A Strategy for Control of “Random” Copolymerization of Lactide and Glycolide: Application to Synthesis of PEG-b-PLGA Block Polymers Having Narrow Dispersity

Abstract

Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable copolymer that is also acceptable for use in a variety of biomedical applications. Typically, a random PLGA polymer is synthesized in a bulk batch polymerization using a tin-based catalyst at high temperatures. This methodology results in relatively broad polydispersity indexes (PDIs) due to transesterification, and the polymer product is often discolored. We report here the use of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), a known, effective, and convenient organocatalyst for the ring-opening polymerization of cyclic esters, to synthesize random copolymers of lactide and glycolide. The polymerization kinetics of the homo- and copolymerizations of lactide and glycolide were explored via NMR spectroscopy. A novel strategy that employs a controlled addition of the more reactive glycolide monomer to a solution containing the lactide monomer, the poly(ethylene glycol) (PEG) macroinitiator, and DBU catalyst was developed. Using this tactic (semi-batch polymerization), we synthesized a series of block copolymers that exhibited excellent correlation of the expected and observed molecular weights and possessed narrow PDIs. We also measured the thermal properties of these block copolymers and observed trends based on the composition of the block copolymer. We also explored the need for experimental rigor in several aspects of the preparations and have identified a set of convenient reaction conditions that provide polymer products that retain the aforementioned desirable characteristics. These polymerizations proceed rapidly at room temperature and without the need for tin-based catalysts to provide PEG-b-PLGAs suitable for use in biomedical investigations.

A method to Quantify the Affinity of Cabazitaxel for PLA-PEG Nanoparticles and Investigate the Influence of the Nano-Assembly Structure on the Drug/Particle Association

“…In preclinical experiments, the PLA was shown to be biodegraded through hydrolysis after intravenous administration within few days, (7) while low molecular weight PEG (M w <10 kDa) is thought to be eliminated by renal clearance (8). From an industrial standpoint, the synthesis of the copolymer by ring-opening polymerization is well-documented and can be performed at multi-gram scale with satisfying purity (9). Finally, the accumulated knowledge of the biopharmacy and the physico-chemistry of these nanoassembled copolymers is another advantage of PLA-PEG nanoparticles.…”

Lactic acid‐ and carbonate‐based crosslinked polymeric micelles for drug delivery

“…This result is not surprising as DBU and mPEG concentrations do not change during polymerization. Qian et al 34 have reported similar first-order dependency with respect to monomer, DBU, and macroinitiator concentrations for ROP of LA and glycolide. 34 Furthermore, ROP of valerolactone using similar amidine catalysts have been shown to follow firstorder kinetics with respect to catalyst, alcohol, initiator and monomer concentration.…”

“…Qian et al 34 have reported similar first-order dependency with respect to monomer, DBU, and macroinitiator concentrations for ROP of LA and glycolide. 34 Furthermore, ROP of valerolactone using similar amidine catalysts have been shown to follow firstorder kinetics with respect to catalyst, alcohol, initiator and monomer concentration. 35 Although we did not systematically study the polymerization kinetics upon addition of CB and LA, a time of 3 h was sufficient to obtain polymers with targeted mass ratios of MAC, CB, and LA for both mPEG 114 -b-PMAC 2.5 -b-P(CB 9 -co-LA 39 ) and mPEG 114 -b-P(CB 8 -co-LA 35 -co-MAC 2.5 ) copolymers (inferred from 1 H NMR spectra).…”

Characterization of Temperature-Responsive Graft Copolymer with Polycarbonate Oligo Segment

“…In the case of biomaterials, both biocompatibility and biodegradability are highly desirable properties. Aliphatic polyesters such as poly(lactic acid)s, poly(glycolic acid)s, and poly(amino acid)s have these properties [3][4][5]. Therefore, these modified copolymers are widely investigated for biomaterial applications.…”