Facile synthesis and self-assembly behaviors of biodegradable amphiphilic hyperbranched copolymers with reducible poly(caprolactone) grafts

The facile synthesis of amphiphilic hyperbranched copolymers with biodegradability generally suffers from sophisticated specific design and multistep preparation procedures integrating different synthetic approaches, leading to difficulty and complexity in scalable manufacture and potential biomedical applications. To develop a robust yet facile strategy toward biodegradable hyperbranched amphiphilic copolymers, we reported in this study the design and synthesis of a reducible macromonomer, 2-((2-hydroxyethyl)disulfanyl)ethyl methacrylate-graft-polycaprolactone (HSEMA-g-PCL). This macromonomer integrates polymerizable vinyl and hydrophobic poly(epsilon-caprolactone) (PCL) units via a disulfide link, which enables the successful preparation of two types of biodegradable amphiphilic hyperbranched copolymers, i.e., a hyperbranched statistical copolymer h-P(OEGMA-st-(HSEMA-g-PCL)) and a hyperbranched block-statistical copolymer h-P(HSEMA-g-PCL)-b-POEGMA, with an identical polymer composition but different polymer architectures via a reversible addition-fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) process. The controlled synthesis of biodegradable hyperbranched copolymer panels was supported by the modulated degrees of branching (DBs) (0.05-0.14), narrow polydispersity indexes (D) (1.36-1.74) and CTA functionalities (f(CTA)) (2.4-4.3). Interestingly, the type and size of the resulting self-assembled aggregates depended on the relative content of the P(HSEMA-g-PCL) segment in the hyperbranched copolymers. A comparison study on the colloidal stability revealed greater stability of micelles formed by h-P(HSEMA-g-PCL)-b-POEGMA than that of micelle analogues self-assembled from h-P(OEGMA-st-(HSEMA-g-PCL)) because of the stronger steric hindrance of an individual POEGMA block in a block architecture. Therefore, the former micelle formulation with greater stability was chosen as a better nanocarrier for prolonged blood circulation. Doxorubicin (DOX)-loaded h-P(HSEMA-g-PCL)-b-POEGMA copolymer micelles showed an intracellular reduction-promoted drug release and efficient inhibition of MCF-7 cell proliferation. Taken together, the reducible hydrophobic macromonomer developed herein provides a facile yet robust strategy for biodegradable amphiphilic hyperbranched copolymers, and the block-statistical structure is identified as a better polymer architecture for controlled release applications.