DOI
https://doi.org/10.25772/WX32-7D35
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Qingguo Xu
Second Advisor
Douglas Sweet
Third Advisor
Matthew Halquist
Fourth Advisor
Joseph McClay
Fifth Advisor
Youngman Oh
Abstract
The eye has multiple protective barriers (tear film, cornea, blood-aqueous barrier, blood-retinal barrier) that limit drug penetration and retention, making targeted delivery to intraocular tissues very difficult. The overarching aim of this dissertation is to develop biodegradable nanoparticle and microparticle-based formulations for sustained drug delivery the anterior and posterior segments of the eye, to overcome the limitations of conventional ocular therapies, such as poor bioavailability, rapid drug clearance, and the need for frequent intraocular injection/administration.
For the first aim, fenofibrate-loaded PLGA microparticles (Feno-MP) were developed with high drug loading (25 wt%) and six-month sustained release suitable for intravitreal injection (Chapter 2). Fenofibrate (FDA-approved low-cost oral drug) is a peroxisome proliferator-activated receptor-α (PPARα) agonist. The lead formulation Feno-MP-F6 maintained therapeutic retinal drug levels for six months in rats and rabbits without toxicity. A 6-month-long therapeutic effects of a single dose of fenofibrate-loaded microparticles (Feno-MP) in both DR and AMD models via a non-VEGF PPARα–dependent mechanism was investigated. Therapeutic efficacy was demonstrated across three disease models: STZ-induced diabetic retinopathy, Vldlr-/- wet-AMD, and Abca4-/-/Rdh8-/- dry-AMD mice. Single injection of Feno-MP restored electroretinogram responses, reduced leukostasis, enhanced blood-retinal barrier function, decreased neovascularization and vascular leakage, and preserved photoreceptor survival with improved mitochondrial function.
For the second aim, A190, a novel non-fibrate PPARα agonist superior to fenofibrate in potency, selectivity and safety, was similarly formulated in biodegradable microparticles (A190-MP) providing six-month retinal drug detection. A190-MP demonstrated therapeutic benefits in both wet- and dry-AMD models, improving electroretinography, preserving cone photoreceptor density and outer nuclear layer thickness, reducing vascular pathology, and enhancing mitochondrial function through PPARα-dependent mechanisms (Chapter 3). In vitro studies confirmed A190's protective effects against oxidative stress in photoreceptor cells, with improved cell viability and mitochondrial function via PPARα activation.
Finally, for the third aim, dexamethasone sodium phosphate was encapsulated in PLGA nanoparticles (PLGA-DSP-NP) using zinc chelation bridging, resulting in 250 nm particles with 6.5 wt% drug loading and two-week sustained release, aimed for drug delivery to the front of the eye. In a nitrogen mustard-induced corneal injury model, single subconjunctival injection of PLGA-DSP-NP significantly outperformed topical drops, reducing corneal neovascularization, ulceration, and opacity by inhibiting inflammatory cytokines, angiogenic factors, and endothelial proliferation over the two-week study period (Chapter 4).
Together, these studies establish the pharmacokinetics, safety and efficacy of sustained-release polymeric microparticles and nanoparticles as viable ocular drug delivery systems for both the front and back of the eye. These formulations offer promising translational potential by minimizing dosing frequency, improving therapeutic outcomes, and enhancing patient adherence in the treatment of sight-threatening ocular disorders.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-30-2025