药理学
甲氨蝶呤
类风湿性关节炎
体内
关节炎
化学
细胞毒性
软骨
毒性
医学
体外
癌症研究
免疫学
内科学
生物化学
生物
生物技术
解剖
作者
Xianbin Wang,Weijun Cao,Chuanfen Sun,Yutie Wang,Mingyu Wang,Jiarong Wu
标识
DOI:10.1016/j.ijpharm.2022.121874
摘要
Rheumatoid arthritis (RA) is a chronic and symmetrical autoimmune disease that primarily characterized with articular synovial hyperplasia, joint swelling, cartilage and bone destruction. The in-depth understanding of the role of immune signaling pathway inhibitors provides inspiration for the construction of new and more effective strategy for RA therapy. In this study, by loading methotrexate (MTX) into an acetalated dextran biopolymer, AcDEX, we developed a pH-sensitive, MTX-loaded and molecularly targeted nanodrug MTX@pH-AcDEX NPs) to decrease the toxicity of MTX and simultaneously enhance its therapeutic effect. The resultant MTX@pH-AcDEX NPs showed the spherical morphology and notable pH-responsiveness with high drug loading of 88.32%. As demonstrated in vitro and in vivo, the reduced cytotoxicity of both RAW264.7 cells and LPS-activated RAW264.7 cells treated with MTX@pH-AcDEX NPs was found compared to free MTX. Upon intravenous administration into adjuvant-induced arthritis (AIA) rat model, the nanodrug had potent pharmacokinetic and pharmacodynamic profiles, which can accumulate in RA lesions and release MTX inhibitors for regulating the JAK-STAT pathways. As a result, the MTX@pH-AcDEX NPs achieved the cartilage and bone protective and a better anti-inflammatory effect with negligible systemic toxicity, suggesting the strong potential of safe and effective nanodrug for RA therapy as well as other autoimmune diseases.
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