Micelle-Forming Dexamethasone Prodrug Attenuates Nephritisin Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

摘要

Nephritis is one of the major complications of systemic lupus erythematosus. While glucocorticoids (GCs) are frequently used as the first-line treatment for lupus nephritis (LN), long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol-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 GCs (e.g., total IgG reduction, adrenal gland atrophy, and osteopenia) were found to be associated with ZSJ-0228 treatment. In vivo imaging and flow cytometry studies revealed that the fluorescent-labeledZSJ-0228 primarily distributed to the inflamed kidney after systemicadministration, with renal myeloid cells and proximal tubular epithelialcells mainly responsible for its kidney retention. Collectively, thesedata suggest that the ZSJ-0228’s potent local anti-inflammatory/immunosuppressiveeffects and improved safety may be attributed to its nephrotropicityand cellular sequestration at the inflamed kidney tissues. Pendingfurther optimization, it may be developed into an effective and safetherapy for improved clinical management of LN.