Synthesis of Heterobifunctional Thiol-poly(lactic acid)-b-poly(ethylene glycol)-hydroxyl for Nanoparticle Drug Delivery Applications

Biocompatible, amphiphilic block copolymers, such as poly(lactic acid)-b-poly(ethylene glycol) (PLA-b-PEG), that can be conjugated to targeting ligands, therapeutics, and imaging agents are required for the development of polymeric nanoparticle drug delivery systems. Synthesis of targetable, heterobifunctional X-PLA-b-PEG-Y has required the use of heterobifunctional PEG, which involves specialty equipment to synthesize and is expensive to purchase. Herein, a new method for the synthesis of bifunctional HS-PLA-b-PEG-OH is described. The approach takes advantage of polymer solution properties to improve a critical purification step, and uses inexpensive and readily available PEG-diol as a starting material. In the method demonstrated here, the ring-opening polymerization of PLA is initiated by both ends of a cleavable bifunctional initiator. PEG is conjugated to each PLA end, resulting in a high molecular weight intermediate which is simple to purify from the excess PEG, with recoveries that are nearly three times higher than when a monofunctional initiator is used. Following purification, the triblock copolymer is cleaved to produce the final HS-PLA-b-PEG-OH product, in which both polymer ends are reactive. Moreover, the polymers successfully stabilize nanoparticles produced by Flash NanoPrecipitation. Importantly, the synthesis method can be adopted by non-polymer experts.