Multicyclic topology-enhanced micelle stability and pH-sensitivity

Cyclic polymers have been reported to show unique properties and often better performance than linear analogues due to the absence of polymer chain ends, therefore great efforts have been devoted to the development of various cyclic polymers for biomedical applications. However, the effect of multicyclic topology on the stimuli-responsiveness of polymers has not been elucidated so far, to our knowledge, likely due to the lack of an efficient and powerful strategy for the controlled preparation of multicyclic polymers with well-defined structures and compositions. Clarification of this structure–property relationship will not only contribute to the rational design and development of novel cyclic polymer-derived materials with better properties for biomedical applications, but also promote greatly the clinical translations of these cyclic topology-based materials. A panel of amphiphilic pH-responsive multicyclic polymers (MCPs) were prepared via reversible addition-fragmentation chain-transfer (RAFT) copolymerization of a cyclic macromonomer, poly(oligoethylene glycol methacrylate) (M− c POEGMA) and N,N -dimethyl aminoethyl methacrylate (DMAEMA). The effect of multicyclic topology on the colloidal stability and stimuli-responsiveness of the resulting self-assembled micelles was investigated in detail. Interestingly, MCP1 micelles with a polymer composition of P(DMAEMA 50 - st -(M− c POEGMA 7 ) 3 ) showed much greater stability with a CMC value as low as 130.5 nM and more complete acidic pH-triggered disassembly than the single cyclic polymers (SCPs)-based micelle counterparts, which further endows the doxorubicin (DOX)-loaded MCP1 micelles with an approximately twofold lower IC 50 value (greater in vitro cytotoxicity) than that of the SCP-based analogues. This study therefore highlights for the first time the incorporation of multicyclic topology as a useful and efficient alternative to the simultaneously enhanced colloidal stability and stimuli-responsiveness of polymeric self-assemblies for controlled release application.