Monomer sequence in PLGA microparticles: Effects on acidic microclimates and in vivo inflammatory response.

Controlling the backbone architecture of poly(lactic-co-glycolic acid)s (PLGAs) is demonstrated to have a strong influence on the production and release of acidic degradation by-products in microparticle matrices. Previous efforts for controlling the internal and external accumulation of acidity for PLGA microparticles have focused on the addition of excipients including neutralization and anti-inflammatory agents. In this report, we utilize a sequence-control strategy to tailor the microstructure of PLGA. The internal acidic microclimate distributions within sequence-defined and random PLGA microparticles were monitored in vitro using a non-invasive ratiometric two-photon microscopy (TPM) methodology. Sequence-defined PLGAs were found to have minimal changes in pH distribution and lower amounts of percolating acidic by-products. A parallel scanning electron microscopy study further linked external morphological events to internal degradation-induced structural changes. The properties of the sequenced and random copolymers characterized in vitro translated to differences in in vivo behavior. The sequence alternating copolymer, poly LG, had lower granulomatous foreign-body reactions compared to random racemic PLGA with a 50:50 ratio of lactic to glycolic acid. This paper demonstrates that changing the monomer sequence in poly(lactic-co-glycolic acid)s (PLGAs) leads to dramatic differences in the rate of degradation and the internal acidic microclimate of microparticles degrading in vitro. We note that the acidic microclimates within these particles were imaged for the first time with two-photon microscopy, which gives an extremely clear and detailed picture of the degradation process. Importantly, we also document that the observed sequence-controlled in vitro processes translate into differences in the in vivo behavior of polymers which have the same L to G composition but differing microstructures. These data, placed in the context of our prior studies on swelling, erosion, and MW loss (Biomaterials2017, 117, 66 and other references cited within the manuscript), provide significant insight not only about sequence effects in PLGAs but into the underlying mechanisms of PLGA degradation in general.