ORCID ID

0000-0002-4635-0685

Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang, PhD

Abstract

Lupus nephritis (LN) is a significant cause of morbidity and mortality among lupus patients. Glucocorticoids (GCs) are uniformly used in clinical LN management. Their notorious toxicities, however, have hampered the long-term clinical application. To circumvent GCs’ adverse effects while maintaining their potent therapeutic efficacy, we have developed a micelle-forming polyethylene glycol (PEG)-conjugated dexamethasone prodrug (ZSJ-0228), which could passively target the inflamed kidney in NZB/W F1 lupus-prone mice. It was found that monthly ZSJ-0228 treatment for five months significantly reduced the incidence of nephritis in NZB/W F1 mice with an improved survival rate. Unlike the dose equivalent daily dexamethasone treatment, long-term monthly ZSJ-0228 did not result in any measurable GC-associated adverse effects. To help the clinical translation of ZSJ-0228, we have employed a dose-escalation design to explore the optimal dose-response of ZSJ-0228 in treating LN in NZB/W F1 mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicated that the most effective dose range for ZSJ-0228 in treating LN was between 1.0 and 3.0 mg/kg/day dexamethasone equivalent. Typical GC-associated adverse effects (e.g., osteopenia and adrenal glands atrophy) were not observed in any ZSJ-0228 treatment groups, confirming its excellent safety profile. Due to the heterogeneity of lupus disease, we evaluated the efficacy and safety of ZSJ-0228 in another lupus mouse model, MRL/lpr mice. Compared to the dose equivalent daily dexamethasone treatment, the monthly ZSJ-0228 treatment was much more effective in treating proteinuria and expanding the lifespan of MRL/lpr mice. More importantly, the monthly ZSJ-0228 administration did not cause any measurable GC-associated adverse effects. With its outstanding efficacy and exceptional safety, it is anticipated that ZSJ-0228 could be developed into a novel therapy for the clinical management of LN.

Available for download on Thursday, January 18, 2024

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