Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery

• DOI: 10.1016/j.biomaterials.2011.10.079
• Publication Date: 2011-11-17T20:06:53Z
• Authors: Sang-Won Lee; Ji-Hye Kim; Min-Chan Park; Yong-Beom Park; Wook Jin Chae; Tomohiro Morio; Dong-Ho Lee; Sang-Hwa Yang; Seung-Kyou Lee; Soo-Kon Lee; Sang-Kyou Lee
• Keywords: Male; Cell Membrane Permeability; Cell Death; Dose-Response Relationship, Drug; Administration, Cutaneous; Arthritis, Experimental; Receptors, Tumor Necrosis Factor; Etanercept; 3. Good health; Arthritis, Rheumatoid; Kinetics; Mice; Tetrahydrofolate Dehydrogenase; 03 medical and health sciences; Drug Delivery Systems; Methotrexate; Treatment Outcome; 0302 clinical medicine; Immunoglobulin G; Animals; Cytokines; Tissue Distribution; Inflammation Mediators

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is initiated and maintained by various inflammatory/immune cells and their cytokines, leading to cartilage degradation and bone erosion. Despite its potent therapeutic efficacy on RA, the oral administration of methotrexate (MTX) provokes serious adverse systemic complications, thus necessitating the local application of MTX. Here, we show that transcutaneous MTX (TC-MTX) can efficiently penetrate joint skin ex vivo and in vivo, and that TC-MTX can significantly improve the various inflammatory symptoms associated with RA. Further, TC-MTX preserved the joint-structures in mice with collagen-induced arthritis (CIA), which was also confirmed by three-dimensional micro-computed tomography scan. TC-MTX markedly decreased the secretion of inflammatory cytokines both in the serum and in inflamed joints of CIA mice. Further, its therapeutic potential is comparable to that of etanercept, a biological agent that block tumor necrosis factor (TNF)-α. Importantly, the systemic cytotoxicity of TC-MTX was not detected. Thus, TC-MTX can be a new therapeutic modality for RA patients without systemic complications.