Off-campus UMass Amherst users: To download campus access dissertations, please use the following link to log into our proxy server with your UMass Amherst user name and password.
Non-UMass Amherst users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Dissertations that have an embargo placed on them will not be available to anyone until the embargo expires.
Author ORCID Identifier
https://orcid.org/0000-0001-8975-1908
AccessType
Campus-Only Access for Five (5) Years
Document Type
dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Chemistry
Year Degree Awarded
2023
Month Degree Awarded
February
First Advisor
S. Thai Thayumanavan
Second Advisor
Hang Xiao
Subject Categories
Biotechnology
Abstract
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.
DOI
https://doi.org/10.7275/32966802
Recommended Citation
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.
https://doi.org/10.7275/32966802
https://scholarworks.umass.edu/dissertations_2/2790
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License