Dr. Wang is an inventor on PCT patent application WO 2005/097073, which discloses the dexamethasone prodrug development.
Systemic Lupus Erythematosus
Dexamethasone prodrug treatment prevents nephritis in lupus-prone (NZB × NZW)F1 mice without causing systemic side effects
Article first published online: 28 NOV 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 12, pages 4029–4039, December 2012
How to Cite
Yuan, F., Nelson, R. K., Tabor, D. E., Zhang, Y., Akhter, M. P., Gould, K. A. and Wang, D. (2012), Dexamethasone prodrug treatment prevents nephritis in lupus-prone (NZB × NZW)F1 mice without causing systemic side effects. Arthritis & Rheumatism, 64: 4029–4039. doi: 10.1002/art.34667
- Issue published online: 28 NOV 2012
- Article first published online: 28 NOV 2012
- Accepted manuscript online: 8 AUG 2012 11:59AM EST
- Manuscript Accepted: 2 AUG 2012
- Manuscript Received: 21 DEC 2011
- NIH. Grant Number: R01-AR-053325
- Centers of Biomedical Research Excellence. Grant Number: RR-021937
To evaluate the potentially improved therapeutic efficacy and safety of nephrotropic macromolecular prodrugs of glucocorticoids (GCs) for the treatment of lupus nephritis.
Lupus-prone female (NZB × NZW)F1 mice received monthly injections of N-(2-hydroxypropyl) methacrylamide copolymer–based dexamethasone prodrug (P-Dex) or daily injections of dexamethasone phosphate sodium (Dex; overall dose equivalent to that of P-Dex) for 2 months. During treatment, the mice were monitored for albuminuria, mean arterial pressure, and serum autoantibody levels. Nephritis, renal immune complex levels, and macrophage infiltration were evaluated histologically. Bone quality was analyzed using peripheral dual x-ray absorptiometry and micro–computed tomography. The in vivo distribution of P-Dex was investigated using optical imaging, immunohistochemistry, and fluorescence-activated cell sorting (FACS). The antiinflammatory effect of P-Dex was validated using lipopolysaccharide-activated human proximal tubule epithelial (HK-2) cells.
Monthly P-Dex injections completely abolished albuminuria in the (NZB × NZW)F1 mice; this approach was significantly more efficacious than daily Dex treatment. P-Dex treatment did not reduce serum levels of anti–double-stranded DNA antibodies or renal immune complexes but did decrease macrophage infiltration, which is a marker of chronic inflammation. Immunohistochemical and FACS analyses revealed that P-Dex was primarily sequestered by proximal tubule epithelial cells, and that it could attenuate the inflammatory response in HK-2 cell culture. In contrast to Dex treatment, P-Dex treatment did not lead to any significant deterioration of bone quality or reduction in the level of total serum IgG.
Macromolecularization of GCs renders them nephrotropic. Protracted retention, subcellular processing, and activation of GC prodrugs by kidney cells would potentiate nephritis resolution, with a reduced risk of systemic toxicities.