期刊
PHARMACEUTICAL RESEARCH
卷 33, 期 1, 页码 186-193出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-015-1776-1
关键词
collagen-induced arthritis; ELVIS; glucocorticoid; HPMA copolymer; prodrug
资金
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [R01 AR053325]
- Nebraska Arthritis Outcome Research Center (NAORC)
- University of Nebraska Medical Center
To investigate the efficacy and safety of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model. HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (mu-CT). The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint mu-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. mu-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity. These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC's on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis.
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