Strategy for Synthesis of Statistically Sequence-Controlled Uniform PLGA, and Effects of Sequence Distribution on Interaction and Drug Release Properties*

Extensive studies have been conducted to elucidate the effects of such parameters as molecular weight, polydispersity and composition on the controlled release properties of poly(D,L-lactic-co-glycolic acid) (PLGA). However, studies dealing with the effect of monomer sequence distribution have been sparse mainly because of the difficulty of precisely controlling monomer sequence in PLGA. Herein, we present a new semi-batch copolymerization strategy (i.e., a slow simultaneous comonomer addition method) that enables production of statistically sequence-controlled “uniform PLGA” polymers through control of the rate of comonomer addition. Using this method, a series of PEG-PLGA samples having an identical molecular weight and composition but different sequence distributions (uniform vs. gradient) were prepared. The properties of these materials (PEG crystallization/melting, hygroscopicity, aqueous sol-gel transition, drug release kinetics) were found to significantly vary, demonstrating that sequence control only at the statistical level still significantly influences the properties of PLGA. Most notably, uniform PLGA exhibited the more sustained drug release behavior, compared to gradient PLGA.