Rational Design of Oral Drugs Targeting Mucosa Delivery

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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.