Career Program: Molecular Design of Surface Modified Vesicles and Liposomes: A Theoretical Study

职业计划：表面修饰囊泡和脂质体的分子设计：理论研究

• 批准号: 9624268
• 负责人: Igal Szleifer
• 金额: $ 28.5万
• 依托单位: Purdue Research Foundation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-15 至 2001-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9624268&HistoricalAwards=false
• 关键词: Career; Program; Molecular; Design; Surface

9624268 Szleifer Vesicles and liposomes are aggregates formed by spherically closed bilayers of amphiphilic molecules. The ability of the lipsome to dissolve large quantities of molecules in their core and its solubility in aqueous environments makes them ideal systems for drug delivery. In recent years it was found that grafting polymers to the surface of the liposomes increases the longevity of these aggregates in the blood stream. Furthermore, by chemically modifying the grafted polymer free end-group with molecules that have large affinities to specific cell receptors, the liposomes can be used for targeted delivery. Despite the importance of polymer-modified liposomes as premier drug carriers, there is no systematic understanding of the factors that govern their stability, longevity, and ability to target specific cells. A systematic theoretical study of the behavior of liposomes and vesicles modified by grafted polymer chairs will be performed. The single-chain mean-field theory will be used to study the behavior of the chain molecules (surfactants and polymers) that comprise the aggregates. This approach provides accurate conformational and thermodynamic information as compared with experimental measurements. The aim of the work is to systematically study the conditions under which modified aggregates can achieve longevity, thermodynamic stability and specific targeting. The work consists of finding the compositions of surfactants ( or lipids), cholesterol and polymer that will form stable vesicles within a range of size that is optimal for drug delivery. The ability of the grafted chains to prevent protein adsorption on the surface of the vesicles will be studied. Specific polymer chains that combine the ability to prevent protein adsorption with conformational properties that enhance targeting of the carrier to specific cells. The microscopic understanding of the behavior of polymer modified vesicles that will be achieved should able the development of new types of ag gregates for use as reagents that can be used in separation processes, such as protein separation and solubilization of small hydrophobic molecules in aqueous media. Theoretical studies will be carried out in close collaboration with three experimental groups that are investigating: 1) the use of end-functionalized polymer-modified liposomes for targeted drug delivery, 2) vesicle-membrane fusion induced by chemical modification of the vesicle and 3) protein adsorption on polymer-modified surfaces. The teaching plan is divided into two parts. One describes the approach to be taken in formal classroom teaching. The other presents the different projects that go beyond the formal teaching requirements. In the former, the basic idea is to provide the students with the links between physical processes, mathematical tools and experimental measurements. Understanding this relationship enables students to quickly grasp new concepts based on previously learned subjects. The informal activities that will be undertaken include special topic discussions, lectures and research for undergraduate students interested in specific applications of the general field of physical chemistry. These activities will be confined to select small groups of students; the aim being to provide the personalized attention that is not generally available in large formal classes. Furthermore, the teaching plan also includes special topic research projects for undergraduate and graduate students. ***

9624268 Szleifer 囊泡和脂质体是由两亲性分子的球形闭合双层形成的聚集体。 脂质体溶解其核心中大量分子的能力及其在水性环境中的溶解度使它们成为药物输送的理想系统。 近年来，人们发现将聚合物接枝到脂质体表面可以延长这些聚集体在血流中的寿命。 此外，通过用对特定细胞受体具有大亲和力的分子对接枝聚合物游离端基进行化学修饰，脂质体可用于靶向递送。 尽管聚合物修饰的脂质体作为主要药物载体非常重要，但对其稳定性、寿命和靶向特定细胞能力的影响因素还没有系统的了解。 对接枝聚合物椅修饰的脂质体和囊泡的行为进行系统的理论研究。 单链平均场理论将用于研究构成聚集体的链分子（表面活性剂和聚合物）的行为。 与实验测量相比，这种方法提供了准确的构象和热力学信息。 这项工作的目的是系统地研究改性聚集体可以实现长寿、热力学稳定性和特定靶向的条件。 这项工作包括寻找表面活性剂（或脂质）、胆固醇和聚合物的组合物，这些组合物将在最适合药物输送的尺寸范围内形成稳定的囊泡。 将研究接枝链防止蛋白质吸附在囊泡表面的能力。 特定的聚合物链将防止蛋白质吸附的能力与增强载体对特定细胞的靶向性的构象特性结合起来。 对聚合物修饰囊泡行为的微观理解将能够开发新型聚集体，用作可用于分离过程的试剂，例如蛋白质分离和疏水性小分子在水介质中的溶解。 理论研究将与三个正在研究的实验组密切合作进行：1）使用末端功能化聚合物修饰的脂质体进行靶向药物输送，2）通过囊泡的化学修饰诱导囊泡-膜融合，3）聚合物改性表面上的蛋白质吸附。 教学计划分为两部分。 其中之一描述了正式课堂教学中应采取的方法。 另一个展示了超出正式教学要求的不同项目。 前者的基本思想是为学生提供物理过程、数学工具和实验测量之间的联系。 理解这种关系使学生能够根据以前学过的科目快速掌握新概念。 将进行的非正式活动包括为对物理化学一般领域的具体应用感兴趣的本科生进行专题讨论、讲座和研究。 这些活动将仅限于选定的一小群学生；目的是提供个性化的关注，这在大型正式课程中通常是不提供的。 此外，教学计划还包括本科生和研究生的专题研究项目。 ***