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Open Access Highly Accessed Research article

Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis

Dong Wang12*, Scott C Miller3, Xin-Ming Liu1, Brian Anderson3, Xu Sherry Wang14 and Steven R Goldring56

Author Affiliations

1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, NE 68198-6025, USA

2 Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA

3 Department of Radiology/Radiobiology Division, University of Utah, 729 Arapeen Dr., Salt Lake City, UT 84108, USA

4 Washington University in St. Louis, 6515 Wydown Blvd., Campus Box 3519, St. Louis, MO 63105, USA

5 Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA

6 New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA

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Arthritis Research & Therapy 2007, 9:R2  doi:10.1186/ar2106

Published: 18 January 2007

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37°C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.