Preparation of Reduction-Sensitive Branched Block–Statistical Copolymers for Controlled Drug Release via a Secondary in Situ Branching Reaction

Branched or hyperbranched polymers with a high degree of branching (DB) and a narrow polydispersity index (PDI) are highly desirable for biomedical applications because of the significant effect of molecular weight (MW), DB, and PDI on their cytotoxicity and delivery efficiency. Although either the self-condensed vinyl polymerization (SCVP) or copolymerization with a small molecular cross-linker has been repeatedly highlighted to be an efficient strategy with respect to (hyper)branched polymers, the preparation of a (hyper)branched polymer with simultaneously a high DB and a narrow PDI has been a significant challenge because an increased DB was usually accompanied by a broad PDI. For this purpose, a reduction-sensitive branched copolymer synthesized via a reversible addition–fragmentation chain transfer (RAFT) copolymerization of a reducible monomer–initiator double-head agent, 2-((2-((2-bromo-2-methylpropanoyl)oxy)ethyl)disulfanyl)ethyl methacrylate (BSSMA), and a divinyl cross-linker, ethane-1,2-diyl diacrylate (DDA), was further reacted with a large amount of AIBN with respect to a simultaneous end-capping of RAFT thiocarbonylthio groups and a secondary in situ branching reaction of the vinyl residues, which resulted in a secondary in situ branched copolymer (SBP), SBP-poly(BSSMA-st-DDA) (SBP-P(BSSMA-st-DDA)), with an increased DB and insignificantly broadened PDI compared to the parent branched copolymer (BP), BP-poly(BSSMA-st-DDA) (BP-P(BSSMA-st-DDA)). To provide sufficient colloidal stability, SBP-P(BSSMA-st-DDA) was further used as a multi-macroinitiator to produce an amphiphilic branched block–statistical copolymer, poly(BSSMA-st-DDA)-b-poly(oligoethylene glycol methacrylate) (SBP-P(BSSMA-st-DDA)-b-POEGMA), by atom transfer radical polymerization (ATRP) of OEGMA. The resultant SBP-P(BSSMA-st-DDA)-b-POEGMA can form unimolecular core–shell micelles with enhanced stability due to the branched structure. The doxorubicin (DOX)-loaded micelles showed an intracellular reduction-promoted drug release, an efficient cellular uptake, and an inhibition of proliferation of HeLa cells. This study therefore developed a facile yet robust strategy to prepare stimuli-responsive branched polymers with a high DB and a narrow PDI for an efficient anticancer drug delivery.