Synthesis, self-assembly and drug release behaviors of reduction-labile multi-responsive block miktobrush quaterpolymers with linear and V-shaped grafts

Abstract

Monocleavable block miktobrush quaterpolymers (BMQs) may provide us with new insights into topology-dependent properties and prospective applications. Considering that densely heterografted brush terpolymers and their derivatives have been scarcely revealed, this study aims at the synthesis and properties of novel thermo-, pH- and reduction-responsive BMQs comprising two terminal poly(N-isopropylacrylamide) blocks and one disulfide-functionalized miktobrush-like block bearing a poly(styrene-alt-maleimide) backbone as well as linear poly(ethylene glycol) and V-shaped poly(ε-caprolactone)-block-poly(acrylic acid) pendent chains. Successive RAFT processes, ring-opening polymerization, ATRP and hydrolysis were used to synthesize the desired copolymers with controlled molecular weights and relatively low dispersity. With the increasing chain length of poly(acrylic acid) grafts, the LCST gradually increased from 37.3 to 42.9 °C. Copolymer assemblies could exhibit intriguing stimuli-induced morphological transitions among large compound micelles, sea cucumber-like micelles, hyperbranched micelles and vesicles. DOX-loaded copolymer aggregates were prone to perform sustained release with prolonging time, and the release kinetics could be efficiently tuned by adopting a single stimulus or combined stimuli. Flow cytometry and confocal laser scanning microscopy measurements confirmed the efficient cellular uptake and intracellular drug release from drug-loaded aggregates, revealing their great potential as smart nanocarriers for controlled drug delivery. Our research affords a general route to construct stimuli-labile miktobrush terpolymers and their derivatives with tailored linear and V-shaped grafts, which further paves the way for exploring the unique properties and multipurpose applications of multicomponent copolymers.