Multiscale Simulation of Biodegradable Diblock Copolymers for Drug Delivery

描述（由申请人提供）：项目概述。在本提案中，概述了一种方案，以开发两种生物相关的，可降解的二嵌段共聚物的多尺度建模工作。这些双嵌段共聚物在水相中自组装成囊泡和蠕虫状胶束，具有高稳定性和形态可调性，以及对疏水药物的高效包封等特点。特别有趣的是，它们能够在血液循环中长时间地对流，从而在组织中穿行，输送高负荷的药物。二嵌段共聚物的疏水部分降解后，从蠕虫状胶束状态转变为球形胶束状态，释放出包封的疏水药物。研究人员提出了多尺度的建模努力，将水解对蠕虫状胶束形态稳定性的影响纳入其中：从原子分子动力学开始，转向新的粗粒度模型，捕捉界面表面和溶解度的实验特性，最后发展到整个蠕虫状胶束的介观模拟。此外，还建立了临床相关抗癌药物紫杉醇的原子模型和粗粒度模型。将研究药物在脂质和二嵌段共聚物膜中的分配，然后将其纳入蠕虫状胶束的介观模型。这个提议的一个中心目标是模拟胶束的降解破裂，与嵌入核心的疏水药物的协调释放递送到细胞目标。的相关性。最先进的模拟和建模技术将被用于研究紫杉醇在由可生物降解的二嵌段共聚物组成的胶束中的封存性质。获得的见解应该为新的抗癌药物输送系统的设计提供信息。

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.