Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang

Abstract

Inflammation is the complex biological response to the stimuli triggered by various factors like pathogens, damaged cells, or irritants. Constant uncontrolled acute inflammation may become chronic conditions, leading to significant tissue damage, contributing to a series of chronic inflammatory diseases. Our lab has been working on the different types of inflammatory diseases and has developed multiple macromolecular prodrug conjugates for the better therapeutic efficacy and reduced toxicity. The general approach we have taken is to incorporate small molecules containing monomers into water-soluble and biocompatible polymers, such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers. The superior and the sustained efficacy of those macromolecular prodrug may due to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS mechanism) at the inflammatory site. To extend of our prodrug application, in my research, (1) we investigated whether the prodrug copolymer system we designed could ameliorate injury-induced inflammation. We established traumatic brain injury model in mice by the controlled cortical impact. We successfully ameliorated the neuroinflammation caused by the traumatic brain injury using HPMA Dexamethasone copolymer conjugates. We also reduced the complication caused by traumatic brain injury such as systemic osteopenia. (2) We utilized HPMA Tofacitinib copolymer conjugates (P-Tofa) to ameliorate the inflammation at the colon in a mouse ulcerative colitis model. We proved its improved therapeutic efficacy by targeting and retaining at the colon tissue. (3) To further reduce the toxicity of systemic administrated therapeutic agents while increasing the targeting property, we designed a local drug delivery system named Local Extracorporeal Vascular Circuit (LEVC). We minimized the systemic exposure of the drug and achieved superior local accumulation of the drug in ischemia-reperfusion injury mouse model. Collectively, the results from these systematic studies provide us the insight of the wider application of these prodrugs in the treatment of inflammatory diseases.

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