Multiscale Simulation of Biodegradable Diblock Copolymers for Drug Delivery

用于药物输送的可生物降解二嵌段共聚物的多尺度模拟

• 批准号: 7812040
• 负责人: Sharon Marie Loverde
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-22 至 2011-02-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812040
• 关键词: Algorithms; Antineoplastic Agents; Arts; Blood Circulation; Cardiovascular Diseases; Cells; Cereals; Characteristics; Clinical; Code; Computer Simulation; Development; Drug Delivery Systems; Drug Design; Dyes; Encapsulated; Ethylene Oxide; Ethylenes; Goals; Hydrolysis; Image; Implant; Investigation; Label; Left; Length; Lipids; Maps; Membrane; Micelles; Modeling; Molecular; Morphology; Motivation; Nature; Paclitaxel; Pharmaceutical Preparations; Phase; Polyesters; Polymers; Property; Scheme; Simulate; Solubility; Stents; Surface; Surgical sutures; System; Techniques; Testing; Thermodynamics; Time; Tissues; Vesicle; aqueous; biodegradable polymer; caprolactone; cellular targeting; clinically relevant; computer studies; copolymer; design; di-block copolymer; fluorescence imaging; insight; interest; interfacial; models and simulation; molecular dynamics; multi-scale modeling; novel; particle; poly(lactic acid); restenosis; segregation; self assembly; simulation; soft tissue

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.

描述（申请人提供）：项目摘要。在此提案中，概述了一项计划，以开发两种具有生物学相关的，可降解的二嵌段共聚物的多尺度建模工作。在水相中，这些二嵌段将自组装成囊泡和类似蠕虫的胶束，具有几种独特的特征 - 高稳定性和形态可调性，并且对疏水药物的有效封装很好。特别有趣的是，它们在很长一段时间内在血液循环中进行对流的能力，从而在组织中导航并提供高负载药物。二嵌段共聚物的疏水部分降解后，从蠕虫样的胶束到球形胶束状态存在过渡，从而释放了封装的疏水药物。提出了多尺度的建模工作，它纳入了对蠕虫样胶束形态稳定性的水解影响：从原子分子动力学开始，转向新的粗粒型模型，这些模型捕获了界面表面和溶解度的实验性能，并最终发展为整个蠕虫片的介体模拟。此外，提出了紫杉醇的原子和粗粒模型，一种临床相关的抗癌药物。将研究该药物在脂质和二嵌段共聚物膜中的分配，然后将其掺入蠕虫类胶束的介观模型中。该提案的一个核心目标是模拟胶束的降解破裂，并在核心中协调释放疏水药物，以递送到细胞靶标。关联。最先进的模拟和建模技术将用于追求由可生物降解的二嵌段共聚物组成的胶束中的紫杉醇隔离的性质。获得的洞察力应告知新型抗癌药物输送系统的设计。