Synthesis and properties of monocleavable amphiphilic comblike copolymers with alternating PEG and PCL grafts

Symmetric reduction‐responsive amphiphilic comblike copolymers mid‐disulfide‐functionalized comblike copolymers with alternating copolymer comprised of styrenic unit and N‐(2‐hydroxyethyl) maleimide (HEMI) unit (poly(St‐alt‐HEMI)) backbones and alternating PEG and PCL side chains (S‐CP(PEG‐alt‐PCL)) with poly(St‐alt‐HEMI) backbones and alternating poly(ε‐caprolactone) (PCL) and poly(ethylene glycol) (PEG) side chains were synthesized and used as nanocarriers for in vitro release of doxorubicin. The target copolymers with predetermined molecular weight and narrow molecular weight distribution (M_w/M_n = 1.15–1.20) were synthesized by reversible addition‐fragmentation chain transfer (RAFT) copolymerization of vinylbenzyl‐terminated PEG and N‐(2‐hydroxyethyl) maleimide mediated by a disulfide‐functionalized RAFT agent S‐CPDB, and followed by ring‐opening polymerization of ε‐caprolactone. When compared with linear block copolymer comprised of poly(ethylene glycol) (PEG) and poly(?‐caprolactone) (PCL) segments (PEG‐b‐PCL) copolymers, comblike copolymers with similar PCL contents usually exhibited decreased crystallization temperature, melting temperature, and degree of crystallinity, indicating the significant influence of copolymer architecture on physicochemical properties. Dynamic light scattering measurements revealed that comblike copolymers were liable to self‐assemble into aggregates involving vesicles and micelles with average diameter in the range of 56–226 nm and particle size distribution ranging between 0.07 and 0.20. In contrast to linear copolymer aggregates, comblike copolymer aggregates with similar compositions were of improved storage stability and enhanced drug‐loading efficiency. In vitro drug release confirmed the disulfide‐linked comblike copolymer aggregates could rapidly release the encapsulated drug when triggered by 10 mM DL ‐dithiothreitol. These reduction‐sensitive, biocompatible, and biodegradable aggregates have a potential as controlled delivery vehicles. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012