Well-defined backbone degradable polymer-drug conjugates synthesized by reversibleaddition-fragmentation chain-transferpolymerization

Despite the recent advances of controlled polymerization methods over the last decades, the lack of backbone degradability of well-defined polymers remains a major synthetic challenge that limits the full exploitation of polymer-drug conjugates (PDCs) in clinical practice. Here, we report the copolymerization of a cyclic ketene acetal (CKA) and a vinyl-based drug-monomer as a proof-of-concept approach to prepare model polyester-based prodrugs via reversible addition-fragmentation chain-transfer (RAFT) polymerization. We demonstrate the versatility of the system toward backbone degradability and control over the chain length while maintaining both low dispersity (D-M) and homogenous distribution of degradation points along the main polymer chain. The resulting PDCs exhibit unique self-assembly properties and potent cytotoxicity against pancreatic cancer cells. A methacrylate prodrug is copolymerized with a CKA co-monomer using RAFT polymerization producing a backbone degradable PDC with well-defined molecular structure. The resulting PDC undergoes controlled backbone degradation and produces by-products of narrow dispersity and low toxicity. In addition, it is demonstrated that the insertion of degradation segments does not affect the cytotoxic properties of the PDC under in vitro conditions.