Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang

Abstract

Nephritis is one of the major complications of systemic lupus erythematosus (SLE). While glucocorticoids (GC) are frequently used as the first line treatment for lupus nephritis, long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol (PEG)-based macromolecular prodrug (ZSJ-0228) of dexamethasone, which self-assembles into micelles in aqueous media. When compared to the dose equivalent daily dexamethasone 21-phosphate disodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for two months significantly improved the survival of lupus-prone NZB/W F1 mice and was much more effective in normalizing proteinuria, with clear histological evidence of nephritis resolution. Different from the dose equivalent daily Dex treatment, monthly ZSJ-0228 administration has no impact on the serum anti-double-stranded DNA (anti-dsDNA) antibody level but can significantly reduce renal immune complex deposition. No significant systemic toxicities of GC (e.g. total IgG reduction, adrenal gland atrophy and osteopenia, etc.) were found to associate with ZSJ-0228 treatment. In vivo imaging, flow cytometry and pharmacokinetic studies reveal that the fluorescent or 125I-labeled ZSJ-0228 primarily distributes to the inflamed kidney after systemic administration, with renal myeloid cells and proximal tubular epithelial cells mainly responsible for its kidney retention. Collectively, these data suggest that the potent local anti-inflammatory/immunosuppressive effects and improved safety of ZSJ-0228 may be attributed to its tropism and cellular sequestration in the kidney. Pending further optimization, ZSJ-0228 may be developed into an effective and safe therapy for improved clinical management of lupus nephritis.

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