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Bioinspired Nanoparticle Polymer Coating to Enhance Targeting to the Lung Epithelium

仿生纳米颗粒聚合物涂层可增强对肺上皮的靶向作用

基本信息

批准号：
2003037
负责人：
Jennifer Fiegel
金额：
$ 49.13万
依托单位：
University of Iowa
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003037&HistoricalAwards=false
关键词：
Bioinspired Nanoparticle Polymer Coating Enhance

项目摘要

NON-TECHNICAL SUMMARY To effectively treat disease, drug molecules must accumulate in sufficient amounts at a specific site in the body. To achieve this, tiny vehicles called carriers are often needed, but unwanted interactions within the body often limit their effectiveness. This project uses knowledge of the molecular interactions between bacterial/viral pathogens and human cells during human infection to design bioinspired polymer coatings for drug carriers. The project will provide deeper insight into chemical structures that simultaneously limit biofouling on the carrier surface and enhance attachment of carriers to human cells. Longer term, these results will enable the development of nanocarriers that can provide better treatment of disease by decreasing the amount of drug required for treatment and limiting side effects. This project will have a direct impact on the educational experience of students at various levels. Two graduate students will perform research for their Ph.D. theses and several undergraduate students from underrepresented groups will participate in the research. Further, a K-12 outreach program in engineering and science will utilize concepts from the research during camps throughout the state of Iowa and provide graduate and undergraduate students with opportunities for teacher training. Research results and discoveries will be disseminated through publications in peer-reviewed journals and presentations at local, national, and international conferences.TECHNICAL SUMMARY Current drug delivery strategies to target specific cells within the body are plagued by low levels of drug accumulation in the areas they are most needed. When drug carriers enter the body and interact with biological fluids, biofouling of the carrier surface occurs and new surface properties develop that control the carrier’s subsequent bio-interactions and fate. Our lack of knowledge of how to design drug carriers with appropriate properties to trigger and mediate their interactions within complex biological environments has significantly hindered progress towards efficient drug delivery. The goal of this proposal is to design a surface coating for nanocarriers to simultaneously address issues of biofouling and cell uptake in complex biological environments. Bioinspired polymeric ligands containing molecular structures that mimic the surfaces of respiratory pathogens known to efficiently penetrate human fluids and the lung epithelium will be developed. The ability of ligand-coated nanoparticle to target lung epithelial cells submerged in natural secretions will be experimentally observed and quantified. Two independent techniques will be pursued to evaluate the molecular recognition of the ligands. First, a high-throughput, optical biosensor technique will quantify the real-time cellular responses to receptor-ligand interactions in living cells. Second, a 3-D homology modeling approach will elucidate the ability of the ligands to dock into the receptor binding pocket. Results from these studies will provide insight into chemical structures that mediate the binding and activation of receptor-mediated processes. Through biomolecular mimicry, the proposed studies will lead to more efficient design of ligands that will enhance nanocarrier delivery.This project is jointly funded by the Biomaterials Program in the Division of Materials Research, the Established Program to Stimulate Competitive Research (EPSCoR), and the Polymers Program in the Division of Materials Research.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.

为了有效地治疗疾病，药物分子必须在体内特定部位积累足够的量。为了实现这一目标，通常需要称为载体的微型车辆，但体内不必要的相互作用往往限制了它们的有效性。该项目利用人类感染过程中细菌/病毒病原体与人类细胞之间的分子相互作用的知识，设计用于药物载体的生物启发聚合物涂层。该项目将提供更深入的了解化学结构，同时限制载体表面的生物污垢，并增强载体与人体细胞的附着。从长远来看，这些结果将使纳米载体的开发能够通过减少治疗所需的药物量和限制副作用来提供更好的疾病治疗。该项目将对各级学生的教育经历产生直接影响。两名研究生将进行博士研究。论文和一些来自代表性不足群体的本科生将参加研究。此外，K-12工程和科学推广计划将利用整个爱荷华州营地期间的研究概念，并为研究生和本科生提供教师培训的机会。研究结果和发现将通过在同行评审的期刊上发表和在地方、国家和国际会议上的演讲来传播。技术概述目前靶向体内特定细胞的药物递送策略受到最需要的区域中药物积累水平低的困扰。当药物载体进入体内并与生物流体相互作用时，载体表面发生生物污染，并产生新的表面性质，控制载体随后的生物相互作用和命运。我们缺乏如何设计具有适当性质的药物载体以触发和介导它们在复杂生物环境中的相互作用的知识，这严重阻碍了有效药物递送的进展。该提案的目标是设计纳米载体的表面涂层，以同时解决复杂生物环境中的生物污染和细胞摄取问题。将开发生物启发的聚合物配体，其含有模拟已知有效穿透人体体液和肺上皮的呼吸道病原体表面的分子结构。配体包被的纳米颗粒靶向浸没在天然分泌物中的肺上皮细胞的能力将通过实验观察和定量。将采用两种独立的技术来评价配体的分子识别。首先，高通量光学生物传感器技术将量化活细胞中受体-配体相互作用的实时细胞反应。第二，3-D同源建模方法将阐明配体对接到受体结合口袋中的能力。这些研究的结果将提供深入了解介导受体介导的过程的结合和激活的化学结构。通过生物分子模拟，拟议的研究将导致更有效的配体设计，这将增强纳米载体的交付。该项目由材料研究部的生物材料计划，刺激竞争研究的既定计划（EPSCoR），该奖项反映了NSF的法定使命，并被认为是值得支持的，使用基金会的知识价值和更广泛的影响审查标准进行评估。