Tailoring multivalent nanoparticle adhesion for efficient and superselective targeting of cells

几十年来，将成像剂或药物特异性地靶向疾病的能力一直是主要的医学目标。靶向是有吸引力的，因为它会将更多的药剂引导到疾病部位，从而提高效力，同时也降低了正常组织中的浓度，从而防止有害的副作用。纳米颗粒载体由于具有高负载能力、保护药剂、易于附着靶向分子和有利的药代动力学等众多属性，在靶向应用中受到了相当大的关注。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重键的支架，这被称为多价粘附。众所周知，多价粘附可以增强结合强度，但对如何控制这种效果知之甚少。高水平控制是必要的一个主要原因是因为疾病生物标志物通常存在于正常和患病细胞上，但水平不同。理想情况下，纳米颗粒将在结合中显示开关样变化，使得不存在对正常细胞的粘附，并且最大程度地粘附于患病细胞以最大化靶向选择性。然而，实现这种类型的行为仍然难以捉摸。因此，需要全新的策略和技术，超越基本的粘附概念，而是使粘附能够以动态的方式定制。如果成功的话，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教育推广计划中传达，重点是K-12，本科生和研究生，以激发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）指导不同教育水平的学生研究人员，（3）开发K-12推广计划，鼓励年轻学生追求科学和医学。该提案的最终目标是开发一个多功能和强大的计算设计平台，用于控制多价纳米颗粒结合并实现超选择性粘附。这将通过显著推进研究团队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是人类中由ICAM 1基因编码的蛋白质。该基因编码通常在内皮细胞和免疫系统细胞上表达的细胞表面糖蛋白。PI将首先添加新的模拟功能，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将使模拟适应活细胞，并设计和测试可以表现出超选择性靶向行为的前瞻性亲和分子-纳米颗粒制剂。这种复杂的行为目前是前所未有的，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和强大的粘合性能的纳米载体的预测工具。这项工作的基本概念将在教育推广计划中传达，重点是K-12，本科生和研究生，以激发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）指导不同教育水平的学生研究人员，（3）开发K-12外展计划，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价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.