Collaborative Research: Zwitterionic polymers for mucosal penetration

第一部分： 非技术总结本项目使用分子相互作用的直接测量来告知聚合物的开发以穿透粘膜屏障。粘液提供屏障以保护组织免受细菌、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心顺应性，并且能够靶向特定器官，同时提供改善的药物生物利用度。因此，粘膜递送方法的成功需要高度灵敏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粘液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上的脂质。该团队使用这些测量提供纳米级分辨率，以了解化学上不同的两性离子聚合物和粘液之间的相互作用，并提取聚合物化学对粘液渗透性的重要性。这项工作的教育影响侧重于对研究生和本科生的培训。通过对西班牙裔学院和大学协会的学生成员进行辅导，努力留住本科生中代表性不足的少数民族。外展活动中心通过科罗拉多-怀俄明州少数民族参与联盟（CO-WY AMP）参与招聘活动和本科生夏季研究机会。重点还放在接待本科生在实验室，并通过SABES（干成就巴尔的摩小学）计划参加K-5干教育。第二部分： 技术概述本研究围绕具有可控粘蛋白渗透的两性离子聚合物和颗粒的开发。为了了解载体-粘液相互作用和粘液运输，我们提出了一系列耦合的目标，这些目标整合了合成生物材料的聚合物设计，将明确定义的分子特征和直接的kT尺度测量其粘液相互作用和粘液运输。控制分子特性，包括两性离子偶极取向和分子量，将使我们能够进行全面的检查，这些特性对它们的性能作为有效的mucopenetrating药物载体的影响。同时，通过采用全内反射显微镜（TIRM），我们将直接和非侵入性地测量颗粒和粘液之间的kT和纳米级相互作用，有和没有硼酸靶向部分。最终，这些研究将提供关键知识，以迭代方式为ZI颗粒的设计和最佳性能提供信息。简而言之，拟议的工作将结合联合收割机的合成和自组装的专业知识Herrera-Alonso实验室与专业知识的贝文实验室的TIRM测量，以了解如何ZI NP的化学和结构导致不同的相互作用与粘液和扩散运输。这个奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

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.