UNS: Collaborative Research: Unique binding geometries: Engineering & Modeling of Sticky Patches on Lipid Nanoparticles for Effective Targeting of Otherwise Untargetable cells

UNS：合作研究：独特的结合几何形状：工程

• 批准号: 1510149
• 负责人: Yannis Kevrekidis
• 金额: $ 22.57万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1510149&HistoricalAwards=false
• 关键词: UNS; Collaborative; Research; Unique; binding

PI: Sofou, Stavroula / Kevrekidis, Yannis G. Proposal Number: 1510015 / 1510149 This proposal aims to explore and understand the behavior of drug-carrying nanoparticles whose surface becomes reorganized and forms "sticky patches" when they get close to cancer cells. These new binding geometries have the potential to significantly expand the types of cancer cells that can be targeted with therapeutic agents. The project combines this targeting approach with single molecule optical measurements and mathematical modeling, to understand the mechanisms, and inform the design of optimized particles. Based on promising initial results in selectively targeting and treating cancer cells using drug-carrying nanoparticles, the investigators will explore and understand the behavior of drug-carrying lipid nanoparticles whose surface phase-separates to form "sticky patches" proximally to tumor cells. The underlying hypotheses are that the targeting success lies in the dense concentration of the binding ligands on these patches, and that the transport and binding kinetics of these novel binding geometries give significantly longer binding times resulting in internalization. These hypotheses will be addressed through four specific aims, which include: 1) Using collective measurements, evaluation of the kinetics of effective cell binding (association), dissociation and internalization processes of sticky lipid nanoparticles; 2) Using single molecule optical tracking techniques, evaluation of the lifetime of the nanoparticle-receptor(s) complex, of the number of nanoparticle-associated receptors that lead to cellular internalization of the complex, and of potential co-localization of receptors for each cell-associated nanoparticle; 3) Development, implementation and use of an experimentally informed general computational tool to test the mechanistic hypotheses, to evaluate the relative importance of the physical and chemical attributes of the nanoparticles used, and ultimately to help design them so as to optimally/selectively target otherwise untargetable cancers; and 4) Utilization of the mathematical model to optimize the design of sticky lipid nanoparticles, and to evaluate their efficacy in vitro. The proposed approach introduces an new geometry for nanoparticles to bind otherwise untargetable cancer cells, and has the potential to ultimately improve the quality of life of patients with advanced cancer and extend their life expectancy. Through this activity the investigators will cross-train one Ph.D. student (at Rutgers) with focus on physical chemistry and self-assembly of heterogeneous lipid membranes, and a second Ph.D. student (at Princeton) with focus on multiscale modeling and experimental biophysics optics. An international collaboration with Applied Mathematics in Oxford will involve a third PhD student, who will repeatedly visit Princeton/Rutgers to interact with the PIs. The investigators will integrate this research in their mentoring of undergraduate students, curriculum development and expansion of undergraduate programs. High school student outreach programs already in place will be supported, in addition to the development and dissemination of educational materials highlighting this research. This award is co-funded by the Biomedical Engineering Program in the Chemical, Bioengineering, Environmental and Transport Systems Division; by Mathematical Sciences through the Mathematical Sciences Innovation Incubator Program; and by the Directorate of Mathematical and Physical Sciences through the Office of Multidisciplinary Activities.

PI：Sofou，Stavroula / Kevrekidis，Yannis G.提案编号：1510015 /1510149该建议旨在探索和了解携带药物的纳米颗粒的行为，这些纳米颗粒的表面被重组并形成“粘稠的斑块”，当它们靠近癌细胞时。这些新的结合几何形状有可能显着扩展可以用治疗剂靶向的癌细胞的类型。该项目将这种靶向方法与单分子光学测量和数学建模相结合，以了解机制并告知优化颗粒的设计。基于有希望的初始结果，使用药物携带纳米颗粒选择性地靶向和治疗癌细胞，研究人员将探索和理解携带药物的脂质纳米颗粒的行为，其表面相分离为在肿瘤细胞上形成“粘性斑块”以形成“粘性斑块”。潜在的假设是，靶向成功在于这些斑块上结合配体的致密浓度，并且这些新型结合几何形状的转运和结合动力学的结合时间显着更长，从而产生了更长的结合时间，从而导致内在化。这些假设将通过四个特定目的来解决，其中包括：1）使用集体测量，评估有效细胞结合的动力学（缔合），粘性脂质纳米颗粒的分离和内在化过程； 2）使用单分子光跟踪技术，评估纳米颗粒受体络合物的寿命，与纳米粒子相关受体的数量，导致复合物的细胞内在化以及每个与每个细胞相关的纳米粒子的受体的潜在共定位； 3）开发，实施和使用实验知情的一般计算工具，以测试机械假设，以评估所使用的纳米粒子的物理和化学属性的相对重要性，并最终帮助设计它们以最佳/选择性地靶向否则否则不可捕获的癌症； 4）利用数学模型来优化粘性脂质纳米颗粒的设计，并在体外评估其功效。提出的方法引入了一种新的几何形状，以使纳米颗粒结合原本不可销的癌细胞，并有可能最终改善晚期癌症患者的生活质量并延长预期寿命。通过这项活动，研究人员将跨越一位博士学位。学生（在罗格斯）着重于物理化学和异质脂质膜的自组装，以及第二博士学位。学生（在普林斯顿）专注于多尺度建模和实验生物物理学光学。与牛津大学应用数学合作的国际合作将涉及第三位博士生，他们将反复访问普林斯顿/罗格斯与PIS互动。研究人员将将这项研究纳入他们对本科生的指导，课程发展和扩大本科课程的扩展。除了开发和传播教育材料以强调这项研究外，还将支持已经制定的高中学生外展计划。该奖项由化学，生物工程，环境和运输系统部的生物医学工程计划共同资助；通过数学科学通过数学科学创新孵化器计划；以及通过多学科活动办公室的数学和物理科学局。