PLA-Based Triblock Copolymer Micelles Exhibiting Dual Acidic pH/Reduction Responses at Dual Core and Core/Corona Interface Locations

Polylactide (PLA)-based amphiphilic block copolymers and their nanoassemblies designed with stimuli-responsive degradation (SRD) hold great potential as promising candidates for tumor-targeting drug delivery. However, most of the smart PLA-based nanoassemblies are designed to respond to a single stimulus (typically reduction or acidic pH). Herein, a new strategy is reported to synthesize PLA-based block copolymer micelles exhibiting dual SRD at dual locations (DL-DSRD). The strategy utilizes a combination of ring opening polymerization, controlled radical polymerization, and facile coupling reactions to synthesize an ABA-type PLA-based triblock copolymer with a hydrophilic polymethacrylate (A) and PLA (B) blocks. Incorporation of an acidic pH-responsive ketal linkage in the center of PLA block and reduction-responsive disulfide linkages at PLA/hydrophilic polymethacrylate blocks ensure the formation of smart nanoassemblies featured with ketal linkages in the PLA cores and disulfide linkages at core/corona interfaces, thus attaining DL-DSRD. Such dual acidic pH/reduction-responses at dual locations lead to not only shedding of coronas at interfaces but also destabilization of cores, resulting in the synergistic and accelerated release of encapsulated model drugs, compared with the single stimulus systems. These results, along with lower cytotoxicity, suggest that DL-DSRD strategy can offer versatility in the development of tumor-targeting drug delivery nanocarriers.