Polymeric dexamethasone prodrugs attenuate lupus nephritis in MRL/lpr mice with reduced glucocorticoid toxicity

• Published in: Nanomedicine Vol. 44; p. 102579
• Main Authors: Zhao, Zhifeng, Jiang, Haochen, Xu, Xiaoke, Jia, Zhenshan, Ren, Rongguo, Foster, Kirk W., Wei, Xin, Chen, Ningrong, Goldring, Steven R., Crow, Mary K., Wang, Dong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2022
• Subjects: Animals; Dexamethasone; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Glucocorticoids; Glucocorticoids - therapeutic use; Kidney; Lupus nephritis; Lupus Nephritis - drug therapy; Mice; Mice, Inbred MRL lpr; Mice, Inbred NZB; Polymeric prodrug; Polymers - pharmacology; Prodrugs - pharmacology; Prodrugs - therapeutic use; Toxicity; Dexamethasone; Lupus nephritis; Glucocorticoids; Toxicity; Polymeric prodrug
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2022.102579

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. Upon i.v. administration, both P-Dex and ZSJ-0228 passively accumulated in nephritic kidneys. When tested in lupus-prone MRL/lpr mice, both monthly P-Dex treatment and monthly ZSJ-0228 treatment demonstrated potent and sustained resolution of nephritis with an improved survival rate. Different from the dose equivalent daily dexamethasone treatment, ZSJ-0228 did not result in any measurable glucocorticoid-associated adverse effects while P-Dex showed limited adrenal gland atrophy. [Display omitted]