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  • To meet the requirement of ferroptosis based therapy a coupl

    2022-01-25

    To meet the requirement of ferroptosis-based therapy, a couple of small molecule drugs and nanomaterials were introduced to the design of ferroptosis inducers, separately. As we know, iron is a key regulator of ferroptosis. When small molecule drugs are employed to induce ferroptosis, the endogenous iron will be essential for Fenton reaction based ROS generation. So how to increase the level of the endogenous iron becomes the key parameter to ferroptosis-based therapy when using small molecules as the drug [139], [151]. Meanwhile, the short half-life in blood, rapid renal clearance, or the poor selectivity against cancer cells associated with small molecule drugs sometimes limit their applications in clinic [25]. Therefore, nanomaterials provide a promising alternative to small molecule drugs considering the following advantages brought by their unique structures: Firstly, nanomaterials can specifically target the cancer cells or tissues through either passive targeting via EPR effect due to their small size or positive targeting by conjugating with specific ligands such as Arctigenin and aptamers [170], [171], [172], which can significantly decrease the side effects of drug to normal cells or tissues. Secondly, iron-based nanomaterials can provide enough exogenous iron to increase the efficiency of Fenton reaction, which results in highly toxic ROS accumulation and eventually accelerates the ferroptotic cancer cell death. Thirdly, the development of nanoparticles with specific functional properties, such as photodynamic effect, photothermal effect, magnetic hyperthermia effect, and imaging property, which are complementary to the traditional disease diagnostic and therapeutic reagents, provides a chance Arctigenin to fabricate multifunctional theranostic nanoplatforms for cancer management [173], [174], [175], [176], [177], [178]. And ferroptosis can be effectively combined with those functions of nanomaterials to form synergistic treatment or multifunctional theranostic tools to enhance the therapy efficiency, achieve real-time monitoring of treatment effect, and ultimately eliminate the tumor tissues. Herein, we systematically summarized the current progresses in developing novel nanomaterials for cancer specific therapy based on iron and ROS dependent ferroptosis. Firstly, the molecular mechanisms and pathways for ferroptosis regulation were fully discussed, including cystine/glutamate antiporter system Xc−, GPX4, iron metabolism and various molecular signaling pathways. By blocking system Xc−, the extracellular cysteine cannot be imported into cytoplasm, impeding GSH synthesis, and thus declining the anti-oxidative ability of cells. Meanwhile, due to the fact that GPX4 plays an important role in protecting cells from oxidative damage by physiologically transforming H2O2, small-molecule peroxides and various lipid peroxides into water or corresponding alcohols with assistance of GSH, the levels of GSH and GPX4 activity in cells are therefore key modulation targets of ferroptotic cell death. Moreover, Fe2+/Fe3+ can directly catalyze disproportionation of H2O2 to produce highly toxic OH via the Fenton reaction and accelerating the ferroptosis process. Then, the recent development of new novel nanomaterials, including iron-based nanomaterials and nanomaterials without iron that are able to induce ferroptotic cell death, were discussed in detail. Iron-based nanomaterials can directly supply Fe2+/Fe3+ to catalyze H2O2, to produce highly toxic ROS via the Fenton reaction, while some nanomaterials without iron can effectively utilize the endogenous iron to enhance the generation of highly toxic ROS in cancer cells, which finally results in cell death.
    Conflict of interests
    Acknowledgments This work was supported by the NSF of China (81771976 and 61527806), the National Key Research and Development Program of China (2017YFA0205301), Open Funding of State Key Laboratory of Oral Diseases (SKLOD2018OF02), Joint Funds of Nanjing Medical University and Southeast University (2017DN19) and Excellent Young Teachers Program of Nanjing Medical University (2015RC11).