Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, Genoa16163, Italy.
Biomacromolecules. 2022 Nov 14;23(11):4678-4686. doi: 10.1021/acs.biomac.2c00903. Epub 2022 Oct 13.
Despite the extensive use of poly-lactic-glycolic-acid (PLGA) in biomedical applications, computational research on the mesoscopic characterization of PLGA-based delivery systems is limited. In this study, a computational model for PLGA is proposed, developed, and validated for the reproducibility of transport properties that can influence drug release, the rate of which remains difficult to control. For computational efficiency, coarse-grained (CG) models of the molecular components under consideration were built using the MARTINI force field version 2.2. The translocation free energy barrier Δ across the PLGA matrix in the aqueous phase of docetaxel and derivatives of varying sizes and solubilities was predicted via molecular dynamics (MD) simulations and compared with experimental release data. The thermodynamic quantity Δ anticipates and can help explain the release kinetics of hydrophobic compounds from the PLGA matrix, albeit within the limit of a drug concentration below a critical aggregation concentration. The proposed computational framework would allow one to predict the pharmacological behavior of polymeric implants loaded with a variety of payloads under different conditions, limiting the experimental workload and associated costs.
尽管聚乳酸-乙醇酸共聚物（PLGA）在生物医学应用中被广泛使用，但基于介观尺度对基于 PLGA 的输送系统进行计算研究的文献却很少。在这项研究中，我们提出、开发并验证了一种用于 PLGA 的计算模型，以重现影响药物释放的输运性质，而药物释放的速率仍然难以控制。为了提高计算效率，使用 MARTINI 力场版本 2.2 构建了所考虑分子成分的粗粒（CG）模型。通过分子动力学（MD）模拟预测了疏水性药物多西他赛及其不同大小和溶解度衍生物在水溶液相中通过 PLGA 基质的迁移自由能势垒Δ，并将其与实验释放数据进行了比较。热力学量Δ可以预测和解释疏水性化合物从 PLGA 基质中的释放动力学，尽管其药物浓度低于临界聚集浓度。所提出的计算框架将允许人们预测在不同条件下加载各种有效载荷的聚合物植入物的药理学行为，从而限制实验工作量和相关成本。
