Background/Purpose: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). Glucocorticoids (GCs) are recommended by ACR as one of the first line treatments for LN. Long-term clinical use of GCs, however, is associated with an array of significant side effects.  To address this challenge, we have developed a novel macromolecular prodrug (ZSJ-0228) of dexamethasone (Dex) that passively targeted to the kidney, thereby effectively attenuates lupus nephritis with improved safety profile.   

Methods: Polyethylene glycol (PEG) was conjugated to Dex via hydrazone (an acid-cleavable linker) to create ZSJ-0228.  NZB/W F1 female mice (28 weeks old) received monthly i.v. injection of the prodrug or daily i.v. injection of dose equivalent dexamethasone phosphate sodium for 2 months.  The albuminuria level was monitored weekly. The end point serum cytokine panel was analyzed.  The bone quality was evaluated using m-CT.  The in vivo distribution of ZSJ-0228 was assessed using near infrared (NIR) imaging and the cell phenotypes that sequester the prodrug were investigated using flow cytometry.    

Results: When compared to dose equivalent daily Dex treatment, ZSJ-0228 markedly improved the survival of NZB/W F1 mice and is significant more effective in normalizing albuminuria; no significant systemic toxicity of GCs (i.e. WBC reduction, adrenal gland atrophy and osteopenia) was observed in the prodrug treated group; and there was a significantly lower serum level of proinflammatory cytokines (MCP-1, IFN-beta, IL-17A and GM-CSF) after 2 months treatment with ZSJ-0228.  NIR imaging showed that the prodrug primarily distributed in inflamed kidneys, and FACS results suggest that the Alexa 488-labeled prodrug was mainly sequestered by intraglomerular mesangial cells and proximal tubule epithelial cells.

Conclusion: Dex prodrug ZSJ-0228 significantly improves the therapeutic efficacy and safety of Dex.  Further structural optimization of the prodrug may lead to a new drug candidate for better and safer treatment of lupus nephritis.