Dexamethasone prodrug nanomedicine (ZSJ-0228) treatment significantly reduces lupus nephritis in mice without measurable side effects — A 5-month study

• Published in: Nanomedicine Vol. 31; p. 102302
• Main Authors: Zhao, Zhifeng, Jia, Zhenshan, Foster, Kirk W., Wei, Xin, Qiao, Fangfang, Jiang, Haochen, Jin, Yan, Li, Guojuan, Chen, Ningrong, Zhao, Gang, Thiele, Geoffrey M., Medlin, Jennifer L., O’Dell, James R., Wang, Dong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021
• Subjects: Animals; Dexamethasone; Dexamethasone - therapeutic use; Glucocorticoids - therapeutic use; Incidence; Lupus nephritis; Lupus Nephritis - drug therapy; Lupus Nephritis - metabolism; Mice; Nanomedicine; Nanomedicine - methods; Prodrug; Prodrugs - therapeutic use; Side effects; ZSJ-0228; ZSJ-0228; Side effects; Dexamethasone; Prodrug; Lupus nephritis; Nanomedicine
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2020.102302

Lupus nephritis (LN) is a major cause of morbidity and mortality among systemic lupus erythematosus patients. Glucocorticoids (GCs) 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 based 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. [Display omitted] •The efficacy and safety of ZSJ-0228 were assessed in a 5-month long-term study.•ZSJ-0228 showed potent therapeutic efficacy with no measurable GC side effects.•Daily dexamethasone was also very effective but presented severe GC side effects.