Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects.
Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects.
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DOI：
10.1021/acsnano.8b01249
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发表时间：
2018-08-28
期刊：
影响因子：
17.1
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Jia Z;Wang X;Wei X;Zhao G;Foster KW;Qiu F;Gao Y;Yuan F;Yu F;Thiele GM;Bronich TK;O'Dell JR;Wang D
肾炎是系统性红斑狼疮的主要并发症之一。虽然糖皮质激素（GC）经常被用作狼疮性肾炎（LN）的一线治疗，但长期使用GC通常会出现严重的不良反应。为了应对这一挑战，我们开发了地塞米松的基于聚乙二醇的大分子前药（PDJ-0228），其在水性介质中自组装成胶束。当与剂量等效的每日地塞米松21-磷酸二钠（Dex）治疗相比时，每月静脉内施用Dexamil J-0228持续两个月显著改善了狼疮倾向NZB/W F1小鼠的存活率，并且在使蛋白尿正常化方面更有效，具有肾炎消退的明确组织学证据。与剂量等效的每日Dex治疗不同，每月给予Dex J-0228对血清抗双链DNA（anti-dsDNA）抗体水平没有影响，但可显著减少肾脏免疫复合物沉积。GC无显著的全身毒性（例如，总IgG减少、肾上腺萎缩和骨质减少）与IGBJ-0228治疗有关。体内成像和流式细胞术研究显示，荧光标记的PADJ-0228在全身给药后主要分布于发炎的肾脏，肾脏骨髓细胞和近端肾小管上皮细胞主要负责其肾脏滞留。总的来说，这些数据表明，PADJ-0228的有效的局部抗炎/免疫抑制作用和改善的安全性可能归因于其向肾性和在发炎的肾组织处的细胞隔离。有待进一步优化，它可能会发展成为一种有效和安全的治疗方法，以改善LN的临床管理。
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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影响因子：
4.9
作者：
Krishnan V;Xu X;Barwe SP;Yang X;Czymmek K;Waldman SA;Mason RW;Jia X;Rajasekaran AK
通讯作者：
Rajasekaran AK
影响因子：
17.1
作者：
Dong H;Dube N;Shu JY;Seo JW;Mahakian LM;Ferrara KW;Xu T
通讯作者：
Xu T
影响因子：
4.7
作者：
Hahn, Bevra H.;McMahon, Maureen A.;Wilkinson, Alan;Wallace, W. Dean;Daikh, David I.;Fitzgerald, John D.;Karpouzas, George A.;Merrill, Joan T.;Wallace, Daniel J.;Yazdany, Jinoos;Ramsey-Goldman, Rosalind;Singh, Karandeep;Khalighi, Mazdak;Choi, Soo-In;Gogia, Maneesh;Kafaja, Suzanne;Kamgar, Mohammad;Lau, Christine;Martin, William J.;Parikh, Sefali;Peng, Justin;Rastogi, Anjay;Chen, Weiling;Grossman, Jennifer M.
通讯作者：
Grossman, Jennifer M.
影响因子：
5.8
作者：
Amsterdam, A;Tajima, K;Sasson, R
通讯作者：
Sasson, R
影响因子：
5
作者：
Bynote, K. K.;Hackenberg, J. M.;Gould, K. A.
通讯作者：
Gould, K. A.