Date of Award
8-19-2024
Degree Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmacology and Experimental Therapeutics
First Advisor
Eileen Foecking
Abstract
Statins lower endogenous production of cholesterol through their inhibition of the mevalonate pathway. Lipophilic statins in particular exhibit anti-inflammatory effects at supraphysiological doses by preventing downstream signaling through small molecule GTPases. Interest lies in development of statins as anti-inflammatory therapeutics, however, achieving effective doses locally incurs serious off-target effects. Our goal was to develop and optimize a targeted delivery system to traffic these drugs to inflamed sites and unload the drug at effective concentrations while avoiding systemic exposure. Lipophilic statins (lovastatin, simvastatin, and atorvastatin) were incorporated into polymeric nanoparticles (NPs) due to their hydrophobicity. We have shown that statins released from NPs are converted into active, hydrophilic metabolites in the body. As such, a parallel strategy was implemented to load statin-hydroxy acids into the core of extracellular vesicles. The surface of both loading strategies were enriched with targeting ligands harvested from monocyte plasma membranes to facilitate preferential migration towards sites of inflamed vasculature. Following synthesis, both nanoformulations were characterized for physical characteristics, such as size and drug loading, followed by analysis of release kinetics. Statin treatment inhibits RhoA activation and subsequent intercellular signaling involved in inflammation. To assess efficacy of each nanoformulation, in vitro assays were performed to assess downstream RhoA GTPase activation and localization in inflamed endothelial cells. Intracellular RhoA content was measured as a functional measure of efficacy of statin-loaded nanoformulations compared with free drug treatment.
Recommended Citation
Judkins, Stephanie, "Development of Targeted, Statin Loaded Nanoparticle Delivery Systems" (2024). Master's Theses. 4530.
https://ecommons.luc.edu/luc_theses/4530
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
