Bone-targeted methotrexate–alendronate conjugate inhibits osteoclastogenesis in vitro and prevents bone loss and inflammation of collagen-induced arthritis in vivo

Drug Delivery

An Qin¹  Jianfeng Zhang²  Shunwu Fan²  Shuai Chen²  Zi’ang Xie³  Pan Tang³  Xuewu Sun³  Guanxiong Liu⁴  Peizhi Zhu⁴ 

[1] Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR Chin;Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China;Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China;Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China;School of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu, China;

关键词: Rheumatoid arthritis;    bone targeting;    methotrexate;    alendronate;    therapeutic;   

DOI  :  10.1080/10717544.2017.1422295

来源: publisher

【 摘 要 】

Rheumatoid arthritis (RA), a disease that causes joint destruction and bone erosion, is related to osteoclast activity. RA is generally treated with methotrexate (MTX). In this study, a MTX–Alendronate (ALN) conjugate was synthesized and characterized. The conjugate dramatically inhibited osteoclast formation and bone resorption compared with MTX and ALN used alone or in combination. Due to the characteristics of ALN, the MTX–ALN conjugate can adhere to the exposed bone surface and enhance drug accumulation in the pathological region for targeted therapy against osteoclastogenesis. Additionally, MTX was rapidly released in the presence of lysozyme under mildly acidic conditions, similar to inflammatory tissue and osteoclast-surviving conditions, which contributes to inflammatory inhibition; this was confirmed by the presence of pro-inflammatory cytokines. Our study highlights the use of the MTX–ALN conjugate as a potential therapeutic approach for RA by targeting osteoclastogenesis.

【 授权许可】

CC BY