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

Dong Wang,Steven R Goldring,Brian Anderson,Scott C Miller,Xin-Ming Liu,X Sherry Wang

doi:10.1186/ar2106

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.

Highlights

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that leads to the destruction of diarthrodial joints
The molecular weight (Mw) of the conjugate was 73 kDa with a polydispersity index of 1.4 and this material was selected for use in the treatment study of the rats
Given that no difference in Mw was observed for P-Dex and its precursor, the possibility that both carbonyl groups in Dex would react with hydrazide and cause cross-linking of the polymer was minimal

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that leads to the destruction of diarthrodial joints. Many consider it to be an autoimmune disorder, the exact cause is unknown. The primary target of the inflammatory process is synovial tissue. The inflamed synovium invades and destroys articular bone and cartilage, leading to significant pain and disability [1,2,3]. The most commonly used medications for treatment and management of the disease include nonsteroidal anti-inflammatory drugs, glucocorticoids (GCs), and disease-modifying anti-rheumatic drugs, including

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