Graduation Date

Summer 8-9-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang, PhD

Second Advisor

Geoffrey M. Thiele, PhD

Abstract

Addressing chronic inflammatory diseases such as focal segmental glomerulosclerosis (FSGS) and psoriasis requires treatments that not only provide effective relief but also minimize adverse effects. Central to our approach is the targeted delivery of potent anti-inflammatory and immune suppressive glucocorticoids (GC) directly to the sites of tissue pathology. This strategy enhances therapeutic efficacy and significantly reduces the side effects typically associated with GC therapy.

In the case of FSGS, a rare nephritis characterized by scarring and podocyte injury, we have developed a polyethylene glycol (PEG)-based dexamethasone (Dex) prodrug (PEG-Dex). This formulation focuses the drug's activity on the kidneys, limiting off-target effects. Our evaluations in an Adriamycin-induced BALB/c mouse model show that a single dose of PEG-Dex administered over five weeks markedly improves kidney function and reduces proteinuria more effectively than traditional Dex, with fewer side effects, indicating a promising advancement for FSGS treatment.

Similarly, for psoriasis—a condition typically treated with topical and intralesional glucocorticoids which can lead to skin atrophy and systemic side effects—we introduced a thermoresponsive Dex prodrug based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer (ProGel-Dex). Administered via a single intradermal injection in an imiquimod (IMQ)-induced psoriasis-like (PL) mouse model, ProGel-Dex significantly ameliorated skin pathology, including scaling, erythema, and inflammatory cytokines, without the glucocorticoid-related adverse effects observed with free Dex.

Both strategies employ highly reproducible and human disease relevant animal models to simulate disease pathology and treatment response. The FSGS model utilized an optimized Adriamycin dosing regimen to ensure consistent pathology while minimizing animal loss, and the psoriasis model enabled detailed assessments of cutaneous drug efficacy and safety. Collectively, these studies underscore the potential of targeted Dex prodrugs to improve treatment outcomes in chronic inflammatory diseases by delivering potent GCs to the sites of inflammation, thereby potentiating the therapy and significantly mitigating associated side effects. This represents a significant advancement in treatment paradigms.

Comments

2024 Copyright, the authors

Download

Available for download on Sunday, August 09, 2026

Share

COinS