Augment of Ferroptosis with Photothermal Enhanced Fenton Reaction and Glutathione Inhibition for Tumor Synergistic Nano-Catalytic Therapy.

INTRODUCTION

Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by elevating intracellular iron levels or inhibiting glutathione peroxidase 4 (GPX4) activity. However, the intracellular antioxidative defense mechanisms endow tumor cells with ferroptosis resistance capacity. The purpose of this study was to develop a synergistic therapeutic platform to enhance the efficacy of ferroptosis-based tumor therapy.

METHODS

In this study, a multifunctional nano-catalytic therapeutic platform (mFeB@PDA-FA) based on chemodynamic therapy (CDT) and photothermal therapy (PTT) was developed to effectively trigger ferroptosis in tumor. In our work, iron-based mesoporous FeO nanoparticles (mFeO NPs) were employed for the encapsulation of L-buthionine sulfoximine (BSO), followed by the modification of folic acid-functionalized polydopamine (PDA) coating on the periphery. Then, the antitumor effect of mFeB@PDA-FA NPs was evaluated using Human OS cells (MNNG/HOS) and a subcutaneous xenograft model of osteosarcoma.

RESULTS

mFeO harboring multivalent elements (Fe) could catalyze hydrogen peroxide (HO) into highly cytotoxic ˙OH, while the tumor microenvironment (TME)-responsive released BSO molecules inhibit the biosynthesis of GSH, thus achieving the deactivation of GPX4 and the enhancement of ferroptosis. Moreover, thanks to the remarkable photothermal conversion performance of mFeO and PDA shell, PTT further synergistically enhanced the efficacy of CDT and facilitated ferroptosis. Both in vivo and in vitro experiments confirmed that this synergistic therapy could achieve excellent tumor inhibition effects.

CONCLUSION

The nanotherapeutic platform mFeB@PDA-FA could effectively disrupted the redox homeostasis in tumor cells for boosting ferroptosis through the combination of CDT, PTT and GSH elimination, which provided a new perspective for the treatment of ferroptosis sensitive tumors.