Effect of co-administration of CoQ10-loaded nanoparticles on the efficacy and cardiotoxicity of doxorubicin-loaded nanoparticles

Abstract

The present study investigates the effects of the antioxidant and anticancer properties of CoQ10-NPs on the efficacy and toxicity of Dox. Cell culture experiments revealed a significantly higher cellular uptake of Dox- and CoQ10-NPs in MCF-7 cells, as compared to their free drug counterparts. Further, intracellular tracking demonstrated preferential localization of Dox-NPs in the vicinity of nucleus while that of CoQ10-NPs with reactive oxygen species (ROS) generating organelles viz. mitochondria and lysosomes. Furthermore, an H2DCFDA assay was employed to evaluate the antioxidant potential of CoQ10 formulations for inhibiting Dox-induced ROS, which was found to be significantly higher in the case of CoQ10-NPs. The concentration and time dependent cytotoxicity of Dox- and CoQ10-NPs against MCF-7 cells was significantly higher, as compared to the respective free drug. Furthermore, the cytotoxicity of the Dox/CoQ10 combination was evaluated and the interaction was analyzed by median-effect analysis. The results revealed antagonism at early time points up to 48h, as compared to their individual treatments which reverted to synergism at 72h. The lowest combination index (CI) 0.24 was observed in the case of the NPs combination for the Dox : CoQ10 in a dose ratio of 1 : 50 at 72h, while it was only 0.86 in the case of the free drug combination, revealing strong synergism in the case of the NPs combination, as compared to the free drug counterparts. In order to resolve the duality observed in cell culture experiments, both the prophylactic (reflecting antioxidant potential) and therapeutic (reflecting cytotoxicity) anticancer efficacy of the CoQ10 formulations were evaluated. CoQ10-NPs showed promising results in both cases. Co-administration of CoQ10-NPs with Dox-NPs showed ~1.69-fold and 4-fold higher antitumor efficacy, as compared to the Dox-NPs alone (per oral) and Dox (i.v.), respectively. In addition, the co-administration of CoQ10-NPs completely abolished the cardiotoxicity of the Dox formulation when measured as a function of levels of various biochemical parameters and by histopathological studies. In a nutshell, the combination regimen could be fruitfully exploited to improve the therapeutic efficacy and reduce the cardiotoxicity of Dox.