Multiscale Simulation of Biodegradable Diblock Copolymers for Drug Delivery

描述(申请人提供)：项目摘要。在这项提案中，概述了一项计划，以发展两个生物相关的，可降解的两嵌段共聚物的多尺度模拟工作。这些二嵌段共聚物在水相中自组装成囊泡和蠕虫状胶束，具有几个独特的特征--高稳定性和形态可调整性，以及疏水药物的有效包裹。特别有趣的是，它们能够在血液循环中持续很长时间的对流，从而在组织中导航，并输送高负荷的药物。当两嵌段共聚物的疏水部分降解时，会从蠕虫状胶束转变为球形胶束状态，从而释放所包裹的疏水药物。提出了多尺度的模拟工作，其中包含了对蠕虫状胶束形态稳定性的水解影响：从原子分子动力学开始，转向捕捉界面表面和溶解度的实验性质的新的粗粒度模型，最后进展到对整个蠕虫状胶束的介观模拟。此外，还提出了临床相关抗癌药物紫杉醇的原子模型和粗粒模型。将研究药物在脂质和两嵌段共聚物膜中的分配，然后将其合并到蠕虫状胶束的介观模型中。这一提议的一个中心目标是模拟胶束的降解性分解，将疏水药物嵌入核心进行协调释放，以传递到细胞靶标。关联性。最先进的模拟和建模技术将被用来探索紫杉醇在由可生物降解的两嵌段共聚物组成的胶束中的封存性质。所获得的洞察力应该为新型抗癌药物输送系统的设计提供指导。

DESCRIPTION (provided by applicant): Project Summary. In this proposal, a scheme is outlined to develop multi-scale modelling efforts of two biologically relevant, degradable diblock copolymers. These diblock copolyers self-assemble into vesicles and worm-like micelles in the aqueous phase with several unique characteristics-high stability and morphological tunability, as well efficient encapsulation of hydrophobic drugs. Particularly interesting is their ability to convect in the blood circulation for a very long time and thereby navigate through tissues and deliver high loads of drug. Upon the degradation of the hydrophobic portion of the diblock copolymer, there is a transition from the worm-like micelle to the spherical micelle state, releasing the encapsulated hydrophobic drug. Multi-scale modelling efforts are proposed that incorporate the hydrolysis effects on the stability of the worm-like micelle morphology: starting from atomistic molecular dynamics, moving to new coarse-grained models that capture experimental properties of the interfacial surface and solubilities, and finally progressing to mesoscopic simulations of entire worm-like micelles. In addition, atomistic and coarse-grained models of paclitaxel, a clinically relevant anti-cancer drug, are proposed. The partitioning of the drug in lipid and diblock copolymer membranes will be studied, and then incorporated into mesoscopic models of the worm- like micelle. A central goal of this proposal is to simulate the degradative break-up of micelles, with coordinated release of hydrophobic drugs embedded in the core for delivery to cellular targets. Relevance. State of the art simulation and modeling techniques will be used to pursue the nature of Taxol sequestration in micelles composed of biodegradable diblock copolymers. Insight gained should inform the design of novel anticancer drug delivery systems.