Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). While glucocorticoids (GC) are frequently being used as the first line treatment for LN, chronic exposure to GC has been associated with severe side effects, such as osteoporosis and immune suppression. To address this major clinical challenge, we have developed a polyethylene glycol (PEG)-based macromolecular dexamethasone prodrug (ZSJ-0228), which self-assembles into micelles. When compared to the dose equivalent daily dexamethasone phosphate sodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for 2 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 and flow cytometry studies reveal that the fluorescent-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 novel prodrug micelle design of ZSJ-0228 can greatly potentiate and prolong the local anti-inflammatory and immunosuppressive effects of Dex by passively targeting and retaining the prodrug to the inflamed kidneys via subcellular sequestration. Pending further optimization, it may be developed into an effective and safe therapy for improved clinical management of LN.

Development of a dexamethasone prodrug (ZSJ-0228) micelle formulation for effective and safe treatment of lupus nephritis

256th National Meeting (2018)

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