Combination chemotherapy regimens have been put forward to achieve a synergistic effect and reduce drug doses for the clinical applications of cancer treatment. One of the principal approaches for killing cancer cells involves triggering apoptotic cell death with anti-cancer drugs. Nevertheless, the efficacy of apoptosis induction in tumors is often restricted on account of intrinsic or acquired resistance of cancer cells to apoptosis. Ferroptosis, which involves reactive oxygen species (ROS), is another way to regulate cell death. Doxorubicin (DOX), a commonly used chemotherapeutic agent, can enter the nucleus and destroy tumor cells while also affecting mitochondria by producing semiquinone radicals. Therefore, a drug system combining ferroptosis and apoptosis, bridged by DOX-induced ROS, was proposed to be designed. Herein, we employed a facile and effective self-assembly method to prepare DOX-loaded nanocomplexes by DOX, Pluronic F-68, tannic acid (TA), and iron ions. TA and iron ions could not only improve the stability of nanocarrier but also facilitate achieving a ferroptotic effect. As a result, DOX@F-68/TA/Fe nanocomplexes showed a strong pro-apoptotic effect as well as an increase in intracellular oxidative stress. The improved oxidative stress further resulted in the ferroptosis of tumor cells. In vivo experiments demonstrated that DOX@F-68/TA/Fe efficiently targeted the tumor following intravenous injection and successfully inhibited tumor development.
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