CAREER: Molecular Diversity in Drug Delivery Design: An Integrated Approach to Research and Education

该奖项由哈佛大学材料研究部生物材料项目颁发，旨在合成和研究斑块脂质体载体，以补充细胞因子激活的内皮细胞表面的异质细胞粘附分子。内皮细胞表面是动态的；它们在细胞表面的饱和脂质微域内分离细胞粘附分子，以调节炎症过程中的结合和信号事件。脂质体是由自组装的脂质双层球包封水体积制备的，缺乏嵌入细胞膜的结构信息。然而，将不饱和脂质和饱和脂质分别划分为液晶和凝胶相域的研究将会影响局部分子的扩散和弹性。除了改变机械性能外，该项目还将结合脂质体微域来设计分子，例如脂质体表面的抗体，以创建集中、分离和特定的结合区域。由脂质体与抗体等配体分子制备的药物传递载体有望以高特异性显著增强药物传递结合。作为更广泛的影响推广活动的一部分，该项目将通过创建一个在线教学策略资源和实践实验，将课堂研究经验融入当地高中，以补充这些高中现有的课程。研究生和本科生的培训将侧重于使用尖端技术来评估分子水平上的特征。这项建议是开发针对炎症部位的药物递送载体，并可能用于治疗许多疾病，如心血管疾病、癌症等。此外，这些药物输送系统将能够靶向身体的特定病变区域，因此有可能改善治疗结果，减少通常与药物毒性相关的副作用。本项目将制备的脂质体载体有望模拟免疫细胞（白细胞），免疫细胞通过对炎症信号作出反应并集中在细胞膜分子上，与发炎的内皮细胞相互作用。这种细胞膜分子的动态重组有望调节免疫反应和设计新的药物递送载体。这种靶向修饰表面的脂质体有望改善与细胞膜上分子结合的药物的递送，增强结合和特异性。其中的外联工作部分将侧重于将研究活动纳入当地高中的课程。该项目将为教学策略和实践实验创建一个在线资源，以补充现有课程。本课程网站将重点介绍：1)利用分子和细胞多样性作为设计原则的研究；2)作为教育工作者、家长和学生的资源。此外，本项目计划开设“设计的多样性”课程，让高中生接触科学和工程主题，以及与本项目相关的研究活动。这门“设计的多样性”课程将在当地高中分为六个模块教授。研究生和本科生的培训将侧重于使用尖端技术来评估分子水平上的特征。

This award by the Biomaterials program in the Division of Materials Research to Harvard University is to synthesize and study patchy liposomal vehicles that complement the heterogeneous cell adhesion molecules on the surface of cytokine-activated endothelial cells. Endothelial cell surfaces are dynamic; they segregate cell adhesion molecules within saturated lipid microdomains on the cell surface to regulate binding and signaling events during inflammation. Liposomes prepared from self-assembled lipid bilayer spheres encapsulating aqueous volumes, lack the structural information embedded within cell membranes. However, the proposed studies by partitioning unsaturated and saturated lipids into liquid crystalline and gel phase domains, respectively, would affect local molecular diffusion and elasticity. In addition to altering the mechanical properties, the project will incorporate liposome microdomains to pattern molecules, such as antibodies on the liposome surface to create concentrated, segregated and specific binding regions. Drug delivery vehicles prepared from liposomes with antibody and other ligand molecules are expected to significantly enhance drug delivery binding with high specificity. As part of broader impact outreach activities, the project will focus on embedding classroom research experiences within the local high schools by creating an online resource for instructional strategies with hands-on experiments that complement existing curricula at these high schools. Graduate and undergraduate training will focus on the use of cutting-edge techniques that assess features at the molecular level.This proposal is to develop drug delivery vehicles that target inflammation sites, and could be useful in treating a number of conditions such as cardiovascular diseases, cancers, etc. In addition, these drug delivery systems will be able to target specific diseased areas of the body, and thus would have the potential to improve therapeutic outcomes with reduced side effects that are usually associated with the drug toxicity. The liposomal vehicles that will be prepared by this project are expected to mimic immune cells (white blood cells) that are interacting with the inflamed endothelial cells by responding to inflammatory signals and concentrating on molecules of the cell membrane. This dynamic restructuring of cell membrane molecules are expected to regulate the immune response and in designing new drug delivery vehicles. This targeting of liposomes with modified surfaces is expected to improve the delivery of drug that binds with molecules on cell membranes with enhanced binding and specificity. The outreach efforts part of this will focus on incorporating research activities within curricula of the local high schools. The project will create an online resource for instructional strategies and hands-on experiments that complement existing curricula. This course website will highlight: 1) research that utilize molecular and cellular diversity as design principles; and 2) as a resource for educators, parents, and students. Additionally, this project plans to develop a course in "Diversity in Design" to expose high school students to science and engineering topics, and research activities related to this project. This "Diversity in Design" course will be taught as six modules at the local high schools. Graduate and undergraduate training will focus on the use of cutting-edge techniques that assess features at the molecular level.