One-pot synthesis of ultrasmall ferric ion coupled mitoxantrone nanoparticles for high bioavailability and effective chemo-ferroptosis combination therapy of breast cancer

Mitoxantrone (MIT) as a first line anticancer drug, is usually suffered from poor bioavailability upon in vivo application. Although previous studies have developed some carriers to improve its bioavailability, they also have the shortage of low drug loading and reproducibility. Herein, we proposed a facile one-pot method to synthesize ultrasmall ferric ion coupled mitoxantrone nanoparticles (Fe-MIT NPs) for effective therapy of breast cancer. The important finding includes: 1) The Fe-MIT NPs exhibited an average size of 40 nm with good dis-persity and prolonged circulation in the bloodstream; 2) Fe-MIT NPs showed a high degree of accumulation within the tumor; 3) Fe-MIT NPs had a notable chemotherapy effect on cancer cells, which was achieved by increasing intracellular levels of reactive oxygen species (ROS); 4) The loaded Fe3+ within Fe-MIT NPs initiated ferroptosis through the Fenton reaction; 5) The ultrasmall size of the Fe-MIT NPs enabled better penetration of tumors. Therefore, when compared to free MIT, the Fe-MIT NPs delivered superior anticancer benefits. These benefits were observed in MCF-7 cells, MCF-7 multicellular tumor spheroids (MCTS), and MCF-7 tumor-bearing models.