Collaborative Research: Zwitterionic polymers for mucosal penetration

第1部分：非技术总结该项目使用分子相互作用的直接测量来为聚合物穿透粘膜屏障的开发提供信息。粘液为保护组织免受细菌、病毒、过敏原和刺激物的侵袭提供了屏障。有趣的是，经粘膜给药是其他更具侵入性方法的一种有前途的替代方法，因为它具有良好的耐受性，并且能够针对特定的器官，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为材料合成策略提供信息。这个合作项目将使用全内反射显微镜实验来直接测量粘液膜和包覆有两性离子聚合物的颗粒之间的相互作用。两性离子聚合物是那些携带相同数量的正电荷和负电荷的聚合物，类似于细胞表面存在的脂类。该团队使用这些提供纳米级分辨率的测量来了解化学上不同的两性离子聚合物与粘液之间的相互作用，并提取聚合物化学对粘液可开透性的重要性。这项工作的教育影响集中在研究生和本科生的培训上。通过对西班牙裔学院和大学协会的学生成员进行辅导，努力留住本科生代表人数不足的少数群体。外展活动的重点是通过科罗拉多州-怀俄明州少数民族参与联盟(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。第2部分：技术总结本研究的中心是开发具有可控疏松作用的两性离子聚合物和粒子。为了了解载体-粘液相互作用和粘液传输，我们提出了一系列耦合目标，这些目标集成了聚合物的合成生物材料设计和明确定义的分子特征，以及对其粘液相互作用和粘液传输的直接KT尺度测量。对分子性质的控制，包括两性离子偶极取向和分子质量，将使我们能够全面检查这些特征对其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与粘液之间的KT和纳米尺度的相互作用，在有或没有硼酸靶向部分的情况下。最终，这些研究将提供关键知识，以迭代的方式为ZI粒子的设计和最佳性能提供信息。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传输的不同相互作用。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。

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.