Combination Treatment of Murine Colon Cancer with Doxorubicin and Redox Nanoparticles.

Abstract

Conventional chemotherapeutic drugs such as doxorubicin (DOX) are associated with severe adverse effects such as cardiac, hepatic, and gastrointestinal (GI) toxicities. Excessive production of reactive oxygen species (ROS) was reported to be one of the main mechanisms underlying these severe adverse effects. Recently, we have developed 2 types of novel redox nanoparticles (RNPs) including pH-sensitive redox nanoparticle (RNP(N)) and pH-insensitive redox nanoparticle (RNP(O)), which effectively scavenge overproduced ROS in inflamed and cancerous tissues. In this study, we investigated the effects of these RNPs on DOX-induced adverse effects during cancer chemotherapy. The DOX-induced body weight loss was significantly attenuated in the mice treated with RNPs, particularly pH-insensitive RNP(O). We also found that cardiac ROS levels in the DOX-treated mice were dramatically decreased by treatment with RNPs, resulting in the reversal of cardiac damage, as confirmed by both plasma cardiac biomarkers and histological analysis. It was interesting to notice that, during cotreatment with DOX and RNPs, the DOX uptake was significantly enhanced in the cancer cells, but not in healthy aortic endothelial cells in vitro. Treatment with RNPs also improved anticancer efficacy of DOX in the colitis-associated colon cancer model mice in vivo. On the basis of these results, a combination of the novel antioxidative nanotherapeutics (RNPs) with conventional anticancer drugs seems to be a robust strategy for well-tolerated anticancer therapy.