Rational Design of Oral Drugs Targeting Mucosa Delivery

靶向粘膜递送的口服药物的合理设计

• 批准号: 10432446
• 负责人: Qun Wang
• 金额: $ 22.95万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432446
• 关键词: Antigens; Behavior; Biological; Cells; Chemistry; Coculture Techniques; Communicable Diseases; Cost efficiency; Data; Development; Drug Delivery Systems; Drug Targeting; Drug Transport; Encapsulated; Epithelial; Future; Glean; Goals; Gold; Gut Mucosa; Harvest; Health Personnel; Immune response; Immunological Models; Inflammatory; Intestinal Mucosa; Intestines; Intravenous infusion procedures; Knowledge; Learning; Liposomes; M cell; Mammalian Orthoreovirus; Mediating; Methods; Mission; Modeling; Modification; Mucosal Immune System; Mucous Membrane; Mutation; National Institute of Biomedical Imaging and Bioengineering; Oral; Oral Administration; Organ; Organoids; Outcome; Pathway interactions; Patients; Peyer' s Patches; Pharmaceutical Preparations; Phycoerythrin; Polymers; Proteins; Publishing; Research; Research Design; Route; Safety; Solid; Subcutaneous Injections; Surface; Testing; Training; Transport Process; Transportation; Vaccines; Virus-like particle; base; cell attachment protein; clinical application; clinical practice; design; drug candidate; improved; in vivo; insight; intestinal barrier; intestinal epithelium; monolayer; mucosa-associated lymphoid tissue; nanocage; nanoparticle; rational design; stem cells; synergism; targeted delivery; translational impact; treatment response; uptake

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.

1.项目摘要 通过肠粘膜的口服药物递送被认为比静脉内输注或静脉内给药对患者更友好。 关于诱导治疗，皮下注射。实际的优点包括减少了对 训练有素的医务人员、成本效益和更高的安全性。虽然取得了越来越多的进展， 潜在的口服递送粘膜药物的稳定性和先天激活， 细胞间和细胞内水平，这使得对特异性和非特异性因素的理解不足 确定候选药物穿过肠上皮的识别和转运。此外，委员会认为， 了解基于纳米颗粒的口服给药系统如何通过肠上皮细胞转运， 如何通过表面改性来操纵运输行为，以创建引导运输路径 通过肠上皮细胞将提供未来设计的基础和必要的知识， 开发用于口服给药的有效药物递送系统。因此，迫切需要填补这些 学习的差距，因为细胞间和器官水平的相互作用和由此产生的生物影响， 对于精确控制靶向肠粘膜的基于纳米颗粒的口服药物递送系统至关重要， 粘膜相关淋巴组织（MALT）。我的长期目标是研究并合理设计纳米颗粒- 用于治疗炎症和感染性疾病的口服药物递送系统。我在这个项目中的总体目标 是确定如何人工病毒样纳米颗粒（AVN）为基础的药物输送系统的目标和运输 在肠道粘膜免疫模型中。我的主要假设是哺乳动物的呼肠孤病毒细胞 附着蛋白σ1（MRV σ1）官能化的聚合AVN将通过诱导的M细胞靶向递送， 离体和体内肠上皮中的MALT细胞。拟议研究的理由是，在- 深入了解确定纳米颗粒在肠道中识别和转运的参数 将收集上皮细胞和体内口服药物递送的引导载体。收获的知识将进一步 使我们了解肠干细胞（ISCs）和MALT细胞在重编程过程中的遗传变化 进展，并提供新的见解，以开发口服药物递送策略，以治疗炎症和 传染病如果成功的话，我的策略将有助于开发精确和高效的 生产合理设计的用于临床应用的口服药物的方法和配方， 从根本上推进了口服给药领域。