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

Xiao Zhang, Bowen Zhao, Shiwei Fu, Ronald S. Seruya, John F. Madey III, Eva Bukhryakova, and Fuwu Zhang

University of Miami

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-responsive polycarbonates through the controlled ring-opening polymerization of cyclic carbonates with activated disulfides. Responsive pendent 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 glutathione (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.