| Co-delivery of two or more chemotherapeutic agents via nano carriers can provide an effective approach to maximize synergistic or additive effects.In this work,we developed novel nanodiamonds(NDs)based nanoparticles co-loading doxorubicin(DOX)and malaridine(MAL)for combination therapy of MCF-7 and multi-drug resistant MCF-7/ADR cells by virtues of good biocompatibility,high drug loading capacity and pHresponsive drug release properties of NDs.The results showed that the combination index(CI)was the smallest,for DOX and MAL against both MCF-7 and MCF-7/ADR cells,when their ratio was 5:1,showing their greatest synergistic effects.The CI values were 0.21 and 0.17,for MCF-7 and MCF-7/ADR cells,respectively.(DOX+MAL)@NDs or FA-PEG-DOX/(DOX+MAL)@NDs with different ratios of DOX to MAL(4:1,5:1 and 6:1)were prepared by simple physical adsorption of DOX,MAL and FA-PEG-DOX.Among them,(DOX+MAL)@NDs with the mass ratio of 5:1 had the smallest CI of 0.26 and 0.08,for MCF-7 and MCF-7/ADR cells,respectively.(DOX+MAL)@NDs were not stable in water,FA-PEGDOX/(DOX+MAL)@NDs could keep stable in water for 24 h due to steric repulsion effects offered by PEG,which also compromised their cytotoxicities to some extent.(DOX+MAL)@NDs or FA-PEGDOX/(DOX+MAL)@NDs presented faster DOX and MAL co-release at pH 5.5 than 7.4.Intracellular trafficking studies proved that all the nanoparticles were internalized into MCF-7/ADR cells via an endosome/lysosome pathway.The nanoparticles could effectively transport drugs into the cells nuclei.The high anti-tumor efficacy suggested that NDs mediated DOX and MAL co-delivery system could be promising for the combination therapy of breast cancer MCF-7 and multi-drug resistant MCF-7/ADR cells. |
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