer composition ranging from 2 to 30 mol-% of NHS-MA.119

Different activated ester monomers, pentafluoro-phenyl acrylate, methacrylate, and so forth, have been promoted and exploited by Theato and coworkers120 and by us.122 These activated-monomers have been homopolymerized or copolymerized using RAFT polymerization.121, 122 The synthesis of functional amphiphilic poly(pentafluoro-phenyl methacrylate)-b-poly (lauryl methacrylate) copolymers was performed using RAFT polymerization with 4-cyano-4-(thiobenzoyl)sulfanyl)pentanoic acid yielding block copolymers with molecular weights from 12,000–28,000 g/mol and PDIs of about 1.2. The pentafluoro-phenyl methacrylate functional groups in the polymer were modified in either the presence of hydroxyl propyl amine or in the presence of a fluorescent dye (4-nitro-7-(piperazin-1-yl)benzo[c][1,2,5]oxadiazole (NBD) yielding poly (HPMA)-b-poly(lauryl methacrylate) or diblock copolymers bearing fluorescent pendant groups, respectively.123 Recently, activated monomers have been used to124 attach different amino-compounds, such as glycine, taurine, PEG functionalized amine and amino sugars122 (Scheme 2) to polymer chains. It should be noted that pentafluorophenyl polymers are more versatile than poly(NHS-A) or poly(NHS-MA) for some applications as they are soluble in a variety of organic media.120

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Scheme 2. Synthesis of biotin functionalized glycopolymer using double click reactions, that is thiol/ene and activate ester amino-sugar.

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Maynard and coworkers125 synthesized polymers with reactive pendant groups using p-nitrophenyl methacrylate (NPMA) polymerized by RAFT polymerization. The activated ester polymer was substituted (up to 86%) using an amino compound, that is, a glycine methyl ester.

Recent interest in 4-vinyl benzoic acid derivatives has extended the pool of polymeric activated esters. Aamer and Tew126 described the RAFT polymerization of the N-succinimide activated ester of 4-vinyl benzoic acid (NHS-VB) yielding poly(NHS-VB) with a low PDI (<1.07) and control over molecular weight. This activate ester presents a better solubility than NHS-A and NHS-MA. Theato and coworkers127, 128 used pentafluorophenyl ester 4-vinyl benzoic acid to give a polymer with excellent solubility in several organic solvents.

Isocyanate Monomers

Isocyanate is another powerful functionality that has been used to create polymeric structures via both addition and condensation polymerizations. Isocyanates can react efficiently with many different functionalities, such as amine, alcohol, carboxylic acid or thiol leading to urea, urethane, amide or thio-urethane groups. Two commercially available monomers are often used: 3-isopropenyl-α,α′-dimethylbenzyl isocyanate (TMI)129 or 2-isocyanatoethyl (meth)acrylate (IEM130 or IEA131). TMI, is reluctant to homopolymerize,132 and so its use is restricted to copolymerizations, while IEM or IEA can be both copolymerized and homopolymerized. These isocyanate monomers have both been previously used in anionic polymerization and free radical (co)polymerizations,133, 134 and more recently, in RAFT polymerization yielding functional polymers.131, 135

Amine Functionalized Monomers

Amine groups can be introduced into polymer backbones using functional monomers, such as 2-(dimethylamino)ethyl methacrylate,136–139 2-aminoethyl methacrylamide hydrochloride,98, 140, 141N-vinyl pyridine142 and N-vinylphthalimide.143 The polymerization of 2-aminoethyl methacrylamide hydrochloride, has been described, using a water/dioxane mixture with the protonated monomer to minimize the Michael addition of amine onto the methacrylate bond144 or degradation of the RAFT agent by aminolysis or hydrolysis.145 Where tertiary amine functional backbones are required, several monomers can be used, such as dimethyl aminoethyl (meth)acrylate or (meth)acrylamide. The presence of cationic charge can be used to complex Si-RNA or DNA102, 146–150 or for their excellent antibacterial properties.139, 151 In the case of N-vinyl phthalimide, the polymerization can be controlled using xanthates. After polymerization, the primary amine can be regenerated by deprotection in the presence of hydrazine yielding poly(vinyl amine).143 Recently, another route to obtain poly (vinyl amine) polymers was proposed by the reduction of poly(acrylonitrile) in the presence of lithium aluminium hydride.152 The condition of this reduction results by a simultaneous reduction of RAFT agent (dithioester) and nitrile group into thiol and amine groups, respectively.

“Clickable” Monomers

Azide or alkyne monomers can also be polymerized in the presence of a RAFT agent yielding copolymers bearing azide or alkyne pendant groups. Zhao and coworkers153 copolymerized propargyl methacrylate (PMA) and oligo(ethylene glycol) methacrylate (OEG-MA) to yield poly(OEG-MA-b-PMA) diblock copolymers with a PDI below to 1.2. The alkyne group was reported to be benign in RAFT polymerization and no significant transfer events were observed. After polymerization, a pyrene modified with azide group was clicked to the alkyne-functional polymer generating pyrene pendant groups. Azide modified (meth)acrylate has also been polymerized and copolymerized using RAFT at different temperatures, as described by Liu and coworkers153 who obtained the double hydrophilic diblock copolymer, poly(N,N-dimethylacrylamide)-b-poly(N-isopropylacrylamide-co-3-azidopropylacrylamide) (PDMA-b-P(NIPAM-co-AzPAM), with a low PDI (PDI < 1.3). After polymerization, the authors cross-linked the chains by click chemistry using a telechelic alkyl to obtain micelles in aqueous media. Benicewicz and coworkers155 reported some problems with the synthesis of azide-containing polymers with a high PDI (>1.4) when the polymerizations were carried out at high temperature for extended times. Benicewicz therefore recommended the adoption of room temperature polymerizations where azide functionality is involved thus minimizing the broadening of the molecular weight distribution. Recently, we observed that azide-terminated acrylate is unstable at room temperature yielding an insoluble compound (attributed to the reaction of azide with the acrylic bond) when stored for several days in the presence of inhibitor. Perrier and coworkers156 have shown that azide can react with double bonds at high temperatures. The reaction between azide and protected 1-buten-3-yne can result in N-functionalized-4-vinyl-1,2,3-triazoles, which have been used in RAFT polymerizations.157

“Unusual” Monomers

Boronic acid-containing monomers have been used to introduce pendant groups in polymer chains as described by Sumerlin and coworkers158, 159 who polymerized 3-acrylamidophenylboronic acid (APBA) and N,N″-dimethyl acrylamide (DMA) in the presence of 2-dodecylsulfanylthiocarbonylsulfanyl-2-methylpropionic acid yielding poly(APBA-b-DMA) diblock copolymers.158 The synthesis of APBA homopolymer was achieved with a PDI < 1.2, and this homopolymer was extended with DMA158 and with NIPAAm.160 The pH of the solution was used to control boronic acid solubility in water. Furthermore, boronic acid was complexed with diol forming cyclic boronate esters (Scheme 3). This type of interactions is reversible and can be exploited to obtain stimuli-reversible structure.

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Scheme 3. Complexation of boronic acid with diol (sugar compounds) to form cyclic boronate esters.

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The RAFT copolymerization of poly(ethylene glycol) methyl ether methacrylate (OEG-MA) with one of two dioxolane-containing monomers, (2,2-dimethyl-1,3-dioxolane)methyl acrylate (DDMA) or (2,2-dimethyl-1,3-dioxolane)methyl acrylamide (DDMAA), has been reported.161 A kinetic study revealed that the OEG-MA was consumed at a higher rate than the dioxolane comonomers, implying that the copolymerization reactivity ratios of OEG-MA (r1 ≈ 1) are superior to those of DDMA (r2 ≈ 0.43) and DDMAA (r2 ≈ 0) at 70 °C. The difference of reactivity ratio yields to the formation of pseudo-gradient copolymer. After copolymerization, the dioxolane functional groups were deprotected to form 1,2-diol groups, before subsequent oxidation with periodic acid (HIO4) to form reactive aldehyde groups (Scheme 4) that were used to form stable conjugates with the iron chelating drug desferrioxamine (DFO). Wooley and coworkers162, 163 have synthesized the functional monomers, 4-vinylbenzaldahyde (VBA) and acetoxystyrene and demonstrated their successful RAFT polymerizations.

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Scheme 4. Chemical modification of (2,2-dimethyl-1,3-dioxolane)methyl acrylate (DDMA) obtained by RAFT polymerization to yield polymers with aldehyde pendant groups by modification in the presence of acetic acid and periodic acid; note Z designs O or NH.

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A new aldehyde-functionalized glycomonomer, 1,2:3,4-di-O-isopropylidene-6-O-(2′-formyl-4′-vinylphenyl)-D-galactopyranose (IVDG), has been described by Lu and coworkers164 The poly-IVDG was deprotected using 88% formic acid at room temperature, yielding a novel amphiphilic polymer containing both galactopyranose and aldehyde functionalities which could be self-assembled into well-defined aldehyde-bearing polymeric micelles in aqueous solution in the absence of surfactant. Protein-bioconjugated nanoparticles were also prepared by the immobilization of bovine serum albumin (as a model protein) onto the aldehyde-functionalized micelles.164

Maynard and coworkers125 synthesized polymers of diethoxypropyl methacrylate (DEPMA) using RAFT. The side chains of poly(DEPMA) were hydrolyzed to aldehyde groups and subsequently reacted with O-benzylhydroxylamine and O-methylhydroxylamine to form stable oxime bond conjugates. The successful conjugation of a model peptide, that is, an aminooxy functionalized RGD peptide, was also demonstrated. More recently, the direct polymerization of an amino acid diamide, that is, N-acryloyl-L-valine N′-methylamide, has been successfully reported via RAFT polymerization.165

Epoxy-functional polymers can also be synthesized using RAFT.166, 167 Glycidyl methacrylate (GMA) can be polymerized successfully with controlled molecular weights,167 provided free thiol is minimized (preventing side thiol-epoxy reactions).168 The epoxy group can be further modified by thiol,169, 170 amino-171–173 or carboxylic acid174 compounds to yield functional polymers or functional materials (resin). Due to the great reactivity of these reactions, several applications are currently used by the industry to produce adhesive, paint, coating, microelectronic, etc...

Specific monomers tailored for applications, such as, electrical, magnetic, catalytic, sensing and nonlinear optical properties have been reported.175, 176 Lu and coworkers used RAFT to synthesize ferrocene monomers bearing an aldehyde group.177 Another monomer containing naphthalene and thiourea groups was developed for the detection of anionic compounds in aqueous solution. The specific interaction of anions (F-, AcO-, H2PO4-) with the thiourea group changes the electron density on the naphthalimide group, and hence alters the color of the compound.178

Introduction of Functional Groups to Polymer Chains Using the RAFT Agent

RAFT can be used to introduce specific chain-end functionality to polymers.179 Functional RAFT agents can be designed to synthesize both α-functional and α,ω-telechelic polymers.180–185 α-End groups can be introduced via the R group (reinitiating group) of the RAFT agent, and ω-functionality can be introduced by either the Z group of the chain transfer agent or by modifying the RAFT group after polymerization (Scheme 5). The postmodification route is often taken, as the RAFT agent is amenable to a wide range of simple transformation procedures, that is, aminolysis,186 thermolysis187–189 or hydrolysis.190 Willcock and O'Reilly38 have recently reviewed chain-end modification of RAFT polymers.

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Scheme 5. Synthesis of functional polymers using RAFT polymerization.

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Introduction of Functional Polymer End Groups via Modification of the R Group

Since the invention of RAFT polymerization by a CSIRO Team,61, 191, 192 a multitude of RAFT agents have been synthesized. The primary function of a RAFT agent is to attain optimal control over polymerization for individual monomers over a range of temperatures.145 Trithiocarbonates (2), dithioesters (1), dithiocarbamates (3 and 5) and xanthates (4) can be used to affect polymerization control even over difficult monomers, such as vinyl acetate154, 193, 194 and vinyl pyridine,195, 196 difficult to control by other controlled radical polymerization techniques (Scheme 6). A secondary design consideration for new RAFT agents has been motivated by a desire for architectural control, for example, the synthesis of macromonomers or telechelic polymers for specific applications, that is, surface modification,77, 197–204 nanomaterials205, 206 or bio-applications.35 Consequently, a large range of functional RAFT agents for example, bearing hydroxyl, carboxylic acid, and allylic groups have been synthesized,179 with carboxylic acid functional RAFT agents as the most ubiquitous (Table 4). Lai et al.207 synthesized several mono- and dicarboxyl terminated RAFT agents, thereby exerting control over a wide range of monomers, such as acrylate, acrylamide, and styrene (exclude methyl methacrylate, MMA) yielding monofunctional and telechelic polymers. Carboxyl functionalized trithiocarbonate or dithioester RAFT agents have been used for exerting control over MMA by the CSIRO team23 and McCormick's and coworkers.41, 44, 208–210 Incorporated carboxylic acid groups are especially useful as they can then be used for the postmodification of polymers employing common coupling chemistry involving for example alcohols, amines, isocyanate, and epoxy.

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Scheme 6. Presentation of different RAFT agents: (1) dithioester; (2) trithiocarbonate; (3) and 5 dithiocarbonate; (4) xanthates.

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Table 4. Structures of Functional RAFT Agents
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Carboxylic Acid, Hydroxyl and Amine Functionalized RAFT Agents

Carboxylic acid groups can be modified in numerous ways, for instance, chlorination, or by modification with an activate ester group, such as pentafluorophenyl group modification, by NHS or by using 2-mercaptothiozaline to increase the reactivity of the acid groups. Bathfield et al.211, 212 synthesized a new RAFT agent bearing a R group functionalized with an activated ester, that is, succinimidyl ester for the attachment of biomolecules, sugar (galactose), N-aminoethylmorpholine212 and a phospholipid.211 Inspired by Bathfield's work, Aamer and Tew126 synthesized a new activated ester RAFT agent by modification of 4-cyanovaleric acid dithiobenzoate with NHS in the presence of DCC and DMAP for control of 4-vinyl benzoic acid (VBC). However, some lack of control over the evolution of molecular weights was noted and attributed to a low efficiency of the RAFT agent. Xu et al.213 synthesized a dithioester bearing a mercaptothiazoline active ester to control the polymerization of HPMA at 70 °C. The polydispersities and molecular weight development were consistent with a well-controlled RAFT polymerization. The 2-mercaptothiazolidine end group remained intact throughout polymerization leading to a α-mercaptothiazolidine terminated poly(HPMA), which was then exploited to attach a dendrimer bearing four mannose groups213 or to conjugate to lysozyme.214 2-mercaptothiazolidine terminated RAFT agent was also attached to silica surface to yield brush polymer.215 Recently, Theato and coworkers123, 216 synthesized a RAFT agent and a diazoinitiator, both containing a pentafluorophenyl activated ester. Subsequent RAFT polymerizations of methyl methacrylate (MMA), diethylene glycol methyl ether methacrylate (DEGMA), poly (ethylene glycol) methyl ether methacrylate (PEGMA), hydroxyl propyl methacrylamide (HPMA), and lauryl methacrylate (LMA) yielded homopolymers and diblock copolymers with excellent control, suitable for further efficient (close to 100%) functionalization exploiting the activated ester end groups.

RAFT agents bearing hydroxyl groups have also been studied leading to α-hydroxyl and α,ω-hydroxyl terminated PMMA or poly(n-BA) polymers.217

Primary and secondary amine groups are difficult to access directly via RAFT as RAFT agents are unstable in the presence of amines.179 Synthetic routes have been proposed to solve this stability problem, such as the protection of amine groups by phthalimido groups218, 219 or by t-Boc groups.220, 221

Webster and coworkers222 synthesized two new epoxy- and oxetane-functional RAFT agents able to control the polymerization of different acrylate monomers. The epoxy end group can be modified in the presence of different functionalities, such as amine and carboxylic acid, to obtain macromonomers. The oxetane group was copolymerized in the presence of 3-ethyl-3-hydroxymethyl oxetane as a comonomer and BF3,(C2H5)2O as a catalyst leading to a tri thiocarbonylthio macromonomer, which was used for living free radical polymerization of butyl acrylate yielding graft copolymers.

Highly Specific Functional RAFT Agents

Highly specific functional RAFT agents bearing α-norbonenyl,223 phosphonic acid,198 α-allyl223 or α,ω-bis-allyl,224 and α-cinnamyl223 groups have been reported.224 The allyl group can be modified by a large excess of thiol in the presence of UV initiator or radical initiator,100, 101 or in the presence of Karstedt's catalyst225 to generate functional polymers or complex architectures.

The pyridyl disulfide group (PDS) has synthetic utility as it can react with thiols to yield a disulfide linkage (Scheme 1); a potentially biodegradable bond. CAMD has developed a range of RAFT agents, with PDS in the R or Z groups, or both, for use in the generation of monofunctional pyridyl disulfide functionalized PSt,226 poly(OEG-A),97, 227 or poly(NIPAAm)97 or telechelic polymers.184 The disulfide bond is largely benign during the polymerization process,97 remaining intact for subsequent postpolymerization modification reactions, yielding bioconjugates with for example proteins, BSA,185, 228, 229 peptides (e.g., NGR peptide (CNGRCGGklaklakklaklak-NH2)198 or glutathione peptide185, 226, 230), or si-RNA231 with high yields.

Bio-Functional RAFT Agents

Hong et al.232 synthesized a biotin modified RAFT agent by coupling biotinylated alcohol and S-1-dodecyl-S′-(α,α′-dimethyl acetic acid) in the presence of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) yielding a biotinylated trithiocarbonate for controlling the polymerizations of NIPAAm and N-(2-hydroxypropylacrylamide) (HPA) and diblock copolymers. The biotin end group was then exploited for conjugation with avidin and streptadivin.

Ten Cate and coworkers233–236 synthesized well-defined peptide-polymer conjugates, using a novel solid-phase synthetic method; peptide was attached onto carboxylic acid functionalized RAFT agent using a traditional coupling catalyst (DMAP/DCC), however, this route was found to suffer from a competitive nucleophilic attack of peptide amine onto the dithioester (aminolysis). An alternative approach was also described, viz, modification of a peptide bearing bromine or chlorine atoms (ATRP initiator), by nucleophilic substitution with a pyridinium salt of the dithiobenzoic acid yielding an oligopeptide macro transfer agent used for polymerization control of n-BA at 60 °C. After the in situ polymerization, the chirality of the peptide was preserved as proven by circular dichroism analysis.

Perrier and coworkers237 used the cysteine residues in peptides to prepare a peptide macroRAFT agent, synthesizing four different peptide-macroRAFT agents at high yields (95%) in methanol. The peptide-RAFT agents could control the polymerization of numerous monomers (N-isopropyl acrylamide (NIPAAm), dimethyl acrylamide (DMA), n-Butyl acrylate, and methyl acrylate). This simple synthetic approach has some limitations for use with more complex peptides for two major reasons; firstly, the experimental conditions used for RAFT synthesis can potentially disrupt the peptide structure (chirality) and secondly, peptides bearing free amine cannot be modified without prior protection to avoid aminolysis.

Functionalization of Polymers Using Azide-Alkyne Click Chemistry

The presence of azido or alkyne groups at the end of polymers can be used in conjunction with “click” chemistry to functionalize polymers,194, 238–241 with well controlled architectures (such as, cyclic polymers,242, 243 diblock copolymers244 or graft copolymers245) and functional nanoparticles.246, 247 Alkyne end groups, require protection (e.g., trimethyl sillyl groups) to avoid side-reactions.248 Sumerlin and coworkers239 prepared diblock poly(DMA-b-NIPAAm) using an azido terminated RAFT agent for subsequent transformation with an alkyne functionalized folic acid for the production of folic acid functional nanoparticles. Sumerlin and coworkers249 also used azido group terminated polymers to modify alkyne modified BSA for protein-polymer conjugation. Chen et al.154 synthesized an azide modified MADIX agent for vinyl acetate polymerization and functionalization with a fluorescent label (propionyloxy coumarin) using click chemistry. Finally, azide-alkyne click reaction was exploited for the attachment of azide terminated polymer onto alkyne modified silica nanoparticles by Perrier and coworkers.247

Chemical Modification of the Z Group of RAFT Agents

The Z group is not a stable group due to the possible degradation by thermolysis,188 UV-irradiation,250 aminolysis.186 In addition, it brings the color to polymers, that is, yellow or red. These reasons have motivated researchers to remove this group. Different pathways have been proposed for the modification of Z groups (Scheme 7). Desterac et al.,251 have summarized the different pathways for the chemical transformation of xanthate functional chain termini MADIX polymers. Recently, Klumperman and coworkers252 presented an original route to modify poly(vinylpyrolidone) (PVP) by hydrolysis of the MADIX end group at pH 4.5 yielding hydroxyl end groups which were then modified via thermolysis to yield aldehyde end groups.

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Scheme 7. Chemical modification of RAFT end group exploiting the thiol formation: thiol exchange; pyridyl disulfide; thiol-ene; thiol-isocyanate; thiol-epoxy; thiol-bromo nucleophilic reaction.

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Azide-alkyne chemistry has a natural complementarily with ATRP,240, 253 as the polymer halogen end groups can be easily converted into azides.254–256 Azide-alkyne chemistry and RAFT have also been combined,239, 246, 257 however, thiol-ene chemistry would appear to display more complementarily with RAFT for building complex structures258 as the cleavage of RAFT and MADIX259 end groups yields thiols in the presence of primary or secondary amines,180, 186, 213, 260 dimethylphenyl phosphine,261 hydrazyne262 or sodium borohydrate.263 Several authors179–181, 217, 260, 264–270 have modified RAFT end group terminated poly(NIPAAm) generating a thiol, for subsequent conjugation using thiol-ene reactions. For example, You and Oupicky270 proposed a two-step strategy, viz., a thiol functionalized poly(NIPAAm) was obtained by degradation of trithiocarbonate end groups in the presence of hexylamine under nitrogen. Subsequently, thiol-terminated poly(NIPAAm) was reacted with 1-biotinamido-4-[4′-(maleimidomethyl) cyclohexanecarboxamido]butane to yield biotin functionalized poly(NIPAAm). In this two-step process, some by-products were observed, including disulfide interchain coupling. Using a similar two step approach, McCormick and coworkers264 successfully conjugated poly (NIPAAm) with fluorescien functionalized maleimide whilst avoiding the formation of disulfide interchain coupling by the addition of tri-n-butyl phosphine as a reductant agent. Sumerlin and coworkers181 used a bismaleimide to react with thiol functionalized poly(NIPAAm) obtained by reduction of the RAFT end group to give a maleimide functionalized poly(NIPAAm) at high yields. To ensure the absence of interchain coupling, a large excess of bismaleimide was used. The maleimide end group was exploited to add another thiol compound using thiol-ene addition. An one pot strategy was exploited by CAMD to attach different functional end groups, such as biotin functionalized maleimide, sugar modified methacrylate or di(meth)acrylate compounds, using thiol-ene addition without formation of disulfide.271, 272 These one pot reactions can generate functional polymers at high yields (close to 95%) and can be exploited for a large range of polymers (poly(acrylate), poly((meth)acrylamide), PSt). The addition of dimethylphenylphosphine has been proposed to catalyst the thiol-ene reaction and to obtain complex architectures, such as star polymers.261, 273, 274 Recently, CAMD in collaboration with Haddleton's group developed an easy method to remove the RAFT end group by the addition of Bis[μ-[(2,3-butanedione dioximato)(2−)-O:O']] tetrafluorodiborato(2−)-N,N′,N″,N′″]cobalt (CoBF) and to generate a vinyl bond in one pot.275 This method requires a very low concentration of this transfer agent (commercially available and already used in the industry for the production of oligomers) to remove the RAFT end groups.

Aminolysis of RAFT-polymers in the presence of 2,2′-dithiopyridyl disulfide (DTP) has been used to generate pyridyl disulfide end groups available for subsequent reactions with different thiol modified biocompounds or thiol terminated polymers to yield complex architecture.271, 272 Theato and coworkers group has proposed an alternative approach to the DTP by the use of methanethiosulfonate for the protection of thiol during the aminolysis of RAFT agent for different polymers, such as PMMA,276 poly(NIPAAm),183 and poly(OEG-MA).182, 183, 216 The presence of methanethiodisulfide end group can be further modified with different functional thiols. Caruso and coworkers277 hydrolysed MADIX end groups on PVP thereby generating thiol end groups which they protected using Ellman's reactant, suppressing disulfide interchain coupling. The advantage of this approach compared to the thiol/ene reaction is the formation of reducible bond, that is, disulfide, able to be reduced in biological condition.278

Another route has been proposed for RAFT end group removal and chain-end modification as described by Perrier et al.279 who used a large excess of radicals generated at the end of polymerization (in the absence of monomers) yielding polymeric chain radicals, that recombined irreversibly with another free radical present in solution, thus forming a dead polymer chain. This ‘initiator’ method removes the RAFT end groups, whilst introducing new functionality at the end of the polymer chains, and recycling the chain transfer agent (Scheme 8). Theato and coworkers216 used this ‘initiator’ approach to remove chain-terminal ω-dithioester groups using a pentafluorophenyl ester diazo compound whilst functionalizing RAFT polymers with a PFP ester at their ω-end. This technique is very efficient for methacrylic polymers, but has some limitations for styrenic or acrylic polymers resulting in a partial functionalization.280

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Scheme 8. Introduction of functional group using radical initiation in the absence of monomers.

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Finally, the addition maleic anhydride or maleimide at the end of the polymerization was proposed to give succinic anhydride or functional terminated polymers in very high yield, respectively.281, 282 The presence of this anhydride group can be exploited to react different alcohols, primary amines and aromatic amines with a very high functionality (75–95%). The polymer can be chain extended using another monomer to introduce mid-chain functionality.

Synthesis of Telechelic Polymers

Two methods have been employed for the synthesis of telechelic polymers283, 284 using RAFT removal. The first approach is the aminolysis of RAFT end groups into thiol, and subsequently, its modification using thiol-ene,182, 183, 217, 269 or thiol-pyridyl disulfide exchange chemistry.272 The second approach is the use of large excess of functional azo-initiators to remove RAFT end groups.168, 229

Thiol-ene addition has been exploited for the synthesis of homo- and hetero-telechelic polymers. Recently, Stucky and coworkers269 developed a convenient methodology involving a cascade aminolysis/ Michael addition and alkyne-azide click reaction to generate well-defined hetero-functional polymeric materials. Firstly, RAFT functionality was reduced to thiol and then, reacted with fluorescein o-acrylate, followed by the modification of azide group in the presence of a dansyl probe via click chemistry to obtain α-fluorescein, ω-dansyl poly(NIPAAm). Theato and coworkers183 synthesized hetero-functional telechelic poly(OEG-A) using a RAFT agent bearing penta-fluoro phenyl activated ester. At the end of the polymerization, the Z group was modified to thiol and reacted with N-biotinylaminoethyl methanethiosulfonate to yield a hetero-telechelic poly(OEG-A). Inspired by Perrier approach, Maynard and coworkers229 synthesized a hetero-telechelic poly(NIPAAm), with termini bearing biotin and maleimide end groups via a radical cross-coupling reaction with a functionalized azo-initiator. Telechelic biotin-maleimide poly(N-isopropylacrylamide) were subsequently used for the formation of streptavidin—bovine serum albumin (BSA) polymer conjugates.

CAMD185 developed hetero-telechelic α-azide, ω-pyridyl disulfide198 or α-phosphonic acid, ω-pyridyl disulfide198 and homo-telechelic pyridyl disulfide184 functional poly(NIPAAm), poly(OEG-A) and PSt offering the possibility of modification with alkyne groups or thiol compounds, respectively.

SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Synthesis of Gradient and Block Copolymers

Copolymerization conducted under RAFT conditions21 can generate copolymers with targeted compositions and controlled architectures. As RAFT is classed as a controlled polymerization,61 or more recently, as a reversible deactivation radical polymerization according IUPAC285 (i.e., the majority of polymer chains are ‘alive’ throughout the polymerization), it is possible to obtain gradient copolymers (dependent on the reactivity ratios). Harrison et al.286 have exploited copolymerizations involving comonomers with disparate reactivity to make diblock-like polymers via the copolymerization of styrene (rstyrene = 0.21) and acrylic acid (rAA = 0.082), where styrene is incorporated into chains preferentially at the earlier stages of polymerization, with acrylic acid favored at the later stages of the reaction.

Diblock copolymers prepared by RAFT are generally made using chain extension procedures. The stability of the macro-radical (i.e., the structure of the leaving group) is an important design consideration when planning chain extension experiments. For example, considering the synthesis of PMMA-b-PS the order of chain growth is important with PMMA growth favored as the initial block, as the tertiary PMMA radical is the favored leaving group over the secondary styryl radical (Scheme 9). Recently, Rizzardo and coworkers287, 288 synthesized a ‘universal’ RAFT agent able to control the polymerization of a variety of monomers, by switching the polarity of a RAFT agent. The authors demonstrated the synthesis of PVAC-b-PSt.287 More recently, the synthesis of diblock copolymers by coupling RAFT and cationic polymerization has been proposed by Kamigaito and coworkers.289 The authors propose the synthesis of PMMA-b-vinyl ether in two steps. First, a conventional RAFT polymerization was achieved using a trithiocarbonate ((CH3)2C(CN)SC(S)SEt) in the presence of MMA or MA to yield block copolymer. In a second step, Lewis acid (SnCl4) and ethyl acetate were added to the solution to generate the cationic propagating specie by complexation of both RAFT end group and the Lewis acid. The poly(MA) was chain extended by the addition of isobutylvinyl ether with an excellent control to yield poly(MA-b-VE) block copolymers (with a PDI < 1.4).

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Scheme 9. Synthesis of diblock copolymers by RAFT polymerization, the route A is possible while the route B will not generate diblock copolymer due to the difference of leaving group. The tertiary PMMA radical is the favored leaving group over the secondary styryl.

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Graft copolymers (and more complex architectures, such as cyclic polymers) can also be made by combining RAFT with click chemistry, using two different approaches (i) the synthesis of macromonomers (as described by Armes and coworkers290) and (ii) the grafting “to” using a copolymer with pendant alkyne groups with an azide terminated polymer.291 Winnik and coworkers exploited azide-alkyne click chemistry for the synthesis of macrocycles by intercoupling heterofunctional telechelic poly(NIPAAm).266, 292

As explained earlier in this review, ATRP and azide alkyne click chemistry form a powerful combination, while thiol chemistry is more appropriate to RAFT polymerization (vide infra).114, 264 Thiol chemistry can be used in a multitude of approaches, such as thiol-ene/yne click chemistry,114, 264, 274 thiol-pyridyl disulfide exchange reactions,213, 272, 293, 294 thiol-bromo nucleophilic substitution105–107 and thiol-isocyanate condensation.131, 295 CAMD researchers prepared a block copolymer of OEG-acrylate (Mn = 2,000 g/mol) and poly(NIPAAm)-SH with relatively high yields for low molecular weight poly(NIPAAm) by Michael nucleophilic reaction. However, this approach is limited by molecular weight with yields decreasing at higher molecular weights (yields around 90% for Mn = 2,000 g/mol, drop to 65% for 10,000 g/mol).271 Thiol/ene reactions have also been exploited to synthesize macromonomers by the addition of a thiol terminated poly(NIPAAm) onto diacrylate monomers in large excess.271 The synthesis of a diblock poly(NIPAAm)-S-S-PEG copolymer with a reducible bond has been reported using thiol-pyridyl disulfide exchange chemistry.293

RAFT polymerization has also been combined with cyclo-Diels-Alder reactions for polymer functionalizations, as demonstrated by the syntheses of block,296, 297 comb298, 299 and star copolymers296 (see Scheme 10). One drawback to this approach is the requirement for a diene group often necessitating postmodification reactions, adding to the complexity of the methodology.298 The approach can be extremely efficient especially when cyclopentadienes are employed.300, 301

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Scheme 10. Synthesis of comb copolymer using HDA click reaction.

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Syntheses of Star Polymers

The synthesis of star polymers can be achieved using two alternative approaches: i) via a core first technique (using the Z group or the R group in the RAFT agent structure) or ii) via an arm first technique.

Star Polymers From a Core First Approach.

A number of compounds have been employed successfully as cores for RAFT-star-syntheses, for example, cyclodextrins,302, 304 aromatic groups,305 dendrimers,306–308 hyperbranched polymers309–311 or metal complexes.312

RAFT functionality can be attached to the core via either the R or Z groups. The advantage of the R approach is that the polymer chain grows away from the core towards the periphery, minimizing steric hindrance during the polymerization. However, the R approach has some limitations as radical-radical termination reactions, particularly, combination reactions, can play a significant role as noted in our first experimental paper305, 313 and later theoretical work.314, 315 In addition, the R approach limits the stability problems of RAFT end group, such as hydrolysis,190 thermal degradation188 or aminolysis.186, 260, 265, 267 Liu et al.316, 317 synthesized 3 or 6 arm biodegradable star polymers using RAFT functionality attached to the core by the R group (via a disulfide bridge). After polymerization Liu and coworkers318 showed that the Z group could be exploited for further modification of the stars by building up supramolecular structures via inclusion complexes.

The RAFT functionality can also be attached to the core using a Z group approach, where polymer grows in solution and transfers to the core yielding a star structure. This Z group approach minimizes problems with radical-radical coupling, however it suffers from a problem with steric hindrance as the RAFT functionality is maintained adjacent to the core as the growing star arms impede access to some extent.319–321 Dendritic cores may offer some advantage over hyperbranched cores as they appear to have an improved presentation of RAFT functionality at the surface of the core,322–323 however, some problems are still observed.324

Z Approach Versus R Approach.

Bernard et al.321 compared the R and Z approaches in the syntheses of poly(vinyl acetate) star polymers. The R approach yielded well-defined star polymers, with a PDI < 1.4, while the Z approach yielded broad distributions. In addition, the authors observed a destruction of the architecture during the hydrolysis of stars generated by the Z group approach, as the hydrolysis also cleaved the xanthate linkage between the arms and the core. The R approach was used for the synthesis of 3-arm star glycopolymers by polymerization of acryloyl glucosamine in the presence of trifunctional trithiocarbonate.306 Recent results reported by Takeshi and coworkers325 confirmed that the R approach was preferred for the synthesis of 4-arm poly(N-vinyl carbazole). The authors reported that the Z approach had a significant effect on the rate of polymerization, while the R approach was less affected.325, 326

Star Polymers Via an Arm First Methodology.

The chain extension of linear polymers with a cross-linker was first used for the synthesis of star polymer with a microgel core.195, 308, 327–333 However, RAFT polymerization results in the formation of star polymers with a PDI greater than 2.0. It is noteworthy that ATRP polymerisation yields stars with PDIs around 1.2–1.5.334, 335 A possible reason for this difference is the mechanisms of ATRP and RAFT, as the RAFT mechanism is based on a reversible transfer mechanism, while ATRP is based on activation/deactivation processes. Steric hindrance may play a significant role.

Alternatively, linear arms can be coupled to a central core using click chemistry for example, using Diels-Alder reactions,296 thiol-pyridyl disulfide exchange,317 thiol-maleimide or anhydride-alcohol.323 Recently, supramolecular chemistry was used for the synthesis of miktoarm star polymers (AB2 type) using the assembling of thymine and diaminopyridine end groups.336

Diels-alder cycloaddition has been employed for the synthesis of star polymers with 3 and 4 arms.296, 337, 338 According to the nature of RAFT agent, that is, phosphoryl Z group339 or pyridinyl Z group,340 different catalyst should be used for the diels-alder reaction. The HDA method has been employed for the syntheses of diblock,338 graft298 and star polymers296 in some cases with very short reaction times.300

Thiol-ene click chemistry has also been used to form star polymers. Lowe and coworkers synthesized three-arm star polymers by the “in situ” reduction of RAFT end groups into thiols and subsequent reaction of thiol onto trifunctional compounds bearing acrylic groups161, 261 in the presence of DMPP, demonstrating a quantitative formation of star poly (DMA) at room temperature in less than 5 minutes.161 Pyridyl disulfide exchange chemistry can be very efficient for creating biodegradable star polymers316–318 and the synthesis of three-arm star polymers has been achieved by the reaction of pyridyl disulfide functionalized poly(NIPAAm) with a trithiol precursor (used as a core) at high efficiencies.317

The synthesis of miktoarm stars has recently received significant attention.341 Feng and Pan323 synthesized miktoarm star polymers based on an initial PSt block polymerized by RAFT, and subsequently chain extended initially by maleic anhydride and then by NIPAAm or methyl acrylate. The maleic anhydride was used to attach PEO (by reaction between the alcohol and the anhydride groups), however, the yield of the anhydride/alcohol coupling reaction (at high molecular weights) required a large excess of alcohol to attain a quantitative yield. Azide-alkyne click chemistry has been used to synthesize different miktoarm star polymers.342, 343 The synthesis of AB2-type miktoarm star polymers using a combination of RAFT, ring opening polymerization (ROP) and Click chemistry has been demonstrated, where343 an azide functional RAFT agent was used to polymerize nBA, OEG-A or NIPAAm monomers. The polymers were subsequently then clicked to propargyl terminated polycaprolactone (PCL) or polylactide (PLA) in the presence of a copper bromide (CuBr) catalyst to yield miktoarm star polymers with a very high purity. Similarly, Pan and coworkers344 synthesized ABCD- 4 miktoarm star copolymers.

Perrier and coworkers345 synthesized miktoarm stars by combining two types of polymerization, that is, RAFT and ring-opening polymerizations (ROP). Hydroxy ethyl acrylate (HEA) and ethyl acrylate (EA) were copolymerized to yield short oligomers with 5–10 units. The hydroxyl groups on HEA were then used to ring-open L-lactide before the RAFT end group was used to chain extend another arm. Combining different polymerization techniques, such as ROP,346 ATRP347–350 or SET,351 with RAFT has facilitated the synthesis of different star polymers.347, 350 For example, Kizhakkedathu and coworkers347 synthesized a multifunctional initiator obtained from hyperbranched polyglycerol, bearing an ATRP initiator and azo-initiator; the authors used the azo-initiator to initiate a RAFT polymerization whilst simultaneously performing an ATRP initiation.

Synthesis of Graft and Comb Copolymers

Graft copolymers can be synthesized from RAFT polymerization, using three different general approaches, viz. grafting through,284 grafting from and grafting onto. The grafting “through” method exploits macromonomers, that is, a polymer (or oligomer) terminated by a double bond.283, 284 The grafting onto approach involves the attachment of RAFT functionality onto a polymeric backbone (or substrate polymer).352, 353 As described previously (vide infra- star polymer syntheses), attachment of the RAFT group can be achieved through either the R or Z groups. Alternatively, initiator can be attached to the backbone chain (substrate), as demonstrated for the modification of films via ozone treatment, introducing peroxide, as used to modify films based on poly(vinylidene fluoride)354 or polyimide.355

The synthesis of comb copolymers using a grafting onto approach has become extremely commonplace since the popular emergence of click chemistry.240, 253 Azide-alkyne reactions have been used for the synthesis of comb or graft copolymers by exploiting the copolymerization of protected alkyne monomers, and a subsequent postmodification using azide functionalized polymers obtained from both ATRP356 and RAFT polymerizations.291

Cycloaddition HDA reactions have been employed for the synthesis of comb polymers via two different routes. Firstly, the low conversion copolymerization of diene monomers to yield copolymers bearing diene groups,299 followed by reaction with RAFT terminated polymers to generate comb copolymers (Scheme 11). Secondly, an alternative method has been proposed to mitigate problems with diene cross-linking: the diene was incorporated by postmodification of poly(HEA) copolymers yielding well-defined graft copolymers.299

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Scheme 11. Synthesis of star polymer via RAFT polymerization via core and arm approaches. For the core first, the synthesis can be carried out using two methods: R (top) and Z (bottom) approaches.

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Synthetic Approaches to Hyperbranched and Nanogel Polymers (Soluble Products)

Hyperbranched polymers have potential uses in bio-applications357 and surface coatings,358–360 and have been synthesized via conventional free radical copolymerization of monomers with difunctional monomers (used as cross-linker) in the presence of thiols361–363 or in the presence of cobalt chain transfer (CCT) agents.364 The emergence of controlled radical polymerizations, such as ATRP, RAFT and NMP, has significantly extended the synthetic scope for generating hyperbranched structures, with improved control over the branching process as well as the overall molecular weight of the branched chains. Several reports have focused on the syntheses of hyperbranched polymers using ethylene glycol dimethacrylate (EGDMA) as a cross-linker with RAFT polymerization of different vinyl monomers yielding hyperbranched polymers.365–367 The properties of synthesized hyperbranched polymer (i.e., number of branches, PDI and molecular weight) are dependent on the specific experimental conditions used, that is, temperature, cross-linker, RAFT agent and monomer concentration (Scheme 12).367 Asymmetric cross-linkers, that is, molecules bearing a higher reactivity double bond (methacrylate) and a lower reactivity norborene group, were successfully employed by Dong et al.368, 369 to yield hyperbranched polymers functionalized by norborene groups. Other asymmetric cross-linkers, such as allyl methacrylate or undecenyl methacrylate, have also been investigated for use in hyperbranched polymer syntheses.370

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Scheme 12. Synthesis of hyperbranched polymer using the copolymerization of cross-linker and monomers. At low conversion, the formation of linear polymer is observed, while at relatively high conversion (˜90), the formation of hyperbranched polymers is achieved, for very high conversion, the formation of gel is observed.

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Armes and coworkers371 used RAFT copolymerization of methyl methacrylate with a disulfide-based dimethacrylate (DSDMA) to yield biodegradable hyperbranched polymers. After degradation (cleavage of disulfide), the linear chains were found to exhibit similar molecular weights and PDIs to linear polymers obtained without the addition of cross-linker. In another study, Armes and coworkers372 compared RAFT and ATRP polymerization in generating hyperbranched structures, CAMD researchers synthesized thermo-responsive hyperbranched polymers based on OEG-acrylate monomers. The LCST of hyperbranched polymers was 5–10 °C lower than the LCSTs obtained for equivalent linear copolymers. Biodegradable hyperbranched polymers for potential gene therapy applications were also investigated by CAMD researchers.373, 374

Another approach to hyperbranched structures includes the preparation of functional control agents bearing a double bond.375, 376 Yang and coworkers377, 378 used a NMP initiator bearing a double bond. Inspired by this work, Zhongmin Wang et al.379 synthesized a dithioester moiety bearing a double bond, for the RAFT polymerization of styrene thereby yielding a highly branched polystyrene structure. Sumerlin and coworkers376–380 used a similar methodology for the synthesis of thermo-responsive hyperbranched polymers by the polymerization of (N-isopropylacrylamide), see Scheme 13.

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Scheme 13. Synthesis of hyperbranched macromonomer using a RAFT agent bearing a reactive double bond. Reproduced from ref.380, with permission from American Chemical Society.

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Whittaker and coworkers381 have demonstrated the design and synthesis of hyperbranched molecules that can be successfully imaged in vivo using 19F MRI. These hyperbranched polymers are obtained by copolymerization of dimethylaminoethylacrylate (DMAEA, 77 mol %) and trifluoroethyl acrylate cytocompatible (23 mol %), following chain extension with PEGMA in the presence of alkyne functionalized trithiocarbonate. The presence of alkyne end group allows the attachment of azide mannose. These functional hyperbranched are cytocompatible and can be successfully imaged in vivo using 19F MRI in under 10 min.

Gels and Hydrogels (Insoluble Products)

The synthesis of hydrogels is of great interest for drug delivery applications,382–385 tissue regeneration386 and cosmetics.387 The addition of cross-linker to a polymerization mixture is a common route to obtain gels (Scheme 12).388 Controlled radical polymerization can obviate problems with compositional drift in cross-linking copolymerization389–390 thereby limiting the formation of free polymer (Scheme 14). Lu and coworkers391 synthesized thermo-responsive poly(NIPAAm) hydrogels by RAFT polymerization with enhanced swelling when compared to hydrogels obtained using free radical polymerization. Recently, Vana and coworkers392 studied the surface morphology of hydrogels using atomic force microscopy, noting improved homogeneity of the hydrogel surfaces when compared to gel surfaces obtained by free radical polymerization. Sumerlin and coworkers393 synthesized gels by reduction of RAFT moieties on the surface of star polymers yielding thiol end groups, which could be easily oxidized to form a disulfide network.

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Scheme 14. Comparison of the structure of gels obtained by free radical polymerization and controlled radical polymerization.

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An alternative approach to obtain gels is to use multiblock copolymers capable of forming physical crosslinks by hydrogen bonding,394, 395 or by hydrophilic or hydrophobic interactions.396–398 Triblock copolymers (A-B-A),393, 397, 399–400 or (A-B-C),401 multiblock,196 graft copolymer402 or star403 architectures have been described. The common feature of the topologies used is the size of the building blocks, with short associative blocks located in the outer part of the macromolecular chain used to favor intermolecular association leading to physical crosslinks. The associative block can also be designed to react to a stimuli (such as temperature) to yield responsive gels with potential applications in drug delivery.398, 404 Recently, the addition of cyclodextrin modified nanoparticles (quantum dot) in the presence of an azobenzene end functionalized block copolymer Poly(DMA)-b-Poly(NIPAAm) has allowed the formation of dual stimuli supramolecular hydrogel. The formation of this gel results by the inclusion complex of azobenzene into cyclodextrin group and by the formation of collapsed domain of Poly(NIPAAm) (formed above the LCST).405

NANOMATERIAL SYNTHESES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Micelles

The association of di- or multiblock polymers in aqueous solution can result in the assembly of nanoobjects, such as micelles, liposomes or vesicles. RAFT polymerization is a particularly versatile synthetic method for building micellar assembles as it is applicable to a wide range of monomer structures (charged, zwitterionic, noncharged)406 with more versatility than ATRP or NMP. As there are a large number of references in this domain, we decided to restrict this review to the most recent examples detailed in the literature. For a detailed review in this area, the readers are invited to read the following reviews.33, 62, 406, 407

Micelle assembly and disassembly can be induced by the application of external stimuli, such as temperature, electrolyte concentration, or pH.33 Micelles can be used as nanoreactors for the synthesis of inorganic compounds or for specific organic reactions.408, 409 Liu and coworkers408 prepared different micelles using double hydrophilic block copolymers, based on poly(NIPAAm)-b-poly(N-vinylimidazole)). The poly(N-vinylimidazole) block catalyzed the esterolysis reaction, while the poly(NIPAAm) block induced micellization stimulated by a change in temperature.

Micelles for drug delivery applications structures have been described using RAFT polymerization.407, 410 For drug delivery applications, micelles are generally targeted with sizes below 200 nm, to avoid elimination by phagocytes and allowing for accumulation in vivo by the enhanced permeability and retention (EPR) effect.411, 412 CAMD researchers have described micelle structures bearing surface sugar moieties based on diblock poly(diethylene glycol-methacrylate- b-hydroxy ethyl methacrylates) (poly(DEG-MA-b-HEMA)) copolymers,104 where the pendant hydroxyl groups were modified into alkene groups by reaction with pentanoic acid, followed by a thiol-ene reaction to introduce sugar moieties on the backbone. The second block DEG-MA exhibited a LCST of 29 °C driving self-assembly. Interesting, the glucose decorated micelles presented a higher binding rate with Concanavalin A, when compared to equivalent linear polymers. Hydrophobic cores can be exploited for the transport and the encapsulation of hydrophobic drugs, such as doxorubicin, prednisone acetate, and paclitaxel for example. Wang and coworkers413 synthesized triblock poly(caprolactone)-b-poly (NIPAAm)-b-poly(caprolactone) copolymers using a combination of ROP and RAFT polymerizations. The resultant copolymers were self assembled into micelles, with an hydrophobic core based on poly(caprolactone), and a hydrophilic shell based on poly(NIPAAm). The core was used to encapsulate prednisone acetate, subsequently the release of this drug was observed by an increase in temperature (Fig. 1). In another study, Gao and coworkers414 used diblock PMMA-b-(OEG-A-co-NIPAAm)-b-PMMA copolymers for folic acid delivery. Micelles have also been used in vitro for the delivery of anticancer drugs.410 For example, paclitaxel was encapsulated into poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(nBuA).

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Figure 1. Synthesis of thermo-responsive micelle for drug delivery. (a) Schematic representation; (b) Release of model drug versus temperature and time (h). Reproduced from ref.413, with permission from Journal of Polymer Science: Part A: Polymer Chemistry.

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For use in vivo, micelles need to be stabilized to prevent disassembly. Thus stabilization via cross-linking has become an area of intense investigation. Different pathways to stabilize micelles have been reported, such as chain extension in the presence of cross-linker415 or functional groups416, 417 in the core or shell.

To facilitate removal of the polymer (postdelivery) by the renal system, biodegradable cross-linking strategies have been developed. Different pH-sensitive cross-linkers have been developed using acetal and ketal groups to yield pH-sensitive nanoparticles (Scheme 15).418, 419 Redox-sensitive micelles have also been developed via chain extension using a cross-linker bearing a disulfide bond420, 421 or by postmodification of polymers.422, 423 In the presence of a reducing agent, such as glutathione, disulfide-stabilized micelles disassemble into unimers, thereby releasing their drug payload. pH-sensitive micelles can liberate drugs in the endosome, while redox-sensitive micelles liberate drugs in the cytoplasm. McCormick and coworkers114, 424, 425 synthesized PEO-b-(DMA-s-NAS)-b-NIPAAm triblock copolymers (with NAS: N-acryloxysuccinimide) thereby yielding micelles above 37 °C (Scheme 16). The presence of NAS was exploited to cross-link the micelles using cistamine, a disulfide based difunctional amine, resulting in micelles that could be disassembled by reduction of disulfide bonds, but subsequently reassembled on exposure to air. Click chemistry using a disulfide containing difunctional azide has been employed to stabilize micelles loaded with cobalt drugs.426 Degradable micelles have also been obtained by cross-linking micelles with a Pt(IV) containing cross-linker, clicked onto the polymer backbone via isocyanates. In the cytoplasm, the crosslinked micelle is cleaved into its constituent block copolymers, releasing Pt(IV). Subsequently, Pt(IV) is reduced to its active form Pt(II).417

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Scheme 15. Synthesis of pH-sensitive cross-link micelles for drug delivery application. Reproduced from ref.418, with permission from American Chemical Society.

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Scheme 16. Cross-linked micelles using a NHS activate ester monomers.

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Targeting agents such as peptides, antibodies, or sugar moieties, can be conjugated to micelle surfaces.427 Alternatively, end groups can be exploited to introduce targeting agents. Liu et al.226 synthesized micelles decorated with pyridyl disulfide end groups for subsequent modification with a model peptide or thio-rhodamine. The presence of trithiocarbonates at the surface of micelles can be exploited for functionalization as illustrated by Perrier and coworkers,428 who proposed a one-pot approach to the cross-linking and modification of micelles using NHS/amine coupling and thiol-ene reactions. In another example, Sumerlin and coworkers used an azide-alkyne reaction to attach folic acid at the surface of micelles.239

While most cross-linking techniques utilize the presence of functional groups on either the core or the shell forming block, the RAFT process itself opens up a further avenue to obtain crosslinked micelles. The presence of the thiocarbonyl functionality at the surface of the micelle or the core of the micelle can permit chain extension, where self-assembled micelles are mixed with divinyl compounds with subsequent polymerization leading to shell or core cross-linking.303, 421, 429 Core-cross-linking with diacrylates is usually highly efficient while reaction with divinyl benzene can be sluggish.430 Degradability of micelles can be achieved by introducing either pH-degradable functional groups or disulfides. A drawback of chain extension with divinyl compounds is the formation of intermicellar crosslinks.431 Emulsion-based chemistry using a chain extension cross-linking approach has been exploited to generate well-defined, highly bioactive, core-shell glyco-nanoparticles (Scheme 17).432

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Scheme 17. Synthesis of glycopolymer nanoparticles using a disulfide cross-linker.

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A cross-linking approach to nanoparticle formation can also exploit the RAFT functionality at the nexus of two blocks in a block copolymer. In this ‘nexus’ approach, a polylactide-based RAFT agent – formed by the ring-opening polymerization of 3,6-Dimethyl-1,4-dioxane-2,5-dione by a functional RAFT agent – was used to polymerize NIPAAm or a glycomonomer.433, 434 As the thiocarbonylthio group was situated between the blocks, the subsequent cross-linking process via RAFT resulted in cross-linking at the interface between core and shell. This “nexus” cross-linking approach yields better phase separation between core and shell,434 and also offers the opportunity to selectively remove the polylactide core creating hollow nanocages.433

Vesicles and More Complex Architectures

Under certain conditions, amphiphilic polymers can self-assemble into specific, complex structures, for example, vesicles or rod structures.435–437 The hydrophilic/hydrophobic balance and the method of preparation can dictate the formation of these specific architectures.438 Eisenberg and coworkers439, 440 have described the morphology evolution dependent on the molecular weight of the hydrophobic block and the nature of the hydrophilic block (charged or noncharged). The polymer concentration and the presence of cosolvents can also affect the morphology of amphiphilic polymer assembly.436, 441, 442

Responsive block copolymers can also be used in the preparation of complex architectures, such as vesicles.76, 415, 431, 443 McCormick and coworkers444 exploited a dually responsive poly(DEAEMA-b-NIPAAm) copolymer capable of "schizophrenic" aggregation in aqueous solution (Fig. 2). The nano-assembly, dictated by the hydrophilic mass fraction, was controlled by the polymer block lengths, by pH, and temperature. Both poly(DEAEMA-b-NIPAAm) (52.5 wt % NIPAAm) and poly(DEAEMA-b-NIPAAm) (70.8 wt % NIPAAm) self-assembled into poly(DEAEMA)-core poly(NIPAAm)-shell spherical micelles with hydrodynamic radii (Rh) of 21 and 25 nm, respectively at temperatures below the LCST of poly (NIPAAm) and at pH values greater than the pKa of PDEAEMA. However, the two block copolymers displayed quite different temperature responsive behaviors at pH < 7.5. At elevated temperature (>42 °C) poly(DEAEMA98-b-NIPAAm209) formed spherical micelles (Rh = 28 nm) with hydrophobic poly(NIPAAm) cores stabilized by a hydrophilic PDEAEMA shell. In contrast, poly(DEAEMA98-b-NIPAAm392) assembled into vesicles (Rh = 99 nm) above 38 °C. Different strategies to cross-link “schizophrenic” structures have been developed to lock in place these unique structures.445

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Figure 2. Synthesis of vesicle by self-assembled of pH-sensitive and thermo-sensitive polymers. Reproduced from ref.444, with permission from American Chemical Society.

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Huang and coworkers446 studied the effect of block molecular weight of PEO and PSt in a (PEO-b-PSt)x multiblock copolymers on the self-assembly behavior. Long rods were observed for a composition containing 23 mol % of PEO and 77 mol % of PSt, however, when PEO was increased to 25 mol %, the polymers formed octopus-like structures, while below 20 mol % PEO, large micelles were observed.

Self-organization of polymers in aqueous media into higher nanostructures can also be driven by end groups.447–449 Moughton and O'Reilly450 introduced a quaternized amine as an end group to poly(NIPAAm-b-tert-BuA) synthesized by RAFT polymerization. Below the LCST of poly(NIPAAm), the copolymers generated micelles with a poly(NIPAAm) shell, while above the LCST, the poly(NIPAAm) became hydrophobic driving a reorganization of the micelle into vesicles. Recently, CAMD451 has prepared spherical and tubular vesicles from hydrophilic homopolymers of N,N-dimethylacrylamide (DMA) and N-(2-hydroxypropyl) methacrylamide (HPMA). These homopolymers were obtained using new RAFT chain transfer agents containing one to four hydrophobic functional groups in the R fragment based on pyrene, cholesterol, or octadecane, resulting in hydrophilic homopolymers containing a low proportion (6–23 wt %) of hydrophobic end groups. Poly-DMA and poly-HPMA homopolymers, of varying molar masses with either bis pyrenyl or cholesteryl end groups self-assembled in aqueous media forming spherical vesicles with sizes in the range of several hundred nm up to about 1 μm. These polymersomes are also able to sequester the hydrophilic compounds.

Recently, Pan and coworkers452, 453 proposed a one-pot approach to polymeric nanomaterials via RAFT polymerization in dispersed media. The authors used a macro-RAFT agent (PVP-RAFT) initially soluble in methanol for the polymerization control of styrene. As conversion increased, phase segregation occurred driven by the poor solubility of the PSt block. Different morphologies from vesicles453 to nanowires454 were obtained depending on the initial [St]0 : [macro-RAFT]0 ratio and the conversion of styrene. In addition, this technique allows the synthesis of multimorphologies (vesicle, nanorods, nanotubes and doughnuts) in a very high concentration as high as 500 mg/mL.452 Recently, Charleux and coworkers455 proposed an emulsion RAFT polymerization route to yield nanofibers, by copolymerization of AA and OEG-A in ethanol at 70 °C. In a second step, poly(AA-co-OEG-A) was then dispersed in basic aqueous media, and the copolymer was chain extended in the presence of styrene to generate nanofibers. The chain extension of poly(AA-co-OEG-A) using styrene as monomer in water results by the formation of insoluble PSt block. These insoluble blocks self-assembled in water to yield nanofibers. This novel emulsion process directly allowed the synthesis of nanofibers at very high concentration of polymer (11 wt %). In addition, a similar result was obtained when the diblock copolymer was self-assembled by continuous addition of water. Armes and coworkers used a similar process to obtain nanoparticles of poly(GMA-b-hydroxyl propyl methacrylate).456

Synthesis of Hybrid Nanoparticles

(a) Grafting From and Onto

The modification of nanoparticle surfaces using RAFT polymers can be achieved using two alternative pathways: grafting from or grafting onto. Grafting “to” uses preformed polymers, while grafting from involves the growth of polymer chains from a surface. Both methods have advantages and disadvantages, for instance, the control of polymer architecture (functionality, composition) is superior when grafting “to” is used, however, the density of polymer chains is more difficult to control. In grafting from the RAFT functionality can be attached via the R or Z groups. The Z approach can be limited by steric hindrance of polymers already grafted onto the surface. The attachment by Z group also confers some instability on the composite material because of the potential for hydrolysis or aminolysis of the RAFT functionality. However, the R approach also has some limitations, with an increased possibility of radical coupling.

The topology of the nanoparticle surface can also have a great influence on the packing density of brushes, as flat and spherical surfaces present different deflection angles. Small nanoparticles can be more amenable to higher grafting densities as they display higher deflection angles.457

(b) Layer-by-layer methodology

Polymer modification of nanoparticle surfaces can also be achieved using a layer-by-layer methodology (LbL).458 This approach has been successfully employed for the modification of a large variety of nanoparticles, such as silica,459 gold,460, 461 iron oxide nanoparticles.462 In LbL, the polymer layers are physio-absorbed at the surface of the nanoparticles by electrostatic interactions or hydrogen bonding, resulting in the formation of thin films (Fig. 3). The thickness of the LbL film can be easily controlled by the deposition process. In addition, the permeability and the functionality of the films are dictated by the nature of the interactions. For example, films cemented by hydrogen bonding are responsive to environmental pH or temperatures. Hydrogen bonding between DNA base pairs allows multilayer films to disassemble when exposed to low ionic strength solutions.463 To improve the mechanical properties and the stability of LbL assembly, layers can be cross-linked by thiol-ene464 or azide-alkyne465–468 click reactions. This cross-linking approach has been exploited for the formation of hollow polymer nanocapsules for drug and gene delivery applications.469 In addition, click reactions can be used to attach therapeutic compounds to nano- and microcapsules.470

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Figure 3. Modification of nanoparticles using layer by layer methodology.

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RAFT and LbL methodologies have been combined for nanoparticle syntheses.66, 471 The self-assembly of poly(styrene sulfonate-b-poly(oligoethylene glycol acrylate) (PSST-b-POEG-A) diblock copolymers on the surface of silica conferred antifouling properties at the nanoparticle surface.472 CAMD researchers exploited a LbL strategy to decorate gold nanoparticles with sugar moieties or with PEG polymers.108, 298

Carbon Nanotubes, Nanodiamond and Graphene

Since the discovery of graphene by Geim and coworkers in 2004,473 it has been touted as a “next generation material” because of its remarkable electronic, optical, and thermal properties, chemical and mechanical stability, and large surface area for applications in both emerging and conventional fields, such as field-effect transistors, sensors, electrochemical devices, electromechanical resonators, polymer nanocomposites, batteries, capacitors, and light emitting devices.474–482 Despite extensive research, graphene-based materials are restricted for practical applications by problems with scalable dispersion and the long-term stability of sheet aggregates held together by Van Der Waals interactions.483 Some problems may be overcome by the manufacture of polymer-graphene hybrids for obtaining highly stable colloidal suspensions of graphene properties. In addition, the addition of graphene into polymer blends result by an enhancement of mechanical and electronic properties. Carbon nanotube/polymer hybrids have also attracted interest for gene delivery. It was demonstrated that carbon nanotubes can pass through cell membranes,484–486 and accumulate in the nuclei of cells.486

RAFT-polymers may be attached onto carbon surfaces in several ways.487 The treatment of graphene and carbon nanotubes with HNO3 results in carboxylic acid functionality suitable for anchoring RAFT agents or polymer.68, 485, 488, 489 RAFT agents attached via the R group have been shown to control the polymerization of different monomers from nanotube surfaces.68, 490 In addition to grafting from, grafting onto has also been reported for the modification of nanotubes, using pyrene terminated polymers. The π interactions between pyrene and nanotube surfaces enable the attachment of polymers.491 This method has also been used successfully for graphene.492, 493 The functionalization of graphene by different charged polymers was exploited using a layer-by-layer process resulting in the formation of well organized graphene sheets.492, 494 Another approach to functionalize graphenes, nanotubes or nanodiamonds is to exploit the presence of carboxylic acid groups at their surfaces for LbL assembly to yield a thin film of polymers. Narain and coworkers495 attached sugar modified poly(2-aminoethyl acrylamide) (poly(AEA)) onto nanotubes surfaces using NHS/amine coupling reactions for gene delivery (Scheme 18). Recently, the modification of nanodiamonds was achieved by RAFT polymerization using the grafting onto approach. He and coworkers496 exploited the presence of carboxylic acid groups at the surface of nanodiamonds to attach a triblock poly(tert-Bu A)-b-(GMA-b-St) copolymers using a carboxylic acid and epoxy reaction.

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Scheme 18. Modification of carbon nanotubes using RAFT polymerization for DNA delivery. Reproduced from ref.495, with permission from American Chemical Society.

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Metallic and Oxide Nanoparticles
Silica Nanoparticles

Silica and titanium oxide nanoparticles can make solid supports with good chemical resistance at a reasonable cost for a large range of applications.497, 498 The attachment of polymer at the surface has been proposed to enhance applications in optics, bio-separations (purification), and electronics. Tsujii et al.499 reported the first surface-initiated RAFT polymerization to modify silica particles using a surface-anchored RAFT agent. Baum and Brittain200 utilized RAFT to graft polystyrene (PSt) and poly(methyl methacrylate) (PMMA) from silica particles using a surface-anchored azo initiator. Surface-initiated RAFT in the modification of silica nanoparticles has since been used with a wide range of polymers using grafting from or onto approaches.203, 215, 500–502 The attachment of polymers on silica surfaces can be achieved by different ways: (i) RAFT agent can be attached using a R approach onto the surface using a RAFT-silane coupling agent or using a coupling reaction between an activated ester RAFT agent and aminated silica nanoparticles, as suggested by Benicewicz and coworkers203, 215, 257, 503; (ii) RAFT agents can be attached using the Z group as proposed by Zhao and Perrier,501, 504 and others503; (iii) grafting of diblock copolymers, using poly(methacryloxypropyltrimethoxylsilane) to anchor the polymers.206, 505

In the recent works of Ranjan and Brittain,506 and Benicewicz and coworkers,257 surface-initiated RAFT polymerization was combined with click chemistry to modify the surface of silica nanoparticles through the use of an immobilized alkyne-terminated RAFT agent or azide pendant polymers. In other work, a new method for the modification of nearly monodispersed silica core-poly(N-vinylcarbazole) shell (SiO2 at PVK) microspheres was proposed by Kang and coworkers507 who described surface-initiated distillation-precipitation polymerization of N-vinylcarbazole in the presence of divinylbenzene from silica template microspheres prepared by the sol-gel reaction of tetraethyl orthosilicate (TEOS) and 3-(trimethoxysilyl)propyl methacrylate (MPP). SiO2 at PVK−PNIPAM core-shell hairy microspheres were subsequently prepared by grafting Poly(NIPAAm) chains, synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization to the SiO2 at PVK microspheres via thiol-ene click chemistry.

Iron Oxide Nanoparticles

Iron oxide nanoparticles (IONPs) can be applied to MRI imaging, drug and gene delivery, and hyperthermia treatment (Scheme 19).508–520 The magnetic properties of iron oxide or iron can be exploited to change the transversal relaxation time of surrounding water molecules in imaging or to guide nanoparticles in the body via an applied external magnetic field. However, iron oxide nanoparticles (and in general metallic or oxide nanoparticles) have poor stability in aqueous or organic solutions resulting in a rapid precipitation caused by their high surface energies (Scheme 20).520 Attaching organic compounds or polymers to the nanoparticle surface can help stabilize them in solution. The functionalization of IONPs can be carried out using a large range of anchoring functions, such as dopamine, carboxylic acid, phosphonic acid, and trimethoxysilane (Scheme 21).299

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Scheme 19. Functionalization of gold surface using thiol- or trithiocarbonate-terminated polymers.

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Scheme 20. Design of hybrid organic/iron oxide nanoparticles for bioapplication.

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Lu and coworkers521 modified IONPs using a RAFT agent bearing a carboxylic acid, followed by the polymerization of NIPAAm to yield IONPs coated with poly(NIPAAm). Stayton, Narain et al. proposed the grafting ‘onto’ approach of biotin terminated poly(NIPAAm) to modify IONPs.522 The presence of biotin groups can be exploited for streptadivin conjugation. CAMD researchers147, 198 modified IONPs using preformed polymers bearing a phosphonic acid group and pyridyl disulfide end groups to stabilize IONPs in both aqueous solution and fetal bovine serum. The pyridyl disulfide end group was then exploited for the conjugation of peptides, while the phosphonic group was used to attach the polymers to the surface of iron oxide nanoparticles.198 Subsequently, two different polymers, that is, poly(OEG-A) and poly (DMAEA) were grafted onto the IONP surfaces. Poly(OEG-A) conferred an antifouling surface to the nanoparticles, while poly(DMAEA) was used to complex siRNA (Fig. 4).147

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Figure 4. Modification of iron oxide nanoparticles using RAFT polymer for siRNA delivery: (a) schematic representation; (b) gel electrophoresis of siRNA complexed to IONPs; c) siRNA delivery to SH-EP cells before treatment and after treatment with siRNA/IONPs (note the expression of green fluorescence was knocked down by siRNA).

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The stabilization of iron oxide has also been achieved using diblock copolymers, with one block composed of carboxylic acid pendant groups to anchor to the IONP surface, and a second block to confer solution stability.523, 524 This strategy was successfully used for the attachment of nanotubes at the surface of IONPs.525

One interesting property of iron oxide nanoparticles is their ability to increase in temperature when exposed to a high frequency magnetic field. Narain and coworkers526 used this property to synthesize thermo-responsive IONPs coated with poly(NIPAAm). The authors show a reversible aggregation of these nanoparticles under a high frequency magnetic field by the LCST behavior of poly(NIPAAm).

Gold, Silver Nanoparticles and Quantum Dots

Gold and silver nanoparticles have numerous potential applications in a number of fields, viz, sensing,527 catalysis,528 nanomedicine527, 529–535 and chemical purification.268 However, in the absence of stabilizing agents, gold nanoparticles are unstable, aggregating and broadening their Plasmon resonance band. Stabilization using organic compounds, such as citric acid, is inefficient when gold nanoparticles (GNPs) are dispersed in saline solution or in serum, limiting potential applications in medical fields. The attachment of polymers can increase the stability of GNPs in saline aqueous solution or organic media, and can also confer new properties. A polymer shell can be used for the encapsulation of therapeutic compounds or for the attachment of targeting functions. “Grafting to” approaches almost exclusively employ the relatively strong Plasmon-gold536 or –silver537 interactions to bind Plasmon-terminated surfactant or polymers onto gold or silver surfaces, an approach well-suited to RAFT polymers. Thiol-modified gold colloids are very stable and behave as robust large molecules being amenable to characterization. In addition dithioester and trithiocarbonate can directly bind with gold (Scheme 20).93, 538, 539

The modification of gold nanoparticles with neutral, anionic, cationic, or zwitterionic presynthesized polymers is well established.540–544 Temperature-sensitive polymeric stabilizers have been extensively used for the modification of gold nanoparticles for sensing applications.93, 545–549 Poly(NIPAAm) homopolymers prepared using the RAFT technique with S-benzyl dithiobenzoate as the RAFT agent have been immobilized onto gold particles by the “grafting to” method following reduction of the dithioester end group with sodium borohydride to provide thiol groups. These thermo-sensitive hybrids retained the LCST of poly(NIPAAm) and exhibited a sharp, reversible phase transition in solution between 25 and 30 °C.550 The addition of salt was found to promote interparticle associations leading to a red shift in the Plasmon band and an increase in the hydrodynamic size, attributed to aggregate formation above the LCST.551 Recently, GNPs modified with thermo-responsive PEG obtained by RAFT copolymerization of OEG-A and DEG-A have been reported. According to the composition of the two monomers, the LCST of copolymers could be tuned from 20 °C to 95 °C. The thermo-sensitive nanoparticles were found to exhibit antifouling properties that were conserved above the LCST (Fig. 5). The self-assembly of two copolymers also facilitated the synthesis of gold nanoparticles presenting two different LCSTs.93 The bond stability between thiol and gold is reversible and is cleavable at high temperature (above 60 °C) reducing dramatically the potential application of these hybrid nanoparticles.552 To overcome this thermal instability problem, different strategies have been developed to cross-link polymer shells around GNPs. Recently, Hawker and coworkers self-assembled RAFT polymers bearing azide pendant groups on GNPs; after exposure to UV, the azide groups facilitated cross-linking by bimolecular coupling reactions.553

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Figure 5. Grafting onto of poly(OEG-A-co-DEG-A) on gold surface to yield thermo-responsive nanoparticles: (A) schematic representation; (B) Evolution of I1/I3 of pyrene versus the temperature in the presence of GNPs/ Mixed polymers [poly(OEG-A)/poly (DEG-A-co-OEG-A)] = 50/50 wt %]; evolution of the gold particle sizes versus the temperature.

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Charged polymer modified gold nanoparticles have also been synthesized by the self-assembly of charged polymers. This type of charged hybrid can potentially be used for the transport of siRNA or DNA. The self-assembly of two different polymers, that is, one charged and one not charged but thermo-responsive, enables the tuning of charge using temperature (Fig. 6).540 Recently, McCormick and coworkers148 grafted charged/neutral diblock copolymer at the surface of gold nanoparticles. The cationic layer was used for encapsulating siRNA. These hybrid nanoparticles protected siRNA against nuclease attack and allowed the transport of siRNA to a number of different cell lines.

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Figure 6. Preparation of thermo-responsive functional gold nanoparticles.

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Narian et al.522, 554–556 synthesized gold nanoparticles decorated with sugar moieties and biotin groups for drug delivery and sensing applications using RAFT polymerization.

Finally, gold nanoparticles have also been used as sacrificial templates for the preparation of hollow nanocapsules by the dissolution of gold nanoparticles after polymer coating.557 To illustrate this example, CAMD558 used diblock poly(HPMA-b-(St-co-MA) obtained by RAFT polymerization to graft to gold surfaces (Fig. 7). Subsequently, a diamine was added to react with maleic anhydride present on the polymer backbone to induce cross-linking. Finally, the gold was dissolved using aqua regia reactant to leave nanocapsules.

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Figure 7. Synthesis of nanocapsules using gold nanoparticles as sacrificial templates by grafting onto of poly(HEMA)-b-(ST-co-MA).

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Finally, quantum dots (QD) obtained from cadmium, zinc, selenium, telerium, and sulfur present a huge potential for imaging applications because of high fluorescence emission properties compared to traditional fluorophores, with a wide excitation and narrow emission window and resist photobleaching.559 The surface of QDs is usually composed of ZnS. The presence of ZnS can be easily modified by thiol terminated polymers.560 Thiol compounds can enhance the fluorescence of QDs by an order of magnitude.560 However, the interactions between thiol and QDs can be displaced by other thiols resulting in a loss of stability of QDs in biological media.561 For this reason, other strategies have been proposed to modify QDs. Liu et al.561 attached polymer-functionalized imidazole at the surface of QDs. The strong affinity of imidazole to QD surfaces resulted in the formation of inorganic/organic nanoparticles stable in biological media over a large range of pH. Emrick and coworkers562 synthesized a phosphine-functionalized RAFT agent able to bind onto QD surfaces. RAFT polymerization was successfully performed with a large range of monomers, such as styrene, methyl acrylate and butyl acrylate.

POLYMERS FOR BIOAPPLICATIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Protein/Peptide Polymer Conjugates

The modification of proteins using a polymer can improve their stability, bio-distribution and half-life time in the body.563 Protein PEGylation is now well established as a commercial approach to improve protein therapy,564–566 as demonstrated by Duncan.567, 568 In addition, the attachment of polymer onto protein can change the protein properties, such as enzymatic activity.

PEGylation technology has been extended to other synthetic polymers to get additional benefits, thus poly(NIPAAm) has been used.569, 570 Early approaches to polymer-protein conjugates used a “grafting onto” method (Scheme 22). Polymers were presynthesized by free radical chain transfer polymerization or by ionic polymerization yielding functional polymers, which were subsequently attached to proteins. Polymers prepared in this way suffered from disadvantages such as poor end group fidelity, molecular weights, and relatively broad PDIs.571 With the emergence of controlled radical polymerization, well-defined polymers became easily accessible for conjugation to proteins or peptides.565 Haddleton,572–576 Maynard and coworkers577–579 exploited functional polymers obtained by ATRP to yield protein-polymer conjugates, with a relative high purity. Polymer modification at specific sites on a given protein is required to maintain protein activity, for example, biotin modified polymers were generated using ATRP580 or RAFT initiators232, 581 or by modification of RAFT polymers,182, 198, 270, 272 for successful conjugation to avidin without altering protein structure.581 CAMD researchers and others have developed a range of functional RAFT agents able to control a range of monomers for the modification of proteins, such as lysozyme214, 582–584 or BSA.185 In the case of lysozyme, the presence of primary amines on its surface can be exploited to attach polymer bearing by aldehyde575 or activated esters, such as NHS,585 mercaptothiazoline214 or pentafluorophenyl activated esters.183 However, the activity of proteins is often diminished by the conjugation process,586 leading CAMD to develop a strategy for biodegradable bioconjugation allowing for a balance between polymer protection and the bioactivity of the protein.58221

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Scheme 21. Groups can be used to anchor polymers on IONP surfaces.

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Scheme 22. Modification of protein using grafting from (A) and to (B) approaches.

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Hoffman and coworkers587 reported on the modification of a thiol-terminal long peptide (used as an anticancer drug) using a PDS-terminal RAFT polymer. An in vitro study proved that the peptide polymer conjugates presented superior stability over the native peptide.

Recent work on polymer bioconjugation has been focused on more complex conjugates incorporating more than one biomolecule.168, 185, 229 Physiologically, protein activity can be regulated by the presence of another protein (or biomolecule). CAMD researchers synthesized heterofunctional polymers bearing azide and pyridyl disulfide termini,185 for conjugation to, BSA and avidin. In this approach the RAFT functionality is retained in the structure which may lead to cytotoxicity or immunogenic responses (dependent on the specific chemistry involved).588 Maynard and coworkers229 synthesized monofunctional biotin polymers using RAFT polymerization followed by the elimination of the RAFT end group using a radical cross-coupling reaction inspired by Perrier et al.279 yielding a heterofunctional polymer with one end terminated by biotin and the other end by maleimide function able to bind with streptavidin and BSA.229

A grafting from has also been developed for modification of proteins, with potential advantages for the production of enhanced purity protein-polymer conjugates. Indeed, only residual unreacted monomers and solvent need to be eliminated to obtain a pure protein-polymer conjugate. Maynard and coworkers579, 589 and Matyjaszewski and coworkers590 presented the first examples of “grafting from” using ATRP polymerization. However, the presence of copper and catalyst may limit the ATRP approach as the copper may complex with protein.

CAMD reported on the modification of protein using a RAFT agent able to control the polymerization of different monomers, such as OEG-A, NIPAAm, and HEA at room temperature in the presence of a gamma source227 or an azo-initiator.591 A RAFT agent bearing a pyridyl disulfide end group was developed, and then, successfully attached to the free thiol of bovine serum albumin (BSA) using a Z approach.185 The modification of protein using thermo-responsive polymers (such as poly(NIPAAm) mediated protein activity.591 Sumerlin and coworkers592 polymerized NIPAAm from BSA using a R approach, and then regulated enzymatic activity (i.e., esterase) of BSA with temperature variations. In both cases, the polymerization was well controlled, and narrow PDI was obtained. This grating from approach has also been successfully employed for the synthesis of hetero-functional conjugates (BSA-polymer-peptide).184

Protein-polymer conjugates obtained by a grafting-from methodology have been shown to exhibit improved pharmacokinetic and bioavability.593 Protein polymer conjugates are currently being investigated in more useful applications, for example, the modification of human growth hormone (rh-GH) by an ATRP initiator was demonstrated by Caliceti and coworkers594 The rh-GH PEG-MA conjugates were administered to rats and the activities were compared to native rh-GH. The rh-GH PEGMA exhibited similar activity as the native rh-GH in vivo when a daily dose of 40 μg was administered. However, when a higher dose of 120 μg was administered with 3 days between injections the bioavailability of the rh-GH PEGMA was significantly better than that of the native protein.

siRNA/DNA Polymer Conjugates

The potential for siRNA therapy has created enormous interest in the scientific literature.595 McCormick and coworkers combined poly(DMAEA-b-HPMA) copolymers obtained using RAFT polymerization with siRNA.146 This polyplex was shown to hinder the degradation of siRNA in serum. siRNA delivery was also promoted by the introduction of folic acid as a targeting moiety to improve complex cell uptake and targeting.141 Valade et al. synthesized a siRNA polyplex by combining RAFT polymerization and thiol-ene chemistry.102 Hoffman and coworkers596 made poly(DMAEA)-b-(n-BA) diblock copolymers able to complex siRNA and to simultaneously encapsulate doxorubicin by hydrophobic interactions. These diblock copolymers formed micelles, with a positively charged cationic poly(DMAEA) corona enabling siRNA condensation. To enhance cytosolic delivery through endosomal release, a pH-responsive copolymer of poly(styrene-alt-maleic anhydride) (pSMA) was electrostatically complexed to the positively charged siRNA/micelle to form a ternary complex. These structures were tested against ovarian cancer cells resistant to doxorubicin treatment. The combination of siRNA and doxorubicin demonstrated an efficacious synergetic effect.

Recently, a collaboration between Maynard and coworkers and CAMD231 resulted in the synthesis of siRNA polymer conjugates exploiting a pyridyl disulfide end group terminated poly(OEG-A). Maynard and coworkers597 synthesized the first siRNA-glycopolymer conjugates using a similar strategy. Another approach to siRNA conjugates was proposed using the modification of poly(AEA-b-HPMA) copolymers with carboxylic acid terminated pyridyl disulfide and folic acid for the introduction of targeting groups and pyridyl disulfide pendant groups on the backbone. Subsequently, the pyridyl disulfide pendant groups were successfully exploited for the attachment of siRNA.98 Finally, our group proposed the synthesis of α-sugar dendrimer, γ-pyridyl disulfide functionalized poly(HPMA). Pyridyl disulfide end group was successfully used to attach siRNA (Scheme 23).213 The presence of sugar dendrimer moiety confers to this polymer targeting properties.

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Scheme 23. siRNA conjugation to sugar terminated poly(HPMA) using pyridyl disulfide.

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Glycopolymers

Carbohydrates play a pivotal role in recognition processes in biology. They are involved in cell–cell trafficking, anti-inflammatory action, disease defence and many more, due to the specific interaction of certain carbohydrates with lectins.598, 599 In an effort to optimize these interaction significant research efforts have been dedicated to the synthesis of glycopolymers, synthetic polymers with pendant carbohydrates.600–602 From a simple beginning where vinyl functionalized sugars were polymerized in a noncontrolled manner with free radical polymerization,603 the synthesis of glycopolymers has now evolved to a more sophisticated level where molecular weight and architecture control do not represent an obstacle.604, 605 RAFT polymerization is a powerful tool for the synthesis of glycopolymer due to its robustness in the presence of functional groups. Indeed, the list of linear glycopolymers prepared by RAFT polymerization is extensive with glycopolymers prepared with good control based on glucose,606–609 mannose,610–612 glucoseamine,303, 306, 419, 611 fructose,613 galactose433, 522, 556, 614 and lactose.555, 615 A very elegant route to glycomonomers is via enzymatic synthesis, which was investigated in detail by CAMD, the enzymes ensuring high regio-selectivity in the six-position without recourse to protective chemistry.607, 609, 616, 617 RAFT polymerization can be performed in water, which is well suited to many glycopolymers,606 however, many researchers have opted for polymerization in organic solvents using protected and therefore oil-soluble glycomonomers (for characterization reasons).433, 608, 618, 619 In many cases unprotected glycomonomers were polymerized in aqueous solutions with the addition of a small amount of organic solvent to aid the solubility of the RAFT agent in water. Protected glycomonomer in conjunction with organic solvents have often been employed for the syntheses of amphiphilic block copolymers. A strong interest in amphiphilic glycopolymer structures for self-assembly into micelles has developed in recent years as a route to bioactive nanoparticles. Spherical micelles have been prepared from poly(3-O-methacryloyl-1,2:5,6-di-O-isopropylidine-D-glucofuranose)-b-polystyrene619 and from the thermo-responsive polymer, poly(N-acryloyl glucosamine)-b-poly(N-isopropyl acrylamide). Core-crosslinked thermo-responsive polymer led to micelles with changing hydrodynamic diameter upon temperature changes.303, 431 A block copolymer with poly(n-butyl acrylate) and poly(2-(β-D-galactosyloxy)ethyl methacrylate) prepared by Cameron et al.620 was found to have a strong tendency to form rod-like self-assembled aggregates. A similar result was observed by Pearson et al.427 The structure of self-assembly could be fine-tuned from micelles to rod simply by adjusting the size of the hydrophobic polymer. Thermo-responsive vesicles composed of poly(2-glucosyloxyethyl methacrylate)-b-poly (diethyleneglycol methacrylate) have also been described.621

Despite all the progress in the synthesis of complex architectures reports on glycol-star polymers using RAFT polymerization are limited. Three-306 and seven-arm303 glycopolymer stars have been described, with recommendations made on overcoming some experimental difficulties; viz, the insolubility of star RAFT agents was addressed by the addition of a few repeat units of 2-hydroxyethyl acrylate before the polymerization making the originally insoluble star RAFT agent water-soluble.

The combination of RAFT with click chemistry has widened the array of available glycopolymer structures further. A new block glycopolymer structure with poly(vinylacetate) was achieved using Cu(I) catalyzed Huisgen click chemistry.622 However, this click approach required a high percentage of end functionalized polymers, a prerequisite, which can be difficult considering the radical RAFT process and it's potential side reaction.

A very popular route to glycopolymers has emerged in the last 5 years using postfunctionalization. An array of chemistry has been employed to modify polymers with various sugars. Thioglucose was utilized in thiol-ene or thiol-bromine/chloride nucleophilic substitution reactions with block copolymers bearing pendant double bonds,104, 623 or chloride/bromine groups.108 Amino functionalized sugar compounds have been reacted in the presence of activated esters, such as pentafluorophenyl or NHS.556 The thiol/bromine approach was also successfully applied to prepare star polymers with high bioactivity towards lectins.624 Another interesting approach proposed by Narain and coworkers556 is the synthesis of glycopolymer using poly(2-aminoethyl methacrylamide) and D-gluconolactone. The authors successfully extended this method for the synthesis of glycomonomers.554

SURFACE MODIFICATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Preparation of Brushes on Inorganic and Organic Surfaces

RAFT polymerization has been achieved on different flat surfaces, such as polymer substrates, silica wafers, gold surface, and clays for several applications, such as membranes or biosensors.276, 625 The addition of polymers to surfaces of inorganic substrates modifies the surfaces and attaches functional groups, such as sugar moieties, biotin and amino groups. Baum and Brittain200 grafted PS, PMMA, and copolymers to the surface of silica wafers, via immobilization of an azo-initiator to the silica surface in the presence of RAFT agents. This method was further exploited by several groups to not only make a range of polymer modified silica surface, but also modified organic surfaces, such as PVDF or PDSM.626, 627

The direct attachment of RAFT agent, using R or Z groups, or the grafting of preformed RAFT-polymers has been used to modify the surface properties of different substrate.204, 383 Recently, the fabrication of smart surfaces able to respond to specific stimuli has been reported using thermo-responsive polymers, poly(NIPAAm) or PEG derived polymers, made by RAFT and ATRP.201, 628, 629 The presence of responsive polymers can be used to change the hydrophobicity of surfaces or reveal a specific function. CAMD researchers modified flat gold surfaces using a mixture of thermo-responsive PEG polymers (with a LCST around 37 °C) and biotin terminated PEG (non–thermo responsive) by the grafting onto method. By changing the temperature, biotin groups present at the surface were revealed or masked, and could be used to capture streptavidin present in the solution (Fig. 8).

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Figure 8. Modification of gold surface using thermo-responsive polymers: below the LCST, PEG polymer is chain extended and biotin groups were masked, while above the LCST, PEG polymer is contracted and exposed biotin group able to bind to adivin or streptadivin.

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Preparation of Honeycomb Films

Honeycomb structured porous films formation has been a research theme in CAMD over the last 10 years. First discovered by Francois and coworkers,630 it was observed that polystyrene star polymers and rod-coil block copolymers solutions yielded porous films with a regular hexagonal array of pores. These so-called honeycomb-structured porous films were the result of breath figure formation of water droplets, formed on the surface of a cold organic solvent. The polymer in solution encapsulate water droplets by instantaneous precipitation and, upon evaporation of solvent and water, the porous films form. The water droplets therefore act as templates in the process.4, 631, 632 While it was initially thought that star polymer architectures were required, it is known that films can now be prepared from a range of polymers.630, 633–645 After careful optimization of temperature, solution concentration, humidity and other processing parameter, the formation of porous films with a regular pore arrangement is possible from almost any polymer. Block copolymers, prepared easily via RAFT polymerization, enable the formation of honeycomb structured films with a porous microstructure and a superimposed nanostructure. Amphiphilic block copolymers can result in films with a hydrophobic surface and hydrophilic pores.646–648 Honeycomb structured porous films prepared from PSt-b-poly(2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glactosyloxy)ethyl methacrylate have a significant enrichment of glycopolymer within the pores. Subsequent conjugation to lectins leads to the specific placement of lectins inside the pores only.433 In a similar approach, a biotin derivative was reacted with polyacrylic acid, which was located inside the pores. Subsequent immobilization of streptavidin allowed for immobilization of biotin labeled bacteria inside the pores (Fig. 9).648 The RAFT process has also found use in the surface modification of honeycomb structured porous films.646, 649

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Figure 9. Synthetic approach to a streptavidin microarray with immobilization of Steptavidin selectively in the pores followed by fixation of biotin labeled E. coli bacteria.648

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CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

One of the major obstacles to the adoption of RAFT polymerization was the easy accessibility of RAFT agents. This obstacle has now been solved by the commercialization of a large range of RAFT agents, for example, dithioesters, trithiocarbonates and xanthates, allowing for the polymerization of a large range of monomers from vinylic to methacrylic monomers. The price of RAFT agents can still be a commercial limitation, but this is predicted to become a lessening issue as with experience and scale up, the price should decrease, creating a very competitive process for the production of well-defined polymers without requirements for change in established industrial plant.

The benefits of controlled radical polymerization are most likely to be maximized and therefore most likely to be realized for complex niche applications such as nanomedicine (for example) and the initial work (described herein) on protein and RNA conjugates has enormous promise for making more complex hybrid materials bringing together synthetic drugs, proteins, peptides and DNA based materials into single molecules. In a similar approach complex inorganic/organic nanoparticles will be combined with biomolecules to form so-called multimodal nanoparticles combining therapeutic delivery with targeting and imaging capability, and the latest papers in the scientific literature are presaging advances in this area.

Finally, a unique advantage of RAFT polymer is the possibility to transform the thiocarbonylthio into thiol end groups. The thiol group is one of the most powerful functions in organic chemistry with the ability to react with a large range of reactants, such as maleimide, (meth)acrylate, epoxy, halide, isocyanate, isothiocyanate, ene, yne, carboxylic acid. This provides a strong opportunity to combine controlled radical polymerization with click chemistry to generate entire libraries of new materials. It is also interesting to note that thiol chemistry is often employed by biologists to modify proteins, peptides and biomolecules in general using organic compounds or macromolecules.650 In addition, using this thiol-based approach it is possible to design and build biodegradable structures of particular utility for bio-applications.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

The authors thank the members of the CSIRO team who invented RAFT polymerization: Ezio Rizzardo who co-supervised with T.P.D., the initial CAMD, PhD student on RAFT (John Quinn) and helped T.P.D. to establish his work on RAFT mechanism at UNSW. Graeme Moad and Richard Evans who also co-supervised PhD students, and San Thang for helping in our initial RAFT work (back in 1998! helping T.P.D. synthesize block copolymers of phosphoryl choline monomers) for biological applications. They also thank the numerous Honours and PhD students and postdoctoral fellows who have worked at CAMD on RAFT related research (too many to specify – sorry!). They acknowledge Tony Fane at the UNESCO Membrane Centre at UNSW for collaborating on the honeycomb film research project established by T.P.D. in the late 1990s. They also thank John Foster (Biological Sciences, UNSW) who collaborated on the enzymatic synthesis of glycomonomers within the glycopolymer research program established by T.P.D. in 2000. This work was supported by the Australian Research Council for continued support both in terms of project support and Fellowships, Australian Professorial Fellowship and Federation Fellowship (to T.P.D.), Future Fellowship (to M.H.S.), and Postdoctoral Fellowship (to C.B.). Significant early funding (to T.P.D.) was sponsored by the ICI Strategic Research Fund (through Derek Irvine), supporting all the initial RAFT research at CAMD from 1999–2004, and the UNSW Capital fund (to T.P.D.) for establishing all the CAMD laboratories and for the ESI mass spectrometry facility.

REFERENCES AND NOTES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information

Biographical Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
Thumbnail image of

Cyrille Boyer

Cyrille Boyer received his Ph.D. in polymer chemistry, in 2005 from the University of Montpellier II. His Ph.D. was in collaboration with Solvay-Solexis and devoted at the synthesis of new graft copolymers using grafting “to”, under the supervision of Profs. B. Boutevin and J.J. Robin. In 2005, he undertook a post-doctorate position with Dupont Performance and Elastomers (Willmington, United States) dealing with the synthesis of original fluorinated elastomers using controlled radical polymerization (e.g., iodine transfer polymerization). In October 2006, he joined the Centre for Advanced Macromolecular Design (CAMD) as a senior research fellow under the direction of Prof. Tom Davis. In 2009, he got an Australian Post-Doctoral Fellowship. His research interests mainly cover the preparation of well-defined polymers, protein-polymer conjugates, and hybrid organic–inorganic nanoparticles using controlled radical polymerization. He has co-authored over 65 peer-reviewed research papers, including two book chapters, and two international patents.

Biographical Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
Thumbnail image of

Martina Stenzel

Martina Stenzel studied chemistry at the University of Bayreuth, Germany, before completing her Ph.D. in 1999 at the Institute of Applied Macromolecular Chemistry, University of Stuttgart, Germany. With a DAAD scholarship (German Academic Exchange Service) in her pocket, she started working as a postdoctoral Fellow at the UNESCO Centre for Membrane Science and Technology at the University of New South Wales (UNSW), Sydney, Australia. In 2002, she took on a position as a lecturer at the University of New South Wales and worked within the Centre for Advanced Macromolecular Design (CAMD) on complex polymer architectures via RAFT polymerization and honeycomb structured porous films. In 2007, she got promoted as Associate Professor. In 2008, she obtained a prestigious ARC Future Fellowship. Her research interest is focused on the synthesis of functional polymers with complex architectures such as glycopolymers and other polymers for biomedical applications, especially polymers with in-build metal complexes for the delivery of metal-based anticancer drugs. Martina Stenzel published more than 150 peer reviewed papers mainly on RAFT polymerization and five book chapters. She is currently the chair of the Polymer division of the Royal Australian Chemical Institute (RACI) and editor of the Australian Journal of Chemistry.

Biographical Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RAFT POLYMERIZATION
  5. SYNTHESIS OF WELL-CONTROL POLYMER ARCHITECTURE USING RAFT POLYMERIZATION
  6. NANOMATERIAL SYNTHESES
  7. POLYMERS FOR BIOAPPLICATIONS
  8. SURFACE MODIFICATION
  9. CONCLUSION ON THE FUTURE OF RAFT POLYMERIZATION FOR NANOMATERIALS
  10. Acknowledgements
  11. REFERENCES AND NOTES
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
Thumbnail image of

Tom Davis

Tom Davis has been an academic at UNSW for 17 years following a stint in industry as a research manager at ICI in the UK. He has co-authored 325+ refereed papers, patents, and book chapters. He is the founding Director of the Centre for Advanced Macromolecular Design (CAMD) at UNSW–where he initiated and built up significant research programs in free radical polymerization (pulsed-laser polymerization); copolymerization mechanism; catalytic chain transfer, RAFT kinetics, mechanism, and synthesis of complex architectures (stars, microgels, blocks, etc); honeycomb films from breath figures; glycopolymers and enzymatic synthesis; biodegradable polymers; soft ionization mass spectrometry of polymers (MALDI and ESI); polymer–protein hybrids and hybrid nanoparticles. He is also a visiting Professor at the Institute for Materials Research & Engineering (IMRE) in Singapore. In 2005 he was awarded a Federation Fellowship by the Australian Research Council. He serves on the editorial advisory boards of Macromolecules, Journal of Polymer Science, Australian Journal of Chemistry, Journal of Materials Chemistry, Journal of Macromolecular Science – Reviews, and Polymer Chemistry.