Collaborative Research: Zwitterionic polymers for mucosal penetration

合作研究：用于粘膜渗透的两性离子聚合物

• 批准号: 2104499
• 负责人: Michael Bevan
• 金额: $ 11.25万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2104499&HistoricalAwards=false
• 关键词: Collaborative; Research; Zwitterionic; polymers; mucosal

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.

第 1 部分：非技术摘要该项目使用分子相互作用的直接测量来为聚合物的开发提供穿透粘膜屏障的信息。粘液提供了一道屏障，保护组织免受细菌、病毒、过敏原和刺激物的侵袭。有趣的是，经粘膜给药是其他更具侵入性的方法的一种有前途的替代方法，因为它具有良好的耐心依从性，并且能够靶向特定器官，同时提供改进的药物生物利用度。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。该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。两性离子聚合物是带有相同数量的正电荷和负电荷的聚合物，类似于细胞表面上存在的脂质。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指导，努力留住本科生中代表性不足的少数群体。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) 参与本科生的招募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。第 2 部分：技术摘要本研究的重点是开发具有可控粘液渗透性的两性离子聚合物和颗粒。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目标，其中整合了聚合物的合成生物材料设计、明确的分子特征以及粘液相互作用和粘液运输的直接 kT 尺度测量。对分子特性的控制，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其作为有效的粘膜穿透药物载体的性能的影响。同时，通过采用全内反射显微镜 (TIRM)，我们将直接且非侵入性地测量颗粒和粘液之间的 kT 和纳米级相互作用，无论是否有硼酸靶向部分。最终，这些研究将提供关键知识，以迭代方式为 ZI 粒子的设计和最佳性能提供信息。简而言之，拟议的工作将把 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相结合，以了解 ZI NP 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 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。