Dexamethasone prodrug nanomedicine (ZSJ-0228) treatment significantly reduces lupus nephritis in mice without measurable side effects - A 5-month study.
Dexamethasone prodrug nanomedicine (ZSJ-0228) treatment significantly reduces lupus nephritis in mice without measurable side effects - A 5-month study.
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DOI：
10.1016/j.nano.2020.102302
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Zhao Z;Jia Z;Foster KW;Wei X;Qiao F;Jiang H;Jin Y;Li G;Chen N;Zhao G;Thiele GM;Medlin JL;O'Dell JR;Wang D
狼疮性肾炎（LN）是系统性红斑狼疮患者发病和死亡的主要原因。糖皮质激素（GC）是临床LN治疗的统一用药。然而，它们臭名昭著的毒性阻碍了长期的临床应用。为了避免GC的副作用，同时保持其有效的治疗效果，我们开发了一种基于地塞米松的大分子前药纳米药物（PDJ-0228）。本研究的重点是研究其在狼疮易感NZB/W F1小鼠中的长期疗效，最重要的是安全性。NZB/W F1小鼠中，每月一次的NZB J-0228治疗5个月显著降低了肾炎的发病率，提高了存活率。与每天使用剂量等效的游离地塞米松治疗相反，长期每月使用GC-J-0228不会导致任何可测量的GC相关副作用。由于其出色的疗效和卓越的安全性，预计RESJJ-0228可能是一种新的治疗LN的长期临床管理。地塞米松前体药物是一种基于PEG的大分子前体药物纳米药物，其在水中可以自组装成胶束。静脉内给药后，PADJ-0228在肾炎肾中被动蓄积。当在患有狼疮性肾炎的NZB/W F1小鼠中测试时，每月一次的NSJ-0228治疗持续5个月显著降低了肾炎事件，提高了总存活率。与剂量等效的每日游离地塞米松治疗不同，每月一次的EPDJ-0228没有导致任何可测量的糖皮质激素相关副作用。
Lupus nephritis (LN) is a major cause of morbidity and mortality among systemic lupus erythematosus patients. Glucocorticoids (GC) are uniformly used in clinical LN management. Their notorious toxicities, however, have hampered the long-term clinical application. To circumvent GC side effects while maintaining their potent therapeutic efficacy, we have developed a macromolecular prodrug nanomedicine base on dexamethasone (ZSJ-0228). The focus of this study was to investigate its long-term efficacy and, most importantly, safety in the lupus-prone NZB/W F1 mouse. Monthly ZSJ-0228 treatment for five months significantly reduced the incidence of nephritis in NZB/W F1 mice with an improved survival rate. In contrast to treatment with dose equivalent daily free dexamethasone, long-term monthly ZSJ-0228 did not result in any measurable GC-associated side effects. With its outstanding efficacy and exceptional safety, it is anticipated that ZSJ-0228 may be a novel therapy for long-term clinical management of LN. As a PEG-based macromolecular prodrug nanomedicine of dexamethasone, ZSJ-0228 can self-assemble into micelles in water. Upon i.v. administration, ZSJ-0228 passively accumulated in nephritic kidneys. When tested in NZB/W F1 mice with lupus nephritis, monthly ZSJ-0228 treatment for 5 months significantly reduced nephritis incident with an improved overall survival rate. Different from the dose equivalent daily free dexamethasone treatment, the monthly ZSJ-0228 did not result in any measurable glucocorticoid-associated side effects.
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影响因子：
17.1
作者：
Quan, Lingdong;Zhang, Yijia;Crielaard, Bart J.;Dusad, Anand;Lele, Subodh M.;Rijcken, Cristianne J. F.;Metselaar, Josbert M.;Kostkova, Hana;Etrych, Tomas;Ulbrich, Karel;Kiessling, Fabian;Mikuls, Ted R.;Hennink, Wim E.;Storm, Gert;Lammers, Twan;Wang, Dong
通讯作者：
Wang, Dong
影响因子：
17.1
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
通讯作者：
Wang D
影响因子：
5
作者：
den Uyl, Debby;Bultink, Irene E. M.;Lems, Willem F.
通讯作者：
Lems, Willem F.
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：
82.9
作者：
通讯作者：
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