Poly-conjugated oligomers (p-COs) for noninvasive functional protein delivery

第一部分： 非技术总结蛋白质类药物由于其比传统的小分子药物更高的安全性，在管理和治疗许多疾病方面显示出巨大的前景和高影响力。不幸的是，目前这些基于蛋白质的药物的给药在很大程度上限于痛苦的侵入性注射，以达到血液中的治疗浓度。这种给药方法对患者来说是痛苦的，并且需要专业人员，这对于更广泛的疾病管理和治疗是明显的负担。这个基本问题是由于蛋白质的不稳定性和大尺寸。该项目最终将引入新型蛋白质递送材料，以解决目前阻碍蛋白质药物更友好使用的主要生物学障碍。在这个简短的项目中，将使用公认的细胞模型系统建立生物材料的蛋白质转运效率的可行性。 第二部分： 技术概述尽管治疗性生物制剂在临床上取得了很高的成功，但由于细胞的不渗透性和生物制剂的不稳定性，目前治疗性蛋白质的给药严重依赖于侵入性注射。对患者友好的非侵入性口服、鼻腔或吸入途径在很大程度上受到粘液扩散和跨上皮转运不良的限制。该项目的最终目标是开发一种概念上新的基于共轭低聚物（CO）的可降解聚合物（p-CO），可用于治疗性蛋白质的非侵入性递送。所提出的生物材料必须表现出与蛋白质的稳定复合、有效的粘液扩散和有效的上皮进入，然后经上皮转运至血液。在这个简短的项目中，模型p-CO/荧光蛋白复合物的跨上皮转运效率将通过监测覆盖有粘液表达上皮细胞单层的transwell基底外侧隔室中蛋白质的荧光强度来评估。该项目的成功完成将加强使用p-CO用于未来非侵入性蛋白质递送的可行性。最终，所提出的系统将对非侵入性（例如，该奖项反映了NSF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 SUMMARYProtein-based drugs have shown great promise and high impact in managing and treating many diseases owing to their higher safety profile than conventional small drugs. Unfortunately, the current administration of those protein-based drugs is largely limited to painful invasive injections to achieve therapeutic concentrations in the blood. Such administration methods are painful to the patient and require specialized personnel, which are an obvious burden for more widespread disease management and treatments. This fundamental issue is due to the instability and large sizes of proteins. This project will ultimately introduce novel protein delivery materials that address the major biological hurdles that currently block more patient-friendly uses of protein-based drugs. In this short project, the feasibility of protein transporting efficiency of a biomaterial will be established using a well-accepted cell model system. PART 2: TECHNICAL SUMMARYDespite the high clinical success of therapeutic biologics, the current administration of therapeutic proteins heavily relies on invasive injections due to cell impermeability and instability of biologics. Patient-friendly noninvasive oral, nasal, or inhalation routes are largely limited by poor mucus diffusion and transepithelial transport. The ultimate goal of this project is to develop a conceptually new conjugated oligomer (CO)-based degradable polymer (p-CO) that can be used for the noninvasive delivery of therapeutic proteins. The proposed biomaterials must exhibit stable complexation with proteins, efficient mucus diffusion, and efficient epithelium entry followed by transepithelial transport to the blood. In this short project, the transepithelial transport efficiency of model p-CO/fluorescent protein complexes will be assessed by monitoring the fluorescent intensity of proteins in the basolateral compartment of the transwell covered with a mucus expressing epithelium cell monolayer. The successful completion of this project would strengthen the feasibility of using p-COs for future noninvasive protein delivery. Ultimately, the proposed system would have a high transformative potential and broader impact on noninvasive (e.g., oral, nasal, or inhalation) delivery of biologics to treat or manage various disease or vaccine development.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.