Activated macrophage-targeted dextran-methotrexate/folate conjugate prevents deterioration of collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, leading to articular synovial hyperplasia, cartilage destruction, and bone erosion. In RA pathophysiology, the activated macrophages contribute to the initiation and maintenance of the disease. Folate receptor, an overexpressed receptor on the activated macrophages, becomes a promising target site for RA treatment. In this work, the folate-modified dextran-methotrexate conjugate (noted as Dex-g-MTX/FA) was synthesized with an untargeted dextran-methotrexate prodrug (referred as Dex-g-MTX) as the control. The two prodrugs self-assembled into spherical micelles with both scales of about 90 nm and exhibited sustained MTX release. Dex-g-MTX/FA exhibited more superior cellular uptake mediated by the folate receptor and higher cytotoxicity toward macrophages activated by lipopolysaccharide (LPS) compared with Dex-g-MTX. Moreover, Dex-g-MTX/FA possessed improved biodistribution at the lesion site and stronger remission of RA through the inhibition of proinflammatory cytokines in comparison with both Dex-g-MTX and free MTX. These results demonstrated that the folate-targeted prodrug, i.e., Dex-g-MTX/FA, is a potential strategy for activated macrophage-targeted therapy of RA.