Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Amelioration of Lupus Nephritis by a Macromolecular Prodrug of Dexamethasone in NZB/W F1 Mice.
Yuan2, Fang, Nelson2, Richard K., Liu2, Xin-ming, Gould2, Karen A., Wang1, Dong
Though developed with specific molecular targets, most lupus nephritis drugs do not have tissue specificity to renal inflammation sites, leading to limited efficacy and potentially severe systemic side effects. To address this problem, we propose to develop P-Dex, a macromolecular prodrug of dexamethasone (Dex) using N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, which would specifically target the kidneys of lupus nephritis subjects to improve efficacy and reduce systemic toxcities associated with Dex phosphate treatment.
Female NZB/W F1 lupus-prone mice (16-wk-old) were treated with Dex phosphate (1.32 mg/kg, daily i.p. injections for 8 wks) and P-Dex (250 mg/kg, monthly i.v. injections for 8 wks) with HPMA homopolymer (PHPMA) and saline as controls. The overall doses of P-Dex and Dex phosphate are equivalent in terms of Dex content. Albuminuria was measured weekly using Ablustix. Mean arterial pressure (MAP) was measured by the tail cuff method every 4 wks. Serum was isolated from blood collected from the saphenous vein every 4 wks. Mice were sacrificed 1 wk after cessation of treatment (wk 9). Kidneys were harvested for histological assessment of nephritis. Femurs were harvested for bone mineral density (BMD) analysis.
P-Dex treatment of NZB/W F1 mice resulted in an attenuated onset of nephritis (as measured by durable albuminuria >= 2 or 100 mg/dL). At wk 9, the incidence of albuminuria was 0% in the P-Dex group, whereas the incidence of albuminuria was 100% in saline treated group, 70 % in PHPMA group and 46.7% in Dex phosphate group (p<0.001). A significant improvement of hypertension (MAP was reduced from 134±16 mmHg to 110±11 mmHg, p < 0.01) was only found in P-Dex treated group. Furthermore, the P-Dex treated group had a significantly higher femur BMD value than the Dex phosphate group (p < 0.001). No significant difference in BMD value was found among the P-Dex, saline and PHPMA groups.
P-Dex displayed highly efficient attenuation of lupus nephritis and improved renal function, compared to the treatment with equivalent dose Dex phosphate. It also significantly reduced the bone loss caused by long-term Dex phosphate treatment. Collectively, these data suggest that the macromolecular prodrug of dexamethasone could provide more effective amelioration of lupus nephritis with reduced systemic toxicity.
To cite this abstract, please use the following information:
Yuan, Fang, Nelson, Richard K., Liu, Xin-ming, Gould, Karen A., Wang, Dong; Amelioration of Lupus Nephritis by a Macromolecular Prodrug of Dexamethasone in NZB/W F1 Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :423