Facile synthesis of a well-defined heteroatom-containing main chain polycarbonate for activated intracellular drug release†
Multi-responsive drug carriers have great advantages in the targeted delivery of drugs in heterogeneous and complicated biological micro-environments. However, the sophisticated fabrication process is a great obstacle for their further application. Herein, ROS/GSH/pH triple responsive polycarbonate was rationally synthesized via the one-pot ring-opening copolymerization of the diselenide and tertiary amine macrocyclic carbonate monomers with methoxy poly(ethylene glycol) as the initiator. The micellar nanoparticles were formed by the amphiphilic block copolymers composed of a PEG segment and diselenide and tertiary amine containing the polycarbonate block via self-assembly. The diselenide and tertiary amine groups allowed for rich ROS/GSH/pH responsiveness, which caused these nanoparticles to undergo changes in the size and morphology. These micellar nanoparticles exhibited a stimuli-responsive drug release profile upon the stimulation of acidic pH, GSH, and ROS, and the release mechanism was elucidated. The blank nanoparticles were cyto-compatible, whereas the triple responsive drug-loaded nanoparticles exhibited an improved concentration-dependent and synergistic cytotoxicity towards the A549 cells. More importantly, the micellar nanoparticles could facilitate cell uptake and realize controlled intracellular release. Thus, the newly developed micellar nanocarriers could open a new avenue for smart antitumor drug delivery applications.