Tailoring multivalent nanoparticle adhesion for efficient and superselective targeting of cells

定制多价纳米颗粒粘附以实现高效和超选择性的细胞靶向

• 批准号: 1929565
• 负责人: Jered Haun
• 金额: $ 50万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929565&HistoricalAwards=false
• 关键词: Tailoring; multivalent; nanoparticle; adhesion; efficient

The ability to target imaging agents or drugs specifically to diseases has been a major medical goal for decades. Targeting is attractive because it would direct more of the agent to the disease site, which improves potency, while also reducing concentrations in normal tissues, which prevents detrimental side effects. Nanoparticle carriers have received considerable attention for targeting applications due to numerous attributes including high-loading capacity, protection of the agent, facile attachment of targeting molecules, and favorable pharmacokinetics. Another advantage of nanoparticles is that they are large enough to serve as a scaffold for forming multiple bonds with target cells, which is referred to as multivalent adhesion. It is well known that multivalent adhesion can enhance binding strength, but little is known about how this effect can be controlled. A major reason that a high level of control is necessary is because disease biomarkers are often present on both normal and diseased cells, but at different levels. Ideally the nanoparticle would display a switch-like change in binding such that there was no adhesion to normal cells and maximal adhesion to diseased cells to maximize targeting selectivity. However, achieving this type of behavior has remained elusive. Thus, entirely new strategies and technologies are needed that go beyond basic adhesion concepts, and instead enable adhesion to be tailored in a dynamic manner. If successful, molecular targeting of diseases inside the body would dramatically change diagnostic and treatment paradigms, enabling early detection and personalized medical practices. Concepts underlying this work will be conveyed in educational outreach programs focused toward K-12, undergraduate, and graduate students to spur interest in biomedical engineering. The educational plan involves: (1) developing new course content, (2) mentoring student researchers at various education levels, and (3) developing K-12 outreach programs to encourage young students to pursue science and medicine. The ultimate goal of this proposal is to develop a versatile and robust computational design platform for controlling multivalent nanoparticle binding and achieving super selective adhesion. This will be accomplished by significantly advancing the novel experimental and computational simulation methods developed by the research team in previous work. The researchers will use vascular inflammation and the target molecule ICAM-1 as a model system. ICAM-1 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. The PIs will first add new simulation capabilities, including the phase of initial attachment from free solution and extension of the methods to nanorods. The PIs will then focus on experimentally testing new molecular bond properties. Finally, the PIs will adapt the simulation to live cells and design and test prospective affinity molecule-nanoparticle formulations that can exhibit super selective targeting behavior. This complex behavior is currently unprecedented, and thus will require the new tools to understand. At the conclusion of the work, the simulation will be positioned to serve as a predictive tool for designing nanocarriers that possess unique and powerful adhesive properties. Concepts underlying this work will be conveyed in educational outreach programs focused toward K-12, undergraduate, and graduate students to spur interest in biomedical engineering. The educational plan involves: (1) developing new course content, (2) mentoring student researchers at various education levels, and (3) developing K-12 outreach programs to encourage young students to pursue science and medicine.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

几十年来，针对疾病的靶向显像剂或药物的能力一直是一个主要的医学目标。靶向是有吸引力的，因为它可以将更多的药物引导到疾病部位，从而提高效力，同时还可以降低正常组织中的浓度，从而防止有害的副作用。纳米粒载体由于具有高载药量、药物保护性、靶向分子易于附着和良好的药代动力学等诸多特性，在靶向应用方面受到了广泛的关注。纳米颗粒的另一个优点是它们足够大，可以作为与靶细胞形成多个键的支架，这被称为多价结合。众所周知，多价结合可以增强结合强度，但对如何控制这种影响知之甚少。需要高水平控制的一个主要原因是，疾病生物标记物通常存在于正常细胞和患病细胞上，但水平不同。理想情况下，纳米颗粒在结合上会表现出开关状的变化，这样就不会对正常细胞产生黏附，而会对疾病细胞产生最大的黏附，从而最大限度地提高靶向选择性。然而，实现这种类型的行为仍然难以捉摸。因此，需要全新的战略和技术，超越基本的粘合概念，使粘合能够以动态的方式进行定制。如果成功，体内疾病的分子靶向将极大地改变诊断和治疗模式，使早期发现和个性化医疗实践成为可能。这项工作的基本概念将在侧重于K-12、本科生和研究生的教育推广计划中传达，以激发人们对生物医学工程的兴趣。教育计划包括：(1)开发新的课程内容，(2)指导各级学生研究人员，以及(3)开发K-12外展计划，鼓励年轻学生攻读科学和医学。这一建议的最终目标是开发一个通用的、健壮的计算设计平台，以控制多价纳米颗粒的结合并实现超选择性黏附。这将通过显著推进研究小组在以前的工作中开发的新颖的实验和计算模拟方法来实现。研究人员将使用血管炎症和靶分子ICAM-1作为模型系统。ICAM-1是一种蛋白质，在人类中由ICAM-1基因编码。该基因编码一种细胞表面糖蛋白，通常在内皮细胞和免疫系统的细胞上表达。PI将首先增加新的模拟能力，包括从自由溶液的初始附着阶段和将方法扩展到纳米棒。然后，PI将专注于实验测试新的分子键特性。最后，PI将使模拟适用于活细胞，并设计和测试能够表现出超选择性靶向行为的预期亲和分子-纳米颗粒配方。这种复杂的行为目前是史无前例的，因此需要新的工具来理解。在工作结束时，模拟将被定位为设计具有独特而强大的粘附性的纳米载体的预测工具。这项工作的基本概念将在侧重于K-12、本科生和研究生的教育推广计划中传达，以激发人们对生物医学工程的兴趣。该教育计划包括：(1)开发新的课程内容，(2)指导不同教育水平的学生研究人员，以及(3)开发K-12扩展计划，以鼓励年轻学生追求科学和医学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。