Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Acta Biomater. 2018 Jan;65:259-271. doi: 10.1016/j.actbio.2017.10.043. Epub 2017 Oct 31.
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.
控制聚（乳酸-共-乙醇酸）（PLGA）的主链结构被证明对微粒基质中酸性降解副产物的产生和释放有很大影响。以前控制 PLGA 微粒内部和外部酸度积累的努力集中在添加赋形剂，包括中和和抗炎剂。在本报告中，我们利用序列控制策略来定制 PLGA 的微观结构。使用非侵入性的比率双光子显微镜（TPM）方法，在体外监测序列定义和随机 PLGA 微粒内的内部酸性微气候分布。发现序列定义的 PLGA 在 pH 分布上变化最小，且渗透酸性副产物的量更少。平行扫描电子显微镜研究进一步将外部形态事件与内部降解诱导的结构变化联系起来。体外表征的序列和随机共聚物的性质转化为体内行为的差异。与 50:50 乳酸：乙醇酸比的随机外消旋 PLGA 相比，序列交替共聚物聚 LG 具有较低的肉芽肿异物反应。
本文证明改变聚（乳酸-共-乙醇酸）（PLGA）中的单体序列会导致体外降解的微粒中降解速率和内部酸性微气候发生巨大差异。我们注意到，这些粒子内的酸性微气候首次通过双光子显微镜进行成像，该显微镜对降解过程提供了非常清晰和详细的图像。重要的是，我们还记录到观察到的序列控制的体外过程转化为具有相同 L 到 G 组成但不同微观结构的聚合物在体内行为的差异。这些数据，结合我们之前关于溶胀、侵蚀和 MW 损失的研究（Biomaterials2017, 117, 66 和本文引用的其他参考文献），不仅提供了关于 PLGA 中序列效应的重要见解，而且还提供了关于 PLGA 降解一般机制的重要见解。
