Graduation Date

Fall 8-17-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Inflammatory bowel disease (IBD) is a chronic and remittent inflammation of the gastrointestinal tract (GIT). Despite extensive research efforts, there is no cure nor a well-defined pathogenesis for IBD. Loss of epithelial barrier function, increased colonic immune cell infiltration and upregulation of pro-inflammatory cytokines are the hallmarks of IBD. Despite treatments like painkillers, aminosalicylates, steroids, and biologics, almost 70% patients require surgery at least once in their life time. The main limitation with most of the current treatments is they are either absorbed systemically or administered systemically resulting in adverse side effects. As a result, there is a huge unmet need for therapies that can be safely and locally delivered to treat inflammation. Chloroquine (CQ) has been used as an anti-malarial for a long time and recently it has found anti-inflammatory applications. However, long term administration of CQ results in severe side effects like retinopathy because of systemic absorption. In this dissertation, we have re-designed CQ into a polymer (pCQ) and evaluated its potential as an orally administered IBD therapeutic. We found that pCQ showed preferential localization in the GIT which almost negligible systemic levels. We further evaluated the anti-inflammatory activity of pCQ in a mouse model of IBD and found reduction in colon v inflammation. We achieved this while reducing the systemic absorption almost 100 times which translates into an increased safety profile. We then assessed the effect of local delivery of combination of TNFα siRNA and polymeric CXCR4 antagonist (PCXA) via chitosan (CS) nanoparticles (NPs) in vivo. We found that the particles not only demonstrated a desirable size but also protected the siRNA against biorelevant conditions which are usually encountered in the GIT. Our results also indicate uptake of these particles by macrophages which are target cells and infiltrated the inflamed colon tissue in IBD. We tested the particles in vivo in a mouse model of colitis. We observed the therapeutic effect due to CXCR4 inhibition as well as observed TNFα silencing in the colon. Both these systems showed promise as local anti-inflammatory therapies. However, further development is needed to enhance their anti-IBD potential.

Available for download on Wednesday, July 29, 2020

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