Highly statistical PLGAs based on L-methylglycolide: the impact of copolymer microstructure on hydrolytic degradation monitored by pH fluorescent sensor

Biomedical applications of poly(lactic-co-glycolic acid)s (PLGAs) are significantly hindered by acidification during hydrolytic degradation of these copolymers, which can cause postoperative complications such as toxic acidic response in surrounding tissues. PLGAs are usually obtained by ring-opening copolymerization (co-ROP) of lactide (LA) and glycolide (GL); marked difference in reactivity of LA and GL results in formation of copolymers with low statisticity. Biodegradation of PLGAs is strongly influenced by lactate/glycolate (L/G) ratios, molecular weight characteristics and microstructure of copolymers. It is believed that the presence of long (G)_n segments is driving fast hydrolysis of PLGAs with a formation of low-MW organic acids and relatively high-MW (L)_n remnants, none of that is good for biocompatibility of PLGAs. In the present work, we proposed the use of l-methylglycolide (l-MeGL) in co-ROP with l-LA to randomize PLGAs. Copolymers with l-LA/l-MeGL molar ratios of 85:15 (PLMG 85/15) and 70:30 (PLMG 70/30), as well as l-MeGL homopolymer PLMG 0/100, were prepared; l-LA/GL copolymers PLGA 85/15 and PLGA 70/30 were synthesized for a comparison. According to ¹H and ¹³C NMR data, l-MeGL-based PLGAs did not contain (G)_n segments with n > 2, DSC studies revealed high statisticity of copolymers. Investigations of hydrolytic degradation of thin PLGA films were conducted by laser scanning microscopy with the use of pH fluorescent sensor 4-PYMPO. These studies revealed the marked difference in hydrolytic behavior of l-MeGL- and GL-based PLGAs: with equal L/G ratios, l-MeGL-based PLGAs proved to be non-acidifying polyesters, which will open wide prospects for their biomedical use.