Micelle-forming dexamethasone prodrug attenuates nephritis in lupus-prone mice without apparent glucocorticoid side effects

Zhenshan Jia, Xiaobei Wang, Xin Wei, Gang Zhao, Kirk W Foster, Fang Qiu, Yangyang Gao, Fang Yuan, Fang Yu, Geoffrey Milton Thiele, Tatiana K Bronich, James Robert O'Dell, Dong Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)7663-7681
Number of pages19
JournalACS Nano
Volume12
Issue number8
DOIs
StatePublished - Aug 28 2018

Fingerprint

nephritis
glucocorticoids
Prodrugs
Micelles
Dexamethasone
Glucocorticoids
mice
micelles
kidneys
dexamethasone 21-phosphate
adrenal gland
atrophy
dosage
normalizing
cytometry
Flow cytometry
Immunosuppressive Agents
Antigen-Antibody Complex
antibodies
Antibodies

Keywords

  • dexamethasone
  • glucocorticoid
  • lupus nephritis
  • micelle
  • prodrug
  • toxicity

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Cite this

Micelle-forming dexamethasone prodrug attenuates nephritis in lupus-prone mice without apparent glucocorticoid side effects. / Jia, Zhenshan; Wang, Xiaobei; Wei, Xin; Zhao, Gang; Foster, Kirk W; Qiu, Fang; Gao, Yangyang; Yuan, Fang; Yu, Fang; Thiele, Geoffrey Milton; Bronich, Tatiana K; O'Dell, James Robert; Wang, Dong.

In: ACS Nano, Vol. 12, No. 8, 28.08.2018, p. 7663-7681.

Research output: Contribution to journalArticle

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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.",
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AU - Foster, Kirk W

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AU - Gao, Yangyang

AU - Yuan, Fang

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AU - Thiele, Geoffrey Milton

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