Synthesis and micellization of redox-responsive dynamic covalent multi-block copolymers

Multi-block copolymers, which are composed of two or more covalent interconnected polymeric segments of different types, offer unparalleled opportunities for designing new nanostructured materials with enhanced functionality and properties. Using double disulfide linkages coupling with complementary double H-bonding sequences, we demonstrated a new synthetic approach to multi-block copolymers that produces alternating architectures. It offers a new synthetic strategy for synthesizing multi-block copolymers which not only applies to PLA and PEG blocks for multi-block copolymers, but also to other kinds of polymers especially for those hard to be linked by a traditional method. In this study, we synthesized an amphiphilic multi-block copolymer [PLA-PEG]_t containing redox-responsive disulfide linkages. Their structures were confirmed by ¹H NMR and GPC. These amphiphilic multi-block copolymers can self-assemble into spherical micelles in aqueous media. Compared with di-block copolymers reported in our previous work, multi-block copolymer micelles have a higher drug loading content (DLC), higher stability and more compact spherical structure, whilst maintaining excellent redox-responsive properties and are able to release drugs triggered by intracellular GSH. Fluorescence microscopy measurements and MTT assay demonstrated that the micelle exhibited faster drug release and higher cellular proliferation inhibition due to intracellular GSH responsiveness. These results suggested that the micelles would provide a favorable platform to construct drug delivery systems for cancer therapy.