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

Abstract

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-labeled ZSJ-0228 primarily distributed 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 ZSJ-0228’s potent local anti-inflammatory/immunosuppressive effects and improved safety may be attributed to its nephrotropicity and cellular sequestration at the inflamed kidney tissues. Pending further optimization, it may be developed into an effective and safe therapy for improved clinical management of LN.

Head-to-head comparative pharmacokinetic and biodistribution (PK/BD) study of two dexamethasone prodrug nanomedicines on lupus-prone NZB/WF1 mice

“…The validity of this new prodrug design was evaluated in the NZB/W F1 mice with established nephritis. 19 As anticipated, the monthly ZSJ-0228 treatment for two months effectively normalized albuminuria with improved animal survival rate. Most importantly, no typical GC side effects, such as osteoporosis, immunosuppression and adrenal gland atrophy was detected.…”

“…Mass spectrometry (ESI and MALDI-TOF) was used to characterize the molecular weight of ZSJ-0228 (PEG-Dex). 19…”

“…Mice with two consecutive albuminuria readings over 2 (≥100 mg/dL) were considered as having established nephritis. 16,19 The mice were treated with either P-Dex-125 I (~280 mg/kg) or PEG-Dex-125 I (~108 mg/kg) by intravenous injection. They contain equivalent dose of Dex at 28 mg/kg as reported previously.…”

“…They contain equivalent dose of Dex at 28 mg/kg as reported previously. 16,19 Before injection, the initial dose (ID) of radioactivity was analyzed using a Packard Cobra II Gamma Counter to calculate the radioactivity per milligram prodrug and the radioactivity per mouse received. For each treatment, the treated mice were randomized into 9 groups (6 mice/group) and euthanized at different pre-designed time points postadministration (0.5, 2, 4, 6, 24, 72, 168, 336 and 672 hours).…”

“…To address this challenge, we proposed the development of ZSJ-0228 (PEG-Dex), an amphiphilic micelle forming PEG-based polymeric prodrug. 15,19 In its structural design, we maintained the same pathology-driven prodrug activation trigger (hydrazone bond, an acidcleavable linker) as P-Dex, but completely revamped the polymeric carrier design. PEG was selected as the carrier instead of HPMA copolymer because we have found the latter to have a relatively higher phagocytic potential.…”