Rational Design of Oral Drugs Targeting Mucosa Delivery

1.项目总结 通过肠道粘膜口服给药被认为比静脉输液或 关于诱导治疗的皮下注射。实际的优势包括减少了对 训练有素的医务人员、成本效益和更高的安全性。在不断取得进展的同时， 潜在的口服粘膜药物的稳定性和先天激活，存在显著的知识差距 细胞间和细胞内水平，这使得对特定和非特定因素的了解很差 确定候选药物在肠道上皮细胞中的识别和转运。此外， 了解纳米粒口服给药系统如何通过肠上皮和肠上皮 如何通过表面修饰来操纵传输行为以创建引导传输路径 将为未来的设计和设计提供基本和必要的知识 开发有效的口服给药系统。因此，迫切需要填补这些空白。 学习上的差距，因为细胞间和器官水平的相互作用以及由此产生的生物学影响 精确控制以肠粘膜和肠粘膜为靶点的纳米粒口服给药系统至关重要 粘膜相关淋巴组织(MALT)。我的长期目标是研究和合理设计纳米粒子- 基于口服给药系统，用于治疗炎症性和传染性疾病。我在这个项目中的总体目标 是确定基于人工病毒样纳米粒(AVNs)的药物递送系统是如何靶向和转运的 在肠道粘膜免疫模型中。我的中心假设是哺乳动物正病毒细胞 黏附蛋白σ1(MRVσ1)功能化的聚合AVNs将通过诱导的M细胞靶向递送 体外和体内肠上皮中的MALT细胞。建议进行研究的理据是： 决定纳米粒在肠道中识别和转运的参数的深度知识 收集体内口服给药的上皮细胞和引导载体。收获的知识将进一步 让我们了解肠道干细胞(ISCs)和MALT细胞在重新编程过程中的遗传变化 进展，并提供新的见解，以开发口服给药策略，以治疗炎症和 传染病。如果它成功了，我的战略将有助于开发精确和高效的 用于生产临床应用的合理设计的口服药物的方法和配方 从根本上推进口服给药领域。

1. PROJECT SUMMARY Oral drug delivery via the gut mucosa is considered more patient-friendly than an intravenous infusion or subcutaneous injection regarding induction of treatment. The practical advantages include reduced need for trained medical personnel, cost efficiency, and increased safety. While progress has been made increasing stability and innate activation of potential orally delivered mucosal drugs, significant knowledge gaps exist at the intercellular and intracellular levels, which leaves poor understanding of the specific and non-specific factors determining recognition and transport of drug candidates across the intestinal epithelia. Furthermore, understanding how nanoparticles-based oral drug delivery systems transport through intestinal epithelium and how the transport behavior can be manipulated through surface modification to create guided transport pathways through intestinal epithelium will provide fundamental and essential knowledge on future design and development of effective drug delivery systems for oral administration. Thus, there is an urgent need to fill these gaps in learning because the intercellular and organ level interactions and resultant biological influences are critical for precise control of nanoparticles-based oral drug delivery systems targeting intestinal mucosa and mucosal-associated lymphoid tissue (MALT). My long-term goal is to study and rationally design nanoparticles- based oral drug delivery systems to treat inflammatory and infectious diseases. My overall objective in this project is to determine how artificial virus-like nanoparticles (AVNs) based drug delivery systems target and transport within a gut mucosal immunological model. My central hypothesis is that the mammalian orthoreovirus cell attachment protein σ1 (MRV σ1) functionalized polymeric AVNs will target delivery through induced M-cells to MALT cells in the intestinal epithelium ex vivo and in vivo. The rationale for the proposed research is that in- depth knowledge of the parameters determining recognition and transport of nanoparticles across the intestinal epithelia and guided vehicle of oral drug delivery in vivo will be gleaned. The harvested knowledge will further equip us to understand genetic changes of intestinal stem cells (ISCs) and MALT cells during reprogramming progression and offer new insights to develop orally available drug delivery strategies to treat inflammatory and infectious diseases. If it is successful, my strategy would be instrumental in developing precise and efficient methods and formulas for producing rationally designed oral drugs for clinical applications, thereby fundamentally advancing the fields of oral drug delivery.