Functional Reversible Addition-fragmentation Chain Transfer Research Articles

Octreotide end-functionalized diblock copolymers facilitated by RAFT polymerization

The incorporation of biologically active targeting ligands into polymeric materials is a key challenge in drug delivery and bioimaging. Reported here is the synthesis of diblock copolymers end-functionalized with the Somatostatin analog Octreotide. This methodology employs a novel Octreotide functional reversible addition-fragmentation chain transfer (RAFT) polymerization chain transfer agent, which is used to mediate the polymerization of N-isopropylacrylamide and subsequent chain-extension with N,N-dimethylacrylamide.

Cyclopropenone-masked dibenzocyclooctyne end-functionalized polymers from reversible addition-fragmentation chain transfer polymerization

Functional reversible addition-fragmentation chain transfer polymerization (RAFT) agent was developed to have a cyclopropenone-masked dibenzocyclooctyne end group. RAFT polymerization was then explored on three typical types of vinyl monomers in free radical polymerization such as styrene, methyl methacrylate, and tert-butyl acrylate. The living polymerization behaviors were demonstrated for all three cases, which guaranteed the production of well-defined polystyrene, poly (methyl methacrylate), and poly (tert-butyl acrylate) end-functionalized with cyclopropenone-masked dibenzocyclooctyne groups from the convenient RAFT polymerization technique. Under UV irradiation, the cyclopropenone-masked dibenzocyclooctyne end group could be quantitatively changed to dibenzocyclooctyne clickable group, which was widely used in the metal-free strain-promoted azide-alkyne cycloaddition (SPAAC) click reaction. Subsequently, using the dibenzocyclooctyne end-functionalized polymers as building blocks, a practical and efficient metal-free method was developed for the formation of topological polymers including block and bottlebrush polymers based on the SPAAC click reaction.

Poly(bromoethyl acrylate): A Reactive Precursor for the Synthesis of Functional RAFT Materials

Postpolymerization modification has become a powerful tool to create a diversity of functional materials. However, simple nucleophilic substitution reactions on halogenated monomers remains relatively unexplored. Here we report the synthesis of poly(bromoethyl acrylate) (pBEA) by reversible addition–fragmentation chain transfer (RAFT) polymerization to generate a highly reactive polymer precursor for postpolymerization nucleophilic substitution. RAFT polymerization of BEA generated well-defined homopolymers and block copolymers over a range of molecular weights. The alkylbromine-containing homopolymer and block copolymer precursors were readily substituted by a range of nucleophiles in good to excellent conversion under mild and efficient reaction conditions without the need of additional catalysts. The broad range of nucleophilic species that are compatible with this postmodification strategy enables facile synthesis of complex functionalities, from permanently charged polyanions to hydrophobic polythioe...

Polymer Functional Nanodiamonds by Light-Induced Ligation

A light-triggered strategy to functionalize nanodiamonds (NDs) with well-defined functional polymers is presented. The employed grafting approach is based on o-methylbenzaldehydes, which upon UV irradiation form o-quinodimethanes that undergo Diels–Alder reactions with dienophiles. A series of well-defined maleimide end-group functional polymers, i.e., poly(styrene) (Mn = 5800 g mol–1; Đ = 1.2), poly(N-isopropylacrylamide) (Mn = 5800 g mol–1, Đ = 1.2), and poly(2-(2′,3′,4′,6′-tetra-O-acetyl-α-d-mannosyloxy)ethyl methacrylate) (Mn = 24 300, 39 000, and 58 800 g mol–1, Đ ≤ 1.3), were prepared via reversible addition–fragmentation chain transfer (RAFT) polymerization of protected maleimide functional RAFT agents. After deprotection of the furan-protected maleimide end groups, the polymers were photografted to o-methylbenzaldehyde functional NDs and characterized in detail via infrared (IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). The grafting density decreas...

Self-healing polymers based on a photo-active reversible addition-fragmentation chain transfer (RAFT) agent

A symmetric photo-active trithiocarbonate was designed and synthesized, which can act not only as a functional reversible addition-fragmentation chain transfer (RAFT) agent, but also as a crosslinker in crosslinking poly(methyl methacrylate-co-hydroxy ethyl acrylate) (poly(MMA-co-HEA)) due to interactions of benzophenone moieties of trithiocarbonate and hydroxyl groups of poly(MMA-co-HEA) under UV irradiation. In addition, the crosslinked poly(MMA-co-HEA) demonstrates photo-promoted self-healing properties by reshuffling C-S bonds of trithiocarbonate.

A facile “graft from” method to prepare molecular‐level dispersed graphene–polymer composites

AbstractGraphene–polymer composites of positive‐charged poly(dimethyl aminoethyl acrylate), negative‐charged poly(acrylic acid), and neutral polystyrene were prepared by “graft from” methodology using reversible addition fragmentation chain transfer (RAFT) polymerization via a pyrene functional RAFT agent (PFRA) modified graphene precursor. Fluorescence spectroscopy and attenuated total reflection infrared (ATR‐IR) evidenced that the PFRA was attached on the graphene basal planes by π–π stacking interactions, which is strong enough to anti‐dissociation in the polymerization mixture up to 80°C. Atomic force microscopy (AFM) revealed that the thickness of a graphene–polymer sheet was about 4.0 nm. Graphene composites of different polymers with the same polymerization degree exhibited similar conductivity; however, when the polymer chain was designed as random copolymer the conductivity was significantly decreased. It was also observed that the longer the grafted polymer chains the lower the conductivity. ATR‐IR spectroscopy and thermogravimetric analysis were also performed to characterize the as‐prepared composites. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

In vivo targeting of alveolar macrophages via RAFT-based glycopolymers

Targeting cell populations via endogenous carbohydrate receptors is an appealing approach for drug delivery. However, to be effective, this strategy requires the production of high affinity carbohydrate ligands capable of engaging with specific cell-surface lectins. To develop materials that exhibit high affinity towards these receptors, we synthesized glycopolymers displaying pendent carbohydrate moieties from carbohydrate-functionalized monomer precursors via reversible addition-fragmentation chain transfer (RAFT) polymerization. These glycopolymers were fluorescently labeled and used to determine macrophage-specific targeting both in vitro and in vivo. Mannose- and N-acetylglucosamine-containing glycopolymers were shown to specifically target mouse bone marrow-derived macrophages (BMDMs) in vitro in a dose-dependent manner as compared to a galactose-containing glycopolymer (30- and 19-fold higher uptake, respectively). In addition, upon macrophage differentiation, the mannose glycopolymer exhibited enhanced uptake in M2-polarized macrophages, an anti-inflammatory macrophage phenotype prevalent in injured tissue. This carbohydrate-specific uptake was retained in vivo, as alveolar macrophages demonstrated 6-fold higher internalization of mannose glycopolymer, as compared to galactose, following intratracheal administration in mice. We have shown the successful synthesis of a class of functional RAFT glycopolymers capable of macrophage-type specific uptake both in vitro and in vivo, with significant implications for the design of future targeted drug delivery systems.

Manipulation of the bioactivity of glucose oxidase via raft‐controlled surface modification

AbstractIn this article, poly[poly(ethyleneglycol) acrylate] (polyPEG‐A) with mercaptothiazoline ester terminal group was synthesized directly by reversible addition fragmentation chain transfer (RAFT) polymerization using a mercaptothiazoline ester functional RAFT agent. The functional polyPEG‐A was then conjugated to glucose oxidase (GOx) via surface‐tethered amino groups through covalent amide coupling. Sorensenformaltitration assay revealed that GOx retained ∼14 free amino groups available for covalent modification. The conjugation reaction turned out to be efficient and mild. Colorimetric method was applied to evaluate the enzymatic activity of native GOx and its derivatives by introducing another enzyme, horseradish peroxidase. The modified GOx with polymeric chains exhibited reduced enzymatic activity toward the catalytical oxidation of glucose, but with significantly increased thermal stability and elongated lifetime. When GOx was modified with polyPEG‐A [molecular weight (MW), 45,000; polydispersity index, 1.12] the enzymatic activity was decreased to 37 U/mg, only 29% left. However, when incubated at 25 °C the modified GOx still retained 9.6% of its original bioactivity after 60 days, whereas the native GOx only lived for 29 days. The more polymer chains or the longer polymer chain attached, the more reduction of the enzymatic activity resulted, however, the longer the lifetime of the enzyme obtained. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Poly(dimethylsiloxane-b-styrene) diblock copolymers prepared by reversible addition-fragmentation chain transfer polymerization: Kinetic model

Well-defined polydimethylsiloxane-block-polystyrene (PDMS-b-PS) diblock copolymers were prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization using a functional PDMS-macro RAFT agent. The RAFT polymerization kinetics was simulated by a mathematical model for the RAFT polymerization in a batch reactor based on the method of moments. The model described molecular weight, monomer conversion, and polydispersity index as a function of polymerization time. Good agreements in the polymerization kinetics were achieved for fitting the kinetic profiles with the developed model. In addition, the model was used to predict the effects of initiator concentration, chain transfer agent concentration, and monomer concentration on the RAFT polymerization kinetics. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

RAFT-synthesized graft copolymers that enhance pH-dependent membrane destabilization and protein circulation times

Here we describe a new graft copolymer architecture of poly(propylacrylic acid) (polyPAA) that displays potent pH-dependent, membrane-destabilizing activity and in addition is shown to enhance protein blood circulation kinetics. PolyPAA containing a single telechelic alkyne functionality was prepared via reversible addition–fragmentation chain transfer (RAFT) polymerization with an alkyne–functional chain transfer agent (CTA) and coupled to RAFT polymerized poly(azidopropyl methacrylate) (polyAPMA) through azide-alkyne [3 + 2] Huisgen cycloaddition. The graft copolymers become membrane destabilizing at endosomal pH values and are active at significantly lower concentrations than the linear polyPAA. A biotin terminated polyPAA graft copolymer was prepared by grafting PAA onto polyAPMA polymerized with a biotin functional RAFT CTA. The blood circulation time and biodistribution of tritium labeled avidin conjugated to the polyPAA graft copolymer was characterized along with a clinically utilized 40 kDa branched polyethylene glycol (PEG) also possessing biotin functionalization. The linear and graft polyPAA increase the area under the curve (AUC) over avidin alone by 9 and 12 times, respectively. Furthermore, polyPAA graft copolymer conjugates accumulated in tumor tissue significantly more than the linear polyPAA and the branched PEG conjugates. The collective data presented in this report indicate that the polyPAA graft copolymers exhibit robust pH-dependent membrane-destabilizing activity, low cytotoxicity, significantly enhanced blood circulation time, and increased tumor accumulation.

Synthesis of polydimethylsiloxane‐containing block copolymers via reversible addition fragmentation chain transfer (RAFT) polymerization

AbstractLow polydispersity polydimethylsiloxane (PDMS) was end functionalized with a reversible addition fragmentation chain transfer (RAFT) agent by the esterification of hydroxyl terminated PDMS with a carboxylic acid functional RAFT agent. These PDMS‐RAFT agents were able to control the free radical polymerization of styrene and substituted styrene monomers to produce PDMS‐containing block copolymers with low polydispersities and targeted molecular weights. A thin film of polydimethylsiloxane‐block‐polystyrene was prepared by spin coating and exhibited a microphase separated morphology from scanning force microscopy measurements. Controlled swelling of these films in solvent vapor produced morphologies with significant long‐range order. This synthetic route will allow the straightforward production of PDMS‐containing block copolymer libraries that will be useful for investigating their thin film morphological behavior, which has applications in the templating of nanostructured materials.© 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Solubilization of quantum dot with new double functional reversible addition–fragmentation chain transfer reagents

To improve dispersion property of alkyl chain modified-quantum dot (QD), we prepared new surfactants with polymerization initiator for surface modification of the QD. That is, sodium 2-alkylsulfanylthiocarbonylsulfanyl-2-methyl propionate with various alkyl chain length (C8, C10, C12, C14, and C16). These compounds also have a specific functional group, which has potential to initiate reversible addition–fragmentation chain transfer (RAFT) polymerization with various vinyl monomers. So, we investigated the relation between chain length of these double functional RAFT reagents and critical micelle concentration (CMC), and the solubilization ability for QD (emission wavelength: 605 nm). As a result, the CMC depended on the chain length and the RAFT reagents with C12 and C14 chains indicated high solubilization abilities for QD due to their good hydrophilic–lipophilic balance.

End-Functionalized Polymers and Junction-Functionalized Diblock Copolymers Via RAFT Chain Extension with Maleimido Monomers

A new strategy is described for functionalizing the omega-terminal end of polymers synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization that provides spatially controlled bioconjugation sites. Traditional methods for preparing omega-functional polymers require the reduction of the RAFT chain-transfer agent to yield secondary or tertiary thiols of low reactivity or the synthesis of novel chain-transfer agents that contain reactive groups. As an additional strategy, N-substituted maleimido monomers have been used in a modified block polymerization to add a single maleimido unit onto the RAFT polymer with nearly quantitative efficiency. Unique reactive groups contained in the N-substituent are thereby added to the omega-terminal end of the polymer and are subsequently available for conjugation reactions. This technique has been demonstrated using N-(2-aminoethyl)maleimide trifluoroacetate to introduce a single primary amine to the omega-terminus of poly(dimethylaminoethyl methacrylate) and poly(N-isopropyl acrylamide) and to a specialized block copolymer for siRNA delivery. Evidence for retention of functional RAFT endgroups is provided by synthesis results where chain-extended polyDMAEMA (M(n) = 10 600 g/mol, M(w)/M(n) = 1.14) was used as a macro chain transfer agent for the polymerization of styrene, yielding a diblock polymer of low polydispersity (M(n) = 20 300 g/mol, M(w)/M(n) = 1.11). It is thus also possible to construct diblock copolymers with a bioconjugation site precisely located at the junction between the two blocks. The chain-extended polymers are functionalized with an amine-reactive fluorescent dye or folic acid at conjugation efficiencies of 86 and 94%, respectively. The versatile chain-extension technique described here offers unique opportunities for the synthesis of well-defined polymeric conjugates to molecules of biological and targeting interest.

A new approach to 3-miktoarm star polymers using a combination of reversible addition–fragmentation chain transfer (RAFT) and ring opening polymerization (ROP) via “Click” chemistry

The synthesis of AB 2-type miktoarm star polymers using a combination of reversible addition–fragmentation chain transfer (RAFT), ring opening polymerization (ROP) and “Click” chemistry was demonstrated in this work. An azide functional RAFT agent was used to polymerize butyl acrylate, polyethylene glycol acrylate and N-isopropylacrylamide monomers. Propargylamine was reacted with glycerine carbonate to obtain a dihydroxy functional alkyne compound which was used for the ring opening polymerization of ɛ-caprolactone (ɛ-CL) and lactide. The resulting alkyne functional polycaprolactone (PCL) and polylactide (PLA) polymers were reacted with azide functional polymers in the presence of copper bromide (CuBr) catalyst to obtain miktoarm star polymers. The polymers were characterized by gel permeation chromatography (GPC), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. The star polymers had low polydispersity (∼1.3) with well-defined structures. These polymers have a number of potential applications including crosslinking agents for polyurethane (PU) coatings for biodegradable and fouling release applications.

Controllable Nanostructured Surface Modification on Quantum Dot for Biomedical Application in Aqueous Medium

To develop biocompatible polymer modification method on a quantum dot (QD) surface, we have studied poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) grafting on trioctylphosphine oxide (TOPO)-coated QD (CdSe/ZnS) surface using new strategy with a double functional reversible addition-fragmentation chain transfer (RAFT) agent. Sodium 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionate (DMP-Na) was focused and prepared as the double functional RAFT agent. As the first function, the DMP-Na possessed surface activity that forms micelle in aqueous solution and solubilize the TOPO-coated QD into the solution. The DMP-Na indicated critical micelle concentration (CMC) from surface tension measurement in an aqueous medium. Over CMC, the QD was able to be solubilized into DMP-Na micelle and showed multicolor fluorescence spectra with narrow full-width at half maximum (FWHM) corresponding to diameter of the QD. Additionally, as the second function, the DMP-Na possessed chain transfer agent ability that synthesizes a poly(MPC)-grafted QD in an aqueous medium. In this strategy, fluorescence properties with narrow FWHM and peak top did not change before and after solubilization into the DMP-Na micelle aqueous solution and even after polymerization of the MPC initiated from the DMP-Na. The poly(MPC)-modified QD showed good biocompatibility based on the poly(MPC) properties, and was able to suppress uptake by HeLa cells despite diameter of the poly(MPC)-modified QD was approximately 12 nm.

A polarity-activation strategy for the high incorporation of 1-alkenes into functional copolymersvia RAFT copolymerization

A new synthetic methodology for the preparation of copolymers having high incorporation of 1-alkene together with multifunctionalities has been developed by polarity-activated reversible addition-fragmentation chain transfer (RAFT) copolymerization. This approach provides well-defined alternating poly(1-decene-alt-maleic anhydride), expanding the monomer types for living copolymerizations. Although neither 1-decene (DE) nor maleic anhydride (MAn) has significant reactivity in RAFT homopolymerization, their copolymers have been synthesized by RAFT copolymerizations. The controlled characteristics of DE-MAn copolymerizations were verified by increased copolymer molecular weights during the copolymerization process. Ternary copolymers of DE and MAn, with high conversion of DE, could be obtained by using additive amounts (5 mol %) of vinyl acetate or styrene (ST), demonstrating further enhanced monomer reactivities and complex chain structures. When ST was selected as the third monomer, copolymers with block structures were obtained, because of fast consumption of ST in the copolymerization. Moreover, a wide variety of well-defined multifunctional copolymers were prepared by RAFT copolymerizations of various functional 1-alkenes with MAn. For each copolymerization, gel permeation chromatography analysis showed that the resulting copolymer had well-controlled Mn values and fairly low polydispersities (PDI = 1.3–1.4), and 1H and 13C NMR spectroscopies indicated strong alternating tendency during copolymerization with high incorporation of 1-alkene units, up to 50 mol %. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 3488–3498, 2008

Facile one pot synthesis of a range of reversible addition–fragmentation chain transfer (RAFT) agents

The application of a universal synthetic strategy for the high yielding and facile synthesis of a wide range of functional RAFT agents including trithiocarbonates, xanthates and dithiocarbamates is described.

Poly(N-isopropylacrylamide) hydrogels with improved shrinking kinetics by RAFT polymerization

Functional poly(N-isopropylacrylamide) (PNIPAM) hydrogels were prepared by reversible addition fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAM) in the presence of N,N-methylenebisacylamide (BIS) as a cross-linker and 4-cyanopentanoic acid dithiobenzoate as chain transfer reagent (CTA). The swelling behaviors were investigated and the hydrogels by RAFT polymerization (RAFT gels) showed accelerated shrinking kinetics and higher swelling ratio comparing with conventional hydrogel (CG). It could be attributed to the presence of dangling chains mainly caused by CTA, which could retard the crosslinking reaction rate greatly. Another CTA, 3-(trithiocarbonyl) propanoic acid, was adopted to further investigate the effect of CTA. It showed the similar effect except the different accelerated degree to the shrinking kinetics. Furthermore, the living character of the RAFT process was used to polymerize a new batch of monomer (NIPAM) from functional RAFT gels to introduce grafted structure. The PNIPAM-g-PNIPAM hydrogels indicted further accelerated shrinking kinetics than functional backbone hydrogels.