Synthesis of degradable PLA-based diblock copolymers with dual acid/reduction-cleavable junction

The development of biocompatible polylactide (PLA)-based block copolymers for constructing self-assembled nanoaggregates degradable in response to endogenous stimuli found in cell environments is promising for enhanced/controlled drug delivery in pharmaceutical science. Despite advances in the synthesis of various PLA-based nanoassemblies featured with only a single stimulus response, the design and development of advanced nanoassemblies integrated with two endogenous stimuli-responsive cleavable linkages for dual stimuli response is challenging. Here we report an approach to the synthesis of a new PLA-based diblock copolymer having dual reduction-cleavable disulfide and acid-labile acetal linkages at the block junction. Key to the approach is the use of a double-head initiator designed uniquely with both acetal and disulfide linkages as well as with both OH and bromine terminal groups. Our comprehensive results from structural analysis and degradation through chemical transition suggest the requirement of a rational combination of controlled polymerization techniques and facile coupling reactions for the synthesis of well-controlled PLA-based diblock copolymer having both disulfide and acetal linkages. The main reason is attributed to the instability of acetal linkages under ROP condition with a tin catalyst at an elevated temperature. The resultant copolymer self-assembles to form shell-sheddable nanoassemblies that are disintegrated in response to dual acid/reduction. This work demonstrates the importance in the development of efficient polymerization strategies by utilizing well-established polymerization techniques to synthesize novel functional copolymers with complicated architectures and various functionalities sensitive to reaction environments.