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

[Image: see text] 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 d...

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Autores principales: Jia, Zhenshan, Wang, Xiaobei, Wei, Xin, Zhao, Gang, Foster, Kirk W., Qiu, Fang, Gao, Yangyang, Yuan, Fang, Yu, Fang, Thiele, Geoffrey M., Bronich, Tatiana K., O’Dell, James R., Wang, Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117746/
https://www.ncbi.nlm.nih.gov/pubmed/29965725
http://dx.doi.org/10.1021/acsnano.8b01249
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author Jia, Zhenshan
Wang, Xiaobei
Wei, Xin
Zhao, Gang
Foster, Kirk W.
Qiu, Fang
Gao, Yangyang
Yuan, Fang
Yu, Fang
Thiele, Geoffrey M.
Bronich, Tatiana K.
O’Dell, James R.
Wang, Dong
author_facet Jia, Zhenshan
Wang, Xiaobei
Wei, Xin
Zhao, Gang
Foster, Kirk W.
Qiu, Fang
Gao, Yangyang
Yuan, Fang
Yu, Fang
Thiele, Geoffrey M.
Bronich, Tatiana K.
O’Dell, James R.
Wang, Dong
author_sort Jia, Zhenshan
collection PubMed
description [Image: see text] 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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spelling pubmed-61177462018-09-04 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 M. Bronich, Tatiana K. O’Dell, James R. Wang, Dong ACS Nano [Image: see text] 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. American Chemical Society 2018-07-02 2018-08-28 /pmc/articles/PMC6117746/ /pubmed/29965725 http://dx.doi.org/10.1021/acsnano.8b01249 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Jia, Zhenshan
Wang, Xiaobei
Wei, Xin
Zhao, Gang
Foster, Kirk W.
Qiu, Fang
Gao, Yangyang
Yuan, Fang
Yu, Fang
Thiele, Geoffrey M.
Bronich, Tatiana K.
O’Dell, James R.
Wang, Dong
Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects
title Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects
title_full Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects
title_fullStr Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects
title_full_unstemmed Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects
title_short Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects
title_sort micelle-forming dexamethasone prodrug attenuates nephritis in lupus-prone mice without apparent glucocorticoid side effects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117746/
https://www.ncbi.nlm.nih.gov/pubmed/29965725
http://dx.doi.org/10.1021/acsnano.8b01249
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