Synthesis and Characterization of Polymer‐Drug Conjugates by Strain‐Promoted Azide‐Alkyne Cycloaddition‐Mediated Polymerization

ABSTRACT Polymer‐drug conjugates (PDCs) modify the biodistribution of small‐molecule anticancer agents to prevent undesired off‐target adverse effects. Here, we report the preparation of two PDCs by strain‐promoted [3 + 2] azide‐alkyne cycloaddition‐mediated step‐growth polymerization. This method does not require the use of a catalyst or high temperatures, and it allows the rapid synthesis of high molecular‐weight PDCs containing gemcitabine (M w ~ 40.18 kDa) and doxorubicin (M w ~ 1800 kDa) with narrow molecular weight distribution and high drug loading (29.2 wt% gemcitabine and 10.3wt% doxorubicin). α‐ω‐ bis ‐azide‐terminated bifunctional gemcitabine‐coupled and doxorubicin‐coupled monomers, with drug linkage via Gly‐Phe‐Leu‐Gly (GFLG), a cathepsin B‐sensitive peptide linker, were separately synthesized and polymerized using a dibenzoazacyclooctyne bifunctional polyethylene glycol monomer. Preliminary in vitro evaluations of the PDCs showed cathepsin B‐catalyzed drug release at pH 5.0. The applied method for the syntheses of the PDCs enables the selective delivery of potent anticancer agents.