Rapid and Versatile Synthesis of Glutathione-Responsive Polycarbonates from Activated Cyclic Carbonates

Aliphatic polycarbonates (APCs) are promising biocompatible and degradable polymers with immense potential for biomedical applications. However, current synthetic approaches to stimuli-responsive APCs remain limited and often complicated, requiring multiple-step postpolymerization reactions. To address these limitations and unlock the full potential of APCs in the development of advanced biomaterials, we developed a rapid and versatile strategy to synthesize glutathione (GSH)-responsive polycarbonates through the controlled ring-opening polymerization of cyclic carbonates with activated disulfides. Responsive pendant moieties could be easily introduced in one step through a highly efficient thiol–disulfide exchange reaction enabled by the reactive pyridyl disulfides, providing a simple and versatile approach to fine-tuning polymer's physiochemical properties for biomedical applications. As a proof of concept, we prepared an amphiphilic GSH-responsive polycarbonate-drug conjugate by initiating the activated cyclic carbonate monomer with methyl polyethylene glycol and then conjugating the anticancer drug mertansine via the thiol–disulfide exchange reaction. The self-assembled nanoparticles were a smart drug delivery system with GSH-triggered drug release specifically within cancer cells and a remarkable selective toxicity toward cancer cells over healthy cells, showcasing the exceptional promise of this GSH-responsive polycarbonate for biomedical applications.