Increasing the Production of Reactive Oxygen Species through a Ferroptosis Pathway Disrupts the Redox Balance of Tumor Cells for Cancer Treatment

Disruption of the balance of cellular redox can increase the cellular concentration of reactive oxygen species (ROS), which leads to oxidative stress-induced apoptosis in cancer cells, therefore minimizing the toxic effects on normal cells. However, this strategy is incomplete in programmable anticancer drug delivery. On the basis of this strategy, we designed, synthesized, and successfully functionalized an amphiphilic copolymer [poly(ethylene glycol) monomethyl ether (mPEG)-b-poly(hydroxyethyl methylacrylate)(PHEMA))-g-SS-hydroxybenzenoborate pinanol ester(HPBAe)/hydroxyethylferrocene (Fc)] that can form stable micelles in water and effectively load the hydrophobic drug doxorubicin (DOX). 1H NMR was used to confirm the structure of the polymers. Transmission electron microscopy (TEM) revealed that the blank or drug-loaded micelles were spherical. Blank micelles displayed negligible cytotoxicity. Ferrocene reacted with H2O2 to form hydroxyl radicals (·OH) through a Fenton or Fenton-like reaction for an enhanced antioxidant ability of cancer cells. H2O2-induced self-destruction of PHEMA can then release quinone methide (QM), which depletes glutathione (GSH) and suppresses the antioxidant capacity of tumor cells. This process can effectively attack cancerous cells through the synergistic effects of DOX, thus maximizing the therapeutic impact. Confocal microscopy also displayed that the drug could be efficiently delivered and released by micelles. Finally, the nano drug loading system containing ferrocene and pinacol phenylborate can actively increase the level of ROS in 4T1 cells and effectively kill 4T1 cells. This amphiphilic copolymer micelle is a stimuli-responsive nanomaterial and a promising therapeutic approach for cancer.