Synergistic Effect and Drug-Resistance Relief of Paclitaxel and Cisplatin Caused by Co-Delivery Using Polymeric Micelles

Combination therapy of paclitaxel (PTX) and cisplatin has been used to treat several cancers in clinic practice, but often causes serious systemic toxicity. Co-delivery of PTX and cisplatin by means of polymeric micelles can reduce the systemic toxicity, but often needs two carrier polymers because of the solubility difference between them. Therefore, a strategy is developed to co-deliver both PTX and cisplatin with only one carrier polymer by encapsulating PTX in the core of a polymeric micelle and cross-linking the micelle with cisplatin. The PTX and Pt contents in the micellar formulation M(PTX/Pt) were 10 and 14 wt %, respectively. In vitro cytotoxicity of M(PTX/Pt) was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in comparison with PTX and its micelle M(PTX), cisplatin and its micelle M(Pt), and PTX/cisplatin combination towards human hepatocarcinoma (SMMC-7721) cells and chemoresistant SMMC-7721(SMMC-7721R) cells. The M(PTX/Pt) exhibited a high synergistic effect in the inhibition of cell growth and proliferation of both SMMC-7721 and SMMC-7721R cells and showed reasonable drug-resistance relief. The synergistic effect and resistance relief were further supported or explained by intracellular uptake measurement of dye-labeled micelles and by the confocal laser scanning microscopy observation of SMMC-7721 and SMMC-7721R cells treated with various formulations. Therefore, M(PTX/Pt) micelles were expected to find potential application in cancer chemotherapy. (C) 2014 Wiley Periodicals, Inc.