Drug-Initiated, Controlled Ring-Opening Polymerization for the Synthesis of Polymer-Drug Conjugates

Paclitaxel, a polyol chemotherapeutic agent, was covalently conjugated through its 2'-OH to polylactide with 100% regioselectivity via controlled polymerization of lactide mediated by paclitaxel/(BDI-II)ZnN(TMS)(2) (BDI-II = 2-((2,6-diisopropylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-2-pentene). The steric bulk of the substituents on the N-aryl groups of the BDI ligand drastically affected the regiochemistry of coordination of the metal catalysts to paclitaxel and the subsequent ring-opening polymerization of lactide. The drug-initiated, controlled polymerization of lactide was extended, again with 100% regioselectivity, to docetaxel, a chemotherapeutic agent that is even more structurally complex than paclitaxel. Regioselective incorporation of paclitaxel (or docetaxel) to other biopolymers (i.e., poly(delta-valerolactone), poly(trimethylene carbonate), and poly(epsilon-caprolactone)) was also achieved through drug/(BDI-II)ZnN(TMS)(2)-mediated controlled polymerization. These drug-polylactide conjugates with precisely controlled structures are expected to be excellent building blocks for drug delivery, coating, and controlled-release applications.