Abstract
BackgroundMethotrexate (MTX) is one of the most widely used medications to treat rheumatoid arthritis (RA), and recent studies have also suggested the potential benefit of the drug for the treatment of osteoarthritis (OA) of the knee. MTX is commonly administered in oral formulations, but is often associated with systemic adverse reactions. In an attempt to address this issue, we have shown previously that a conjugate of hyaluronic acid (HA) and MTX exhibits potential as a drug candidate for intra-articular treatment of inflammatory arthritis. In this study, we compare the efficacy and safety of an optimized HA-MTX conjugate, DK226, with that of MTX in inflammatory arthritis rat models.MethodsIn vitro activity of DK226 was assessed in human fibroblast-like synoviocytes (HFLS) and a synovial sarcoma cell line, SW982. Release of MTX from DK226 was investigated after incubation with rabbit synovial tissue homogenate or synovial fluid. In vivo efficacy of DK226 was evaluated in antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) in the rat knee. Pharmacokinetics and hematological toxicity after treatment with oral MTX or an intra-articular injection of DK226 were compared in AIA.ResultsProliferation of HFLS and SW982 cells was inhibited by DK226, and the inhibitory activity was reversed by cotreatment with excess HA or anti-CD44 antibody. MTX was released from DK226 by incubation with rabbit synovial tissue homogenate or synovial fluid at pH 4.0, but not at pH 7.4. AIA was ameliorated by intra-articular DK226, but not by HA, as potently as oral MTX. Hematological toxicity was induced by oral MTX, but not by DK226. The maximum plasma concentration of MTX after oral MTX was 40 times higher than the concentration of MTX after an intra-articular injection of DK226. Knee swelling in AIA was inhibited by intra-articular injections of DK226, but not by free MTX or a mixture of HA and MTX. In CIA, an injection of DK226 into the right knee joint significantly reduced swelling and synovial inflammation of the treated knee joint, but had no effect on the untreated contralateral knee joint.ConclusionsDK226 exerted anti-arthritic effects in two different models of arthritis. The conjugate had a wider therapeutic window than oral MTX, and could be a future drug for treatment of arthritic disorders, including inflammatory OA.
Highlights
Methotrexate (MTX) is one of the most widely used medications to treat rheumatoid arthritis (RA), and recent studies have suggested the potential benefit of the drug for the treatment of osteoarthritis (OA) of the knee
PK parameters [time to reach maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), area under the plasma concentration-time curve calculated from time zero to infinity (AUCinf), and terminal phase elimination half-life (t1/2)] were calculated by a non-compartmental model
Anti-proliferative effects on synovial cells To verify the biological activity of DK226 and to confirm whether the conjugate binds to hyaluronic acid (HA) receptors, we examined the effects of DK226 on proliferation of synovial cells with or without exogenously added HA or antiCD44 antibody
Summary
Methotrexate (MTX) is one of the most widely used medications to treat rheumatoid arthritis (RA), and recent studies have suggested the potential benefit of the drug for the treatment of osteoarthritis (OA) of the knee. Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common chronic inflammatory joint diseases, but despite decades of extended research, there are still unmet needs in the treatment of these arthritic disorders, and notably, there are no disease-modifying OA drugs available at present [1]. Because recent clinical studies have shown that MTX reduces pain and inflammation in knee OA, MTX has been suggested as a new therapeutic option for OA treatment [13, 14]. An oral treatment such as MTX is not appropriate to treat OA, which is usually regarded as a localized disease, for which the optimal treatment is a therapy applied directly to the affected joint [17, 18]
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