Multiscale Simulation of Biodegradable Diblock Copolymers for Drug Delivery

描述（由申请人提供）：项目摘要。在这个建议中，一个计划概述了两个生物相关的，可降解的二嵌段共聚物的多尺度建模工作。这些二嵌段共聚物在水相中自组装成囊泡和蠕虫状胶束，具有几个独特的特性-高稳定性和形态可调性，以及疏水药物的有效包封。特别令人感兴趣的是它们在血液循环中对流很长时间的能力，从而在组织中导航并输送高负荷的药物。在二嵌段共聚物的疏水部分降解时，存在从蠕虫状胶束到球形胶束状态的转变，释放包封的疏水药物。多尺度建模的努力，提出了将水解的蠕虫状胶束形态的稳定性的影响：从原子分子动力学开始，移动到新的粗粒度模型，捕捉实验性质的界面表面和溶解度，并最终进展到介观模拟整个蠕虫状胶束。此外，紫杉醇，一种临床相关的抗癌药物，原子和粗粒度的模型，提出。将研究药物在脂质和二嵌段共聚物膜中的分配，然后将其纳入蠕虫样胶束的介观模型中。该提议的一个中心目标是模拟胶束的降解分解，其中嵌入核心中的疏水性药物的协调释放用于递送到细胞靶点。本案无关国家的最先进的模拟和建模技术将被用来追求的性质，紫杉醇螯合在胶束组成的可生物降解的二嵌段共聚物。获得的见解应通知新的抗癌药物输送系统的设计。

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.