Collaborative Research: Zwitterionic polymers for mucosal penetration

第1部分：非技术概述本项目使用分子相互作用的直接测量来告知聚合物的发展，以穿透粘膜屏障。粘液提供了一个屏障，保护组织免受细菌、病毒、过敏原和刺激物的侵袭。有趣的是，经黏膜给药是一种有希望的替代其他更具侵入性的方法，因为它具有良好的耐心依从性，能够靶向特定器官，同时提供更好的药物生物利用度。因此，粘膜递送方法的成功需要高度敏感的测量来告知材料合成策略。这个合作项目将使用全内反射显微镜实验来直接测量黏液薄膜和涂有两性离子聚合物的颗粒之间的相互作用。两性离子聚合物是携带相同数量的正电荷和负电荷的聚合物，类似于存在于细胞表面的脂质。该团队利用这些提供纳米级分辨率的测量结果，来了解化学上不同的两性离子聚合物和黏液之间的相互作用，并提取聚合物化学对黏液渗透性的重要性。这项工作的教育影响主要集中在培养研究生和本科生。通过为西班牙裔学院和大学协会的学生成员提供指导，努力保留未被充分代表的本科生少数民族。外展活动的中心是通过科罗拉多-怀俄明少数民族参与联盟（CO-WY AMP）为本科生参与招聘活动和暑期研究机会。重点还放在实验室接待本科生，并通过SABES（巴尔的摩小学STEM成就）计划参与K-5 STEM教育。本研究的重点是开发具有可控黏液穿透性的两性离子聚合物和颗粒。为了理解载体-黏液相互作用和黏液运输，我们提出了一系列耦合目标，这些目标结合了聚合物的合成生物材料设计、明确的分子特征以及它们的黏液相互作用和黏液运输的直接kt尺度测量。控制分子特性，包括两性离子偶极子取向和分子量，将使我们能够全面检查这些特性对它们作为有效的黏液穿透药物载体的性能的影响。同时，通过使用全内反射显微镜（TIRM），我们将直接和非侵入性地测量颗粒和粘液之间的kT和纳米尺度的相互作用，有或没有硼酸靶向部分。最终，这些研究将以迭代的方式为ZI粒子的设计和最佳性能提供关键知识。简而言之，拟议的工作将结合Herrera-Alonso实验室的合成和自组装专业知识与Bevan实验室在TIRM测量方面的专业知识，以了解ZI NP的化学和结构如何导致与粘液和扩散运输的不同相互作用。该奖项反映了美国国家科学基金会的法定使命，并通过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，被认为值得支持。

PART 1: NON-TECHNICAL SUMMARYThis project uses direct measurements of molecular interactions to inform the development of polymers to penetrate the mucosal barrier. Mucus provides a barrier to protect tissue from invasion by bacteria, viruses, allergens, and irritants. Interestingly, transmucosal drug delivery is a promising alternative to other more invasive methods as it has good patience compliance and is able to target particular organs while offering improved drug bioavailability. The success of mucosal delivery methods thus requires highly sensitive measurements to inform materials synthesis strategies. This collaborative project will use total internal reflection microscopy experiments to directly measure interactions between mucus films and particles coated with zwitterionic polymers. Zwitterionic polymers are those that carry an equal number of positive and negative charges, similar to lipids present on the surfaces of cells. The team uses these measurements, which provide nanometer-scale resolution, to inform of the interactions between chemically different zwitterionic polymers and mucus, and to extract the importance of polymer chemistry on mucopenetrability. Educational impacts of this work are focused on training of students at graduate and undergraduate levels. Efforts to retain undergraduate underrepresented minorities are undertaken through mentoring for student members of the Hispanic Association of Colleges and Universities. Outreach activities center on involvement in recruiting activities and summer research opportunities for undergraduates through The Colorado-Wyoming Alliance for Minority Participation (CO-WY AMP). Focus is also placed on hosting undergraduate students in the laboratory and to participate in K-5 STEM education via the SABES (STEM Achievement in Baltimore Elementary Schools) program. PART 2: TECHNICAL SUMMARYThis research centers around the development of zwitterionic polymers and particles with controllable mucopenetration. To understand carrier-mucus interactions and mucus transport, we propose a series of coupled aims which integrate synthetic biomaterials design of polymers will well-defined molecular characteristics and the direct kT-scale measurements of their mucus interactions and mucus transport. Control over molecular properties, including zwitterion dipole orientation and molecular weight, will enable us to carry out a comprehensive examination of the effects of these characteristics on their performance as effective mucopenetrating drug carriers. Simultaneously, by employing Total Internal Reflection Microscopy (TIRM) we will directly and non-intrusively measure kT and nanometer scale interactions between particles and mucus, with and without boronic acid targeting moieties. Ultimately, these studies will provide critical knowledge to inform the design and optimal performance of ZI particles in an iterative fashion. In short, the proposed work will combine the synthetic and self-assembly expertise of the Herrera-Alonso lab with the expertise of the Bevan lab on TIRM measurements to understand how ZI NP chemistry and structure lead to different interactions with mucus and diffusive transport.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.