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: 2104498
• 负责人: Margarita Herrera-Alonso
• 金额: $ 11.25万
• 依托单位: Colorado State 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 2024-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2104498&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：非技术摘要此项目使用分子相互作用的直接测量，以告知聚合物的发展以穿透粘膜屏障。粘液提供了保护组织免受细菌，病毒，过敏原和刺激性侵袭的障碍。有趣的是，透射药物输送是其他更具侵入性方法的有前途替代方法，因为它具有良好的耐心合规性，并且能够靶向特定的器官，同时提供改善的药物生物利用度。因此，粘膜输送方法的成功需要高度敏感的测量，以告知材料合成策略。该协作项目将使用全部内部反射显微镜实验直接测量粘液膜和涂有Zwitterionic聚合物的颗粒之间的相互作用。 Zwitterionic聚合物是携带相等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。该团队使用这些测量值（提供纳米尺度分辨率）来告知化学上不同的Zwitterionic聚合物和粘液之间的相互作用，并提取聚合物化学对粘液糖浆性的重要性。这项工作的教育影响重点是培训研究生和本科生的学生。通过为西班牙裔学院和大学协会的学生指导，为保留本科生不足的少数群体而努力做出了努力。外展活动集中于参与招募活动和夏季研究机会，以通过科罗拉多州的少数民族参与（Co-Wy Amp）为本科生提供本科生。重点还放在主持实验室的本科生，并通过SABE（巴尔的摩小学的STEM成就）计划参加K-5 STEM教育。第2部分：技术摘要研究围绕具有可控胶粘剂化训练的Zwitterionic聚合物和颗粒的发展。为了了解载体粘液相互作用和粘液转运，我们提出了一系列耦合的目标，这些目标整合聚合物的合成生物材料设计将定义明确的分子特性以及其粘液相互作用和粘液转运的直接KT量表测量。控制分子特性的控制，包括偶极子方向和分子量，将使我们能够全面检查这些特征对它们作为有效粘液胶化药物载体的性能的影响。同时，通过采用总内反射显微镜（TIRM），我们将直接和非智力测量颗粒与粘液之间的KT和纳米尺度相互作用，并具有有和没有硼酸靶向部分的硼酸。最终，这些研究将提供关键的知识，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，拟议的工作将结合Herrera-Alonso实验室的合成和自组装专业知识与Bevan Lab在TIRM测量方面的专业知识，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。奖项反映了NSF的法定任务，并通过使用基金会的智力优点和更广泛的影响审查标准评估值得支持。