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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\u2019s 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.<\/jats:p>","DOI":"10.1021\/acsnano.8b01249","type":"journal-article","created":{"date-parts":[[2018,7,2]],"date-time":"2018-07-02T16:56:59Z","timestamp":1530550619000},"page":"7663-7681","source":"Crossref","is-referenced-by-count":51,"title":["Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis\nin Lupus-Prone Mice without Apparent Glucocorticoid Side Effects"],"prefix":"10.1021","volume":"12","author":[{"given":"Zhenshan","family":"Jia","sequence":"first","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobei","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4213-451X","authenticated-orcid":true,"given":"Xin","family":"Wei","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zhao","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk W.","family":"Foster","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qiu","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Gao","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yuan","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yu","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey M.","family":"Thiele","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana K.","family":"Bronich","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"O\u2019Dell","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8340-2763","authenticated-orcid":true,"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , , ,","place":["Omaha, Nebraska, United States, 68198-6125"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,7,2]]},"reference":[{"key":"2026090308470742900_cit1","unstructured":"Lupus Foundation of America.\n          \n          https:\/\/resources.lupus.org\/entry\/facts-and-statistics. 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