Dual-responsive polycarbonate micelles for activating intracellular drug release

Stimulus-responsive drug carriers have significant potential for enabling smart drug delivery within the intricate microenvironment of tumors. However, a single stimulus source and complex synthesis process limit its application. In this study, we successfully synthesized a pH/GSH-stimulated responsive polycarbonate (PSSA) through ring-opening polymerization and post-esterification reactions. PSSA can self-assemble into homogeneous and stable micelles, effectively encapsulating the anticancer drug doxorubicin (DOX). The carbon backbone of PSSA contains disulfide and acetal linkages, which allow for extensive responsiveness to changes in pH and GSH. This results in variations in particle size and micellar morphology. The micelles loaded with DOX demonstrate responsive drug-releasing properties when stimulated by pH/GSH. The dual-response micelles exhibit superior drug release compared to single stimulus sources. The blank micelles are non-cytotoxic, while the DOX-loaded micelles show dose-dependent cytotoxicity towards HepG2 cells. Importantly, DOX-loaded micelles enable precise intracellular drug release by responding to the microenvironment of tumor cells. Therefore, this dual-responsive micellar nano-carrier, which maintains extracellular stability but activates intracellular drug release, presents a novel approach for smart anti-tumor drug delivery applications.