Nanodiamond mediated co-delivery of doxorubicin and malaridine to maximize synergistic anti-tumor effects on multi-drug resistant MCF-7/ADR cells.

Co-delivery of two or more chemotherapeutic agents via nanocarriers can provide an effective approach to maximize synergistic or additive effects. In this work, we developed novel nanodiamond (ND) based nanoparticle co-loading of doxorubicin (DOX) and malaridine (MAL) for treatment of MCF-7/ADR cells by virtue of the good biocompatibility, high drug loading capacity and pH-responsive drug release properties of NDs. The combination index (CI) was the smallest, 0.17, for DOX and MAL against MCF-7/ADR cells, when their ratio was 5 : 1, showing the greatest synergistic effects. (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 0.08. The concentrations of DOX and MAL for (DOX + MAL)@NDs producing 50% growth inhibition were 1.90 and 0.35 μg mL-1, respectively, smaller than the 50% inhibitory concentrations for DOX@NDs and MAL@NDs (10.75 and 4.38 μg mL-1) and for free DOX and free MAL (49.65 and 9.03 μg mL-1). (DOX + MAL)@NDs were not stable in water, FA-PEG-DOX/(DOX + MAL)@NDs could stay 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-PEG-DOX/(DOX + MAL)@NDs presented faster DOX and MAL co-release at pH 5.5 than 7.4. The high anti-tumor efficacy suggested that the ND mediated DOX and MAL co-delivery system could be promising for the treatment of multi-drug resistant cancer.