Multi-postpolymerization Functionalization of PLA Enabled by Sulfide Tetrazines as a Single End-Group Moiety

The synthesis of well-defined and multifunctional polymeric systems for drug delivery is a topic of intense research. However, a major limitation in the functionalization of these systems for nanomedical applications is the reliance on toxic catalysts or non-biocompatible strategies for polymer coupling and ligation, as well as the need for extensive purification steps when multiple functionalization reactions are performed. In this work, we introduce tetrazines containing both a methyl sulfide and hydroxyl functionality as the initiator for ring opening polymerization of l-lactide. We demonstrate that the obtained polymer can be successfully conjugated to mPEG-SH by chemoselective tetrazine-thiol exchange in a traceless manner. The byproduct, methanethiol, is easily eliminated during the course of the reaction, thus avoiding the use of a toxic catalyst. Additionally, the same end group allows for further functionalization via inverse electron demand Diels-Alder chemistry using trans-cyclooctene. These findings highlight the potential of TeTEx to access complex polymeric systems for biomedical applications by enabling two distinct postpolymerization functionalizations at a single end group, notably in a truly traceless manner.