Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA.
Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5900, USA.
Nanomedicine. 2022 Aug;44:102579. doi: 10.1016/j.nano.2022.102579. Epub 2022 Jun 26.
Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.
由于糖皮质激素（GCs）具有强大的免疫抑制和抗炎作用，因此被广泛用于治疗狼疮肾炎（LN）。然而，长期使用 GCs 会引起许多非靶向不良反应。为了减少 GCs 的不良反应，我们之前开发了两种聚合物地塞米松前药纳米药物：N-(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物地塞米松前药（P-Dex）和胶束形成的聚乙二醇（PEG）-based dexamethasone prodrug (ZSJ-0228)。P-Dex 和 ZSJ-0228 均能持续改善狼疮易感 NZB/W F1 小鼠的 LN ，同时减少 GC 相关不良反应。在这里，我们将研究扩展到 LN 的 MRL/lpr 小鼠模型。与等效剂量的地塞米松磷酸钠（Dex）每日治疗相比，每月 P-Dex 或 ZSJ-0228 治疗能更有效地减少蛋白尿并延长 MRL/lpr 小鼠的寿命。与每日 Dex 治疗不同，ZSJ-0228 与可测量的 GC 相关不良反应无关。相比之下，在 P-Dex 治疗的小鼠中观察到肾上腺萎缩。
