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DEVELOPMENT OF AN ANIONIC NANOGEL SYSTEM FOR TARGETING DELIVERY OF THYROMIMETICS TO LIVER IN THE TREATMENT OF NONALCOHOLIC STEATOHEPATITIS (NASH) DISEASE
Author ORCID Identifier
Campus-Only Access for Five (5) Years
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
S. Thai Thayumanavan
Nonalcoholic fatty liver disease (NAFLD) has become a worldwide prevalent chronic disease but without approved treatment strategy so far. It is considered the manifestation of the metabolic syndrome and is a complex spectrum of liver diseases ranging from hepatic steatosis to its more aggressive inflammation phenotype, nonalcoholic steatohepatitis (NASH), which is characterized by inflammation, cellular ballooning and fibrosis in varying degrees. A potential medical intervention involves administration of synthetic thyroid hormone mimetics. However, the positive effects of thyromimetics on lipid metabolism are counterbalanced by their low biocompatibility and harmful effects in extrahepatic axis. In this dissertation, a novel liver-targeting anionic nanogel system is introduced to endow the liver selectivity to thyroid hormone mimetics and thereafter improve the therapeutic efficacy of them in the treatment of NASH disease.
In the first half of this dissertation, the liver-targeting cross-linked anionic nanogel (ANG) system prepared from a random co-polymer based on polyethyleneglycol-methacrylate hydrophilic monomer and pyridyldisullfide methacrylate hydrophobic monomer is demonstrated. The intracellular uptake studies and biodistribution studies suggested that the drugs were released from ANG and were delivered into liver efficiently. The potent therapeutic effect of thyromimetics encapsulated ANG is further evaluated using a healthy C57BL/6J mice model. All the findings in this part unraveled the successful preparation of a novel liver-targeting nanogel system for delivering thyromimetic drugs and the utility of ANG vehicle offers unique potential for treatment of NASH.
In the second half of this dissertation, the NASH disease models by maintaining C57BL/6J mice on a NASH-promoting diet is established. 5 week-treatment of CGS-ANG at a very low dose (10 μg/kg/day) on NASH-mice showed great efficiency in preventing or reversing NASH. Furthermore, the mechanism of CGS-ANG inhibition on liver steatosis, inflammatory liver injury and fibrosis is investigated. The results demonstrate a great potential of anionic nanogels to push forward the clinical application of thyromimetic drugs in NASH and its related metabolic dysfunction.
Wu, Ruiling, "DEVELOPMENT OF AN ANIONIC NANOGEL SYSTEM FOR TARGETING DELIVERY OF THYROMIMETICS TO LIVER IN THE TREATMENT OF NONALCOHOLIC STEATOHEPATITIS (NASH) DISEASE" (2023). Doctoral Dissertations. 2790.
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