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

Int J Nanomedicine. 2024 Nov 16:19:11923-11940. doi: 10.2147/IJN.S480586. eCollection 2024.

Abstract

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 Fe3O4 nanoparticles (mFe3O4 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: mFe3O4 harboring multivalent elements (Fe2+/3+) could catalyze hydrogen peroxide (H2O2) 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 mFe3O4 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.

Keywords: BSO; Fenton reaction; chemodynamic therapy; ferroptosis; photothermal therapy.

MeSH terms

  • Animals
  • Buthionine Sulfoximine / pharmacology
  • Cell Line, Tumor
  • Ferroptosis* / drug effects
  • Glutathione* / metabolism
  • Humans
  • Hydrogen Peroxide / chemistry
  • Hydrogen Peroxide / pharmacology
  • Indoles* / chemistry
  • Indoles* / pharmacology
  • Iron / chemistry
  • Magnetite Nanoparticles / chemistry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Photothermal Therapy* / methods
  • Polymers / chemistry
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Glutathione
  • Indoles
  • Hydrogen Peroxide
  • polydopamine
  • Buthionine Sulfoximine
  • Polymers
  • Iron
  • Magnetite Nanoparticles