Iron Oxide Nanocarrier-Mediated Combination Therapy of Cisplatin and Artemisinin for Combating Drug Resistance through Highly Increased Toxic Reactive Oxygen Species Generation

Combination therapy with multiple drugs through a multi-pronged assault as a strategy to combat cisplatin resistance shows great potential in biochemical therapy for cancer. However, inherent issues such as low drug loading and the poor synergistic effects of multiple drugs partially limit the further application of combination therapy. Here, we synthesized a new compound, ART-Chol, by coupling artemisinin and cholesterol as a base material combined with cyclic (Arg-Gly-Asp-D-Phe-Lys)]-poly(ethylene glycol) distearoylphosphatidylcholine (cRGD-PEG-DSPE) and phospholipids to form a magnetic liposome cRGD-AFePt@NPs encapsulating superparamagnetic ferric oxide nanoparticles and cisplatin for achieving high drug loading and a better synergistic effect. The cRG-DAFePt@NPs could be effectively internalized and responsively release loading cargos under alternating magnetic field irradiation due to local hyperthermia generated from magnetic nanoparticles by hysteresis loss and Neel relaxation. The generated Fe2+/Fe3+ from Fe3O4 NPs in the acid lysosomes motivated cisplatin and catalyzed the Fe-dependent anticancer drug artemisinin (ART) to generate highly toxic ROS through the Fenton reaction, which greatly enhances the anticancer effect of cisplatin with minimized side effects. In vitro cytotoxicity tests demonstrated that the cRGD-AFePt@NPs exhibited a 15.17-fold lower IC50 value of free cisplatin (IC50 = 32.47 mu M) against A549/R cells. Further flow-cytometry tests also showed obviously increased intracellular ROS generation and cell apoptosis rates. We highlight the potential for Fe2+/Fe3+-mediated combination therapy of cisplatin and ART for circumventing cisplatin drug resistance.