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

第1部分：基于蛋白质的非技术性药物在许多疾病的管理和治疗中显示出巨大的前景和高度的影响，因为它们比传统的小剂量药物具有更高的安全性。不幸的是，目前这些基于蛋白质的药物的使用在很大程度上仅限于痛苦的侵入性注射，以实现血液中的治疗浓度。这种给药方法对患者来说是痛苦的，需要专门的人员，这对更广泛的疾病管理和治疗来说是一个明显的负担。这一根本问题是由于蛋白质的不稳定和大尺寸造成的。该项目最终将引入新的蛋白质输送材料，以解决目前阻碍蛋白质药物更有利于患者使用的主要生物障碍。在这个简短的项目中，将使用一个被广泛接受的细胞模型系统来建立生物材料蛋白质运输效率的可行性。技术综述尽管治疗性生物制剂在临床上取得了很高的成功，但由于生物制剂的细胞不通透性和不稳定性，目前的治疗蛋白给药严重依赖侵入性注射。患者友好的非侵入性口腔、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)，可用于非侵入性输送治疗性蛋白质。建议的生物材料必须表现出与蛋白质的稳定络合，高效的粘液扩散，以及高效的上皮进入，然后跨上皮运输到血液。在这个简短的项目中，将通过监测覆盖有粘液表达上皮细胞单层的跨孔基底外侧室中蛋白质的荧光强度来评估模型p-CO/荧光蛋白复合体的跨上皮转运效率。该项目的成功完成将加强将p-CoS用于未来非侵入性蛋白质输送的可行性。最终，拟议的系统将对非侵入性(例如，口服、鼻腔或吸入)生物制剂的交付产生高度的变革潜力和更广泛的影响，以治疗或管理各种疾病或疫苗开发。该奖项反映了NSF的法定使命，并已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 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.