Successive Reversible Addition-fragmentation Chain Transfer Research Articles

Angiopep2-Conjugated Star-Shaped Polyprodrug Amphiphiles for Simultaneous Glioma-Targeting Therapy and MR Imaging.

The development of valuable theranostic agents for overcoming the blood-brain barrier (BBB) to achieve efficient imaging-guided glioma-targeting delivery of therapeutics remains a great challenge for personalized glioma therapy. We herein developed a novel functional star-shaped polyprodrug amphiphile (denoted as CPP-2) via a combination of successive reversible addition-fragmentation chain transfer (RAFT) polymerization and click functionalization. In a diluted solution, the star amphiphile existed as structurally stable unimolecular micelles, containing hydrophobic cores conjugated with reduction-responsive camptothecin prodrugs Camptothecin (CPT) prodrug monomer (CPTM) and a tertiary amine monomer (2-(diethylamine) ethyl methacrylate, DEA) and hydrophilic oligo-(ethylene glycol) monomethyl ether methacrylat (OEGMA) outer coronas covalently decorated with dual-targeting moieties Angiopep2 (ANG) and small magnetic resonance imaging (MRI) contrast agents DOTA-Gd. In vitro and in vivo data in this study demonstrated that the ANG-modified micelles were capable of efficiently penetrating the BBB and delivering loaded cargoes such as CPT and Gd3+ contrast agents to glioma cells, leading to a considerably enhanced t1 relaxivity as well as antiglioma efficacy. Simultaneously, the targeted antiglioma efficacy and noninvasive MR imaging for a visualized therapy were realized. These collective findings augured well for the star polyprodrug amphiphiles to be utilized as a novel theranostic platform for clinical application in glioma therapy.

Dual Orthogonal Switching of the “Schizophrenic” Self-Assembly of Diblock Copolymers

Based on diblock copolymers, a pair of “schizophrenic” micellar systems is designed by combining a nonionic and thermoresponsive block with a zwitterionic block, which is thermoresponsive and salt-sensitive. The nonionic block is poly(N-isopropylacrylamide) (PNIPAM) or poly(N-isopropylmethacrylamide) (PNIPMAM) and exhibits a lower critical solution temperature (LCST) behavior in aqueous solution. The zwitterionic block is a polysulfobetaine, i.e., poly(4-((3-methacrylamidopropyl)dimethylammonio)butane-1-sulfonate) (PSBP), and has an upper critical solution temperature (UCST) behavior with the clearing point decreasing with increasing salt concentration. The PSBP-b-PNIPAM and PSBP-b-PNIPMAM diblock copolymers are prepared by successive reversible addition–fragmentation chain transfer (RAFT) polymerizations. The PSBP block is chosen such that the clearing point of the homopolymer is significantly higher in pure water than the cloud point of PNIPAM or PNIPMAM. Using turbidimetry, 1H NMR, and small-angle neut...

PHEA-g-PMMA Well-Defined Graft Copolymer: ATRP Synthesis, Self-Assembly, and Synchronous Encapsulation of Both Hydrophobic and Hydrophilic Guest Molecules

A series of well-defined amphiphilic graft copolymer bearing a hydrophilic poly(2-hydroxyethyl acrylate) (PHEA) backbone and hydrophobic poly(methyl methacrylate) (PMMA) side chains was synthesized by successive reversible addition-fragmentation chain transfer (RAFT) polymerization and atom transfer radical polymerization (ATRP) through the grafting-from strategy. A well-defined PHEA-based backbone with Cl-containing ATRP initiating group in every repeated unit (Mw/Mn = 1.08), poly(2-hydroxyethyl 2-((2-chloropropanoyloxy)methyl)acrylate) (PHECPMA), was first prepared by RAFT homopolymerization of 2-hydroxyethyl 2-((2-chloropropanoyloxy)methyl)acrylate (HECPMA), a Cl-containing trifunctional acrylate. ATRP of methyl methacrylate was subsequently initiated by PHECPMA homopolymer to afford the target well-defined poly(2-hydroxyethyl acrylate)-graft-poly(methyl methacrylate) (PHEA-g-PMMA) graft copolymers (Mw/Mn ≤ 1.36) with 34 PMMA side chains and 34 pendant hydroxyls in PHEA backbone using CuCl/dHbpy as catalytic system. The critical micelle concentration (cmc) of the obtained graft copolymer was determined by fluorescence spectroscopy using N-phenyl-1-naphthylamine as probe while micellar morphologies in aqueous media were visualized by transmission electron microscopy. Interestingly, PHEA-g-PMMA graft copolymer could self-assemble into large compound micelles rather than common spherical micelles, which can encapsulate hydrophilic rhodamine 6 G and hydrophobic pyrene separately or simultaneously.

Synthesis of hyperbranched polymers and hyperbranched block copolymers through “A2 + B3” click reaction

Long-chain hyperbranched and hyperbranched block polymers were synthesized through Cu catalyzed azide-alkyne cycloaddition (CuAAC) of A2 macromonomers with two alkyne groups and B3 coupling reagent with three azide groups. Polystyrene (PSt) homopolymers and block copolymers of styrene and butyl acrylate (P(St-b-BA-b-St)) with two alkyne groups were obtained via reversible addition-fragmentation chain transfer (RAFT) polymerization using a RAFT agent with two alkyne groups, S, S′-bis(α, α′-dimethyl – α″-propargyl acetate) trithio carbonate (BPTTC). Besides, the hyperbranched block copolymers were also prepared through the successive RAFT polymerization of BA with the hyperbranched PSt as RAFT agents. The evidence of 1H NMR, IR and GPC-Viscosity-MALLS measurements conformed the structure of the polymers. Dpws, the ratio of the weight average molecular weights of the hyperbranched polymers to those of the macromonomers, reached above 60 at most, calculated from MALLS measurement, which showed a high degree of the coupling reaction. The degree of branched of the hyperbranched polymers kept on increasing with the reaction time, according to the branching factor, g′.

Synthesis and self-assembly of temperature-responsive copolymers based on N-vinylpyrrolidone and triethylene glycol methacrylate.

Polyvinylpyrrolidone (PVP) is a biocompatible, water-soluble polymer with unique physicochemical properties and attractive biological features that has found widespread use in several industries. Owing to advances in controlled polymerisation techniques, PVP can be easily synthesised with robust control over its architecture. However, the synthesis of PVP copolymers, which can allow tailoring of its properties and expand the scope of this polymeric material, is challenging and rarely reported. Here, we demonstrate the synthesis of well-defined, temperature-responsive polyvinylpyrrolidone-co-poly(triethylene glycol methacrylate) (PVP-co-pTEGMA) block copolymers via successive Reversible Addition-Fragmentation chain Transfer (RAFT) and Activators ReGenerated by Electron Transfer Atom Transfer Radical Polymerisation (ARGET-ATRP) techniques. We show that PVP-co-pTEGMA block copolymers display temperature-responsive behaviour and self-assemble above their cloud point temperature (Tcp) to form spherical nanostructures of 100-200 nm in diameter. Finally, we demonstrate stabilisation of these assemblies below their Tcp by cross-linking through the PVP block.

Facile RAFT synthesis of side-chain amino acids containing pH-responsive hyperbranched and star architectures

This work reports the design and synthesis of amino acid-based hyperbranched polymers via the combination of self-condensing vinyl polymerization (SCVP) and reversible addition–fragmentation chain transfer (RAFT) polymerization from tert-butyl carbamate (Boc)-L-valine acryloyloxyethyl ester (Boc-Val-HEA) and S-(4-vinyl)benzyl S′-butyltrithiocarbonate (VBBT) with variable degrees of branching (DB), molecular weights (Mn), and chain end functionalities. Copolymerization kinetics reveal that the molecular weight increases and the DB decreases linearly with time as the branch length increases with the conversion of the Boc-Val-HEA monomer. These hyperbranched polymers, P(Boc-Val-HEA-co-VBBT), with tuneable Mn and DB have been further employed via successive RAFT polymerizations for the synthesis of star polymers with variable arm numbers and lengths. The removal of Boc groups from the polymers results in water soluble pH-responsive cationic hyperbranched architectures with tuneable pH responsiveness, differing from 6.8–7.5 due to the incorporation of various degrees of hydrophobic chain end functionalities with the variation of monomer feed compositions. Dynamic light scattering (DLS), atomic force microscopy (AFM) and scanning electron microscopy (SEM) reveal the interesting self-assembly of the Boc-deprotected star polymers in aqueous media with amino acid-based cores and water soluble thermoresponsive arms. Below the hydrophilic to hydrophobic transition pH and temperature, star polymers remain as unimers in aqueous solution. However, above the transition pH (and below the transition temperature), they form multi-micellar aggregates, which further fuse together to form larger aggregates above the transition temperature.

TBCPMA: a new trifunctional acrylic monomer for convenient synthesis of a well-defined amphiphilic graft copolymer by successive RDRP

A series of well-defined amphiphilic graft copolymers, consisting of a hydrophobic poly(tert-butyl acrylate) backbone and hydrophilic poly(N-isopropylacrylamide) side chains, were synthesized by successive reversible addition–fragmentation chain transfer (RAFT) polymerization and supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP) in the presence of Cu(0). A new Cl-containing acrylate monomer, tert-butyl 2-((2-chloropropanoyloxy)methyl)acrylate, was first RAFT homopolymerized in a controlled way to give a well-defined homopolymer with a narrow molecular weight distribution (Mw/Mn = 1.10). This homopolymer directly initiated SARA ATRP of N-isopropylacrylamide to afford well-defined poly(tert-butyl acrylate)-g-poly(N-isopropylacrylamide) (PtBA-g-PNIPAM) graft copolymers (Mw/Mn ≤ 1.30) via the grafting—from a strategy without polymeric functionality transformation to introduce the initiating group. Finally, the hydrophobic PtBA backbone was selectively hydrolyzed in an acidic environment without affecting PNIPAM side chains to provide poly(acrylic acid)-g-poly(N-isopropylacrylamide) (PAA-g-PNIPAM) graft copolymers. The influences of the length of PNIPAM side chains and the salinity on the critical micelle concentration of the PtBA-g-PNIPAM amphiphilic graft copolymer were examined by fluorescence spectroscopy. Furthermore, thermo-responsive behaviors of the copolymers were investigated by UV-vis spectroscopy, dynamic light scattering, and transmission electron microscopy.

A novel poly(N-vinylcaprolactam)-based well-defined amphiphilic graft copolymer synthesized by successive RAFT and ATRP

A series of well-defined amphiphilic graft copolymers consisting of a hydrophobic poly(tert-butyl acrylate) (PtBA) backbone and hydrophilic poly(N-vinylcaprolactam) (PNVCL) side chains were synthesized via the combination of reversible addition–fragmentation chain transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), and the grafting-from strategy without any polymeric functional transformation. RAFT homopolymerization of tert-butyl 2-((2-bromopropanoyloxy)methyl)acrylate (tBBPMA) was first performed to give a well-defined Br-containing PtBBPMA backbone with a low polydispersity (Mw/Mn = 1.22). PNVCL side chains were grown from the backbone via straightforward ATRP of N-vinylcaprolactam using CuBr/Me6Cyclam as the catalytic system in 1,4-dioxane to afford the target PtBA-g-PNVCL amphiphilic graft copolymers with narrow molecular weight distributions (Mw/Mn ≤ 1.32). The self-assembly behavior of these graft copolymers in aqueous media was studied by fluorescence spectroscopy and transmission electron microscopy (TEM), and furthermore, their thermo-responsive behavior was investigated by UV-vis and dynamic light scattering (DLS). Finally, the hydrophobic PtBA backbone was selectively hydrolyzed into a hydrophilic PAA backbone without affecting PNVCL side chains in the acidic environment to provide PAA-g-PNVCL graft copolymers.

Precise Synthesis of ABCDE Star Quintopolymers by Combination of Controlled Polymerization and Azide–Alkyne Cycloaddition Reaction

A facile approach based on integrated utilization of ring-opening polymerization (ROP), reversible addition–fragmentation chain transfer (RAFT) process, and azide–alkyne cycloaddition reaction was efficiently used to construct amphiphilic 5-arm ABCDE star quintopolymers. The miktoarm stars are composed of poly(ethylene glycol) (A), poly(e-caprolactone) (B), polystyrene (C), poly(l-lactide) (D), poly(N,N-dimethylaminoethyl methacrylate) (E1), poly(methyl methacrylate) (E2), and poly(methyl acrylate) (E3). Alkyne-in-chain-functionalized BC and DE diblock copolymers were synthesized by successive ROP and RAFT process. Selective [3 + 2] click reaction between two-azide-end-functionalized PEG and BC copolymer gave azide-core-functionalized ABC star terpolymer, and a subsequent click reaction with DE copolymer afforded well-defined ABCDE stars with well-controlled molecular weight, low polydispersity, and precise composition, as evidenced from 1H NMR, GPC, and GPC-MALLS analyses. DSC analyses revealed part of p...

Thermogelling of Double Hydrophilic Multiblock and Triblock Copolymers of N,N-Dimethylacrylamide and N-Isopropylacrylamide: Chain Architectural and Hofmeister Effects

A series of thermoresponsive double hydrophilic (AB)(n) multiblock and ABA triblock copolymers of N,N-dimethylacrylamide (DMA) and N-isopropylacrylamide (NIPAM) with varying sequence lengths were synthesized via successive reversible addition-fragmentation chain transfer (RAFT) polymerizations by employing polytrithiocarbonate as the chain transfer agent. Previously, we reported that multiblock copolymers in dilute aqueous solutions can form either unimolecular or multimolecular micelles at elevated temperatures depending on the relative chain lengths of PDMA and PNIPAM sequences (Zhou et al. Langmuir 2007, 23, 13076-13084). In this follow-up work, we further explored and compared the chain architectural (multiblock vs triblock) and Hofmeister effects (addition of various sodium salts) on the gelation behavior of multiblock and ABA triblock copolymers at high concentrations and attempted to establish a correlation between the aggregation behavior and gelation properties of multiblock copolymers at low and high polymer concentrations, respectively. It was found that only m-PDMA(p)-PNIPAM(q) multiblock copolymers with PDMA and PNIPAM sequence lengths located within a specific range can form physical gels at elevated temperatures. Rheology measurements revealed that multiblock copolymers possess considerably lower critical gelation temperatures (CGT) and higher gel storage modulus, G'(gel), as compared to those of PNIPAM-b-PDMA-b-PNIPAM triblock copolymers possessing comparable sequence lengths. The addition of inorganic sodium salts can effectively facilitate thermogelling for multiblock and triblock copolymers, resulting in decreasing CGTs and critical gelation concentrations (CGCs) in the order of Hofmeister series with increasing hydration capabilities. The unique thermogelling behavior of aqueous multiblock copolymer solutions in the absence and presence of inorganic salts, as compared to that of ABA triblock copolymers, augurs well for their potential applications in various fields such as biomaterials and biomedicines.

Preparation of miktoarm star-block copolymers PSn-b-PVAc4-n via combination of ATRP and RAFT polymerization

Three tetrafunctional bromoxanthate agents (Xanthate3-Br, Xanthate2-Br2, and Xanthate-Br3) were synthesized. Initiative atom transfer radical polymerizations (ATRP) of styrene (St) or reversible addition fragmentation chain transfer (RAFT) polymerizations of vinyl acetate (VAc) proceeded in a controlled manner in the presence of Xanthate3-Br, Xanthate2-Br2, or Xanthate-Br3, respectively. The miktoarm star-block copolymers containing polystyrene (PS) and poly(vinyl acetate) (PVAc) chains, PSn-b-PVAc4-n (n = 1, 2, and 3), with controlled structures were successfully prepared by successive RAFT and ATRP chain-extension experiments using VAc and St as the second monomers, respectively. The architecture of the miktoarm star-block copolymers PSn-b-PVAc4-n (n = 1, 2, and 3) were characterized by gel permeation chromatography and 1H NMR spectra. Furthermore, the results of the cleavage of PS3-b-PVAc and PVAc2-b-PS2 confirmed the structures of the obtained miktoarm star-block copolymers. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010

Synthesis of diblock copolymers containing poly(N‐vinylcarbazole) by reversible addition‐fragmentation chain transfer polymerization

AbstractThe reversible addition‐fragmentation chain transfer (RAFT) polymerization of N‐vinylcarbazole (NVK) mediated by macromolecular xanthates was used to prepare three types of block copolymers containing poly(N‐vinylcarbazole) (PVK). Using a poly(ethylene glycol) monomethyl ether based xanthate (PEG‐X), the RAFT polymerization of NVK proceeded in a controlled way to afford a series of PEG‐b‐PVK with different PVK chain lengths. Successive RAFT polymerization of NVK and vinyl acetate (VAc) with a small molecule xanthate (X1) as the chain transfer agent was tested to prepare PVK‐b‐PVAc. Though both monomers can be homopolymerized in a controlled manner with this xanthate, only by polymerizing NVK first could give well‐defined block copolymers. The xanthate groups in the end of PVK could be removed by radical‐induced reduction using tributylstannane, and PVK‐b‐PVA was obtained by further hydrolysis of PVK‐b‐PVAc under basic conditions. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010

Synthesis of poly(vinyl acetate) block copolymers by successive RAFT and ATRP with a bromoxanthate iniferter

Poly(vinyl acetate)-b-polystyrene, poly(vinyl acetate)-b-poly(methyl acrylate) and poly(vinyl acetate)-b-poly(methyl methacrylate) block copolymers with low polydispersity (M(w)/M(n) < 1.25) were prepared by successive reversible addition-fragmentation chain transfer (RAFT) polymerization and atom transfer radical polymerization (ATRP) employing a bromoxanthate iniferter (initiator-transfer agent-terminator).

Dendrimer‐star polymer and block copolymer prepared by reversible addition‐fragmentation chain transfer (RAFT) polymerization with dendritic chain transfer agent

AbstractA new reversible addition‐fragmentation chain transfer (RAFT) agent, dendritic polyester with 16 dithiobenzoate terminal groups, was prepared and used in the RAFT polymerization of styrene (St) to produce star polystyrene (PSt) with a dendrimer core. It was found that this polymerization was of living characters, the molecular weight of the dendrimer‐star polymers could be controlled and the polydispersities were narrow. The dendrimer‐star block copolymers of St and methyl acrylate (MA) were also prepared by the successive RAFT polymerization using the dendrimer‐star PSt as macro chain transfer agent. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 6379–6393, 2005

Preparation of star polymers based on polystyrene or poly(styrene- b- N-isopropyl acrylamide) and divinylbenzene via reversible addition-fragmentation chain transfer polymerization

Star polymers based on styrene/divinyl benzene (St/DVB) and PSt- b-poly( N-isopropyl acrylamide) (NIPAAM)/DVB have been successively prepared by ‘arm-first’ method via reversible addition-fragmentation chain transfer (RAFT) polymerization. The linear macro RAFT agent PSt-SC(S)Ph was prepared by RAFT polymerization of St using benzyl dithiobenzoate and AIBN as RAFT agent and initiator. Successive RAFT polymerization of NIPAAM with PSt-SC(S)Ph as macro RAFT agent to afford diblock copolymer, PSt-b-PNIPAAM-SC(S)Ph. The coupling reactions of PSt-SC(S)Ph or PSt-b-PNIPAAM-SC(S)Ph in the presence of DVB produced the star copolymers, C(PSt) n or C(PSt-b-PNIPAAM) n . The molar ratio of DVB/PSt-SC(S)Ph and polymerization time influenced the yields, molecular weight and distribution of the star-shaped polymers, which was characterized by 1H NMR and IR spectra, GPC measurements as well as DLS.