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A methotrexate (MTX) conjugated polymeric mixed micelles for MDR cancer therapy was developed in this study. To the best of our knowledge, MTX was firstly reported to be conjugated with Pluronic P105 (P105-MTX). The Pluronic F127 and P105-MTX polymeric mixed micelles (F127/P105-MTX) were fabricated by thin-film hydration technique, and performed superiority over physically entrapped MTX mixed micelles in drug loading capacity. The drug loading of MTX in F127/P105-MTX was found to be 3.42-fold higher than that of physically entrapped MTX mixed micelles. By conjugated to Pluronic, the amount of MTX in mixed micelles was increased 3.42-fold. In vitro cytotoxicity, cell apoptosis and cell cycle arrest studies also demonstrated that F127/P105-MTX had better antitumor efficacy in KBv MDR cells compared to that of physically entrapped mixed micelles. In comparison with MTX injection, F127/P105-MTX can significantly enhance blood circulation time of MTX in rats. Moreover, a much stronger antitumor efficacy in KBv xenografts mice was observed in F127/P105-MTX group than that of MTX. Therefore, MTX-conjugated mixed micelles might be an effective platform for delivering chemotherapeutic agents to MDR tumors.