Therapeutic Approaches with Iron Oxide Nanoparticles to Induce Ferroptosis and Overcome Radioresistance in Cancers

Abstract

The emergence of nanotechnology in medicine, particularly using iron oxide nanoparticles (IONPs), may impact cancer treatment strategies. IONPs exhibit unique properties, such as superparamagnetism, biocompatibility, and ease of surface modification, making them ideal candidates for imaging, and therapeutic interventions. Their application in targeted drug delivery, especially with traditional chemotherapeutic agents like cisplatin, has shown potential in overcoming limitations such as low bioavailability and systemic toxicity of chemotherapies. Moreover, IONPs, by releasing iron ions, can induce ferroptosis, a form of iron-dependent cell death, which offers a promising pathway to reverse radio- and chemoresistance in cancer therapy. In particular, IONPs demonstrate significant potential as radiosensitisers, enhancing the effects of radiotherapy by promoting reactive oxygen species (ROS) generation, lipid peroxidation, and modulating the tumour microenvironment to stimulate antitumour immune responses. This review explores the multifunctional roles of IONPs in radiosensitisation through ferroptosis induction, highlighting their promise in advancing treatment for head and neck cancers. Additional research is crucial to fully addressing their potential in clinical settings, offering a novel approach to personalised cancer treatment.

Keywords: ferroptosis; head and neck cancers; metallic nanoparticles.

Figure 5

Representative transmission electron microscopy (TEM) images of variously shaped IONPs. (A) Nanospheres, (B) hexagons, (C) tetrahedrons, (D) cubes, (E) truncated octahedrons, (F) octahedrons, (G) concave cubes, (H) octapods, and (I) polypods. Reproduced from [139] under the terms of the Creative Commons Attribution (CC BY-NC) license. Since the potential applications of an IONP platform depend on its physicochemical properties (i.e., size, surface–volume ratio, crystallinity, and shape) (Figure 5), which can be modified through the synthesis processes employed, numerous synthesis strategies have been developed and optimised throughout the years. Each of them has their advantages and their disadvantages, which are briefly summarised in Table 2.

Figure 1

Overview of the different pathways involved in the induction of ferroptosis. Ferroptosis is a cell death pathway dependent on iron metabolism, lipid metabolism, and ROS metabolism. ROS production through the Fenton reaction can lead to the conversion of phospholipids hydroperoxide into phospholipid hydroperoxy radicals and promote excessive lipid peroxidation. Red dots: Fe³⁺ ions, yellow dots: Fe²⁺ ions, Tf: transferrin, STEAP3: STEAP3 metalloreductase, DMT1: divalent metal transporter 1, labile iron pool: represented in yellow and contains Fe²⁺, PCBP: poly (rC)-binding protein 1, NCOA4: nuclear receptor coactivator 4, ROS: reactive oxygen species, DHODH: dihydroorotate dehydrogenase (quinone), FSP1: ferroptosis suppressor protein 1, CoQ: coenzyme Q (ubiquinone), CoQH2: reduced form of coenzyme Q10 (ubiquinol), PUFAs: polyunsaturated fatty acids, PUFA-PLs: PUFA phospholipids, PUFA-PL-OOH: phospholipid hydroperoxide, PUFA-PL-OH: phospholipid alcohol, ACSL4: acyl-CoA synthetase long-chain family member 4, LPCAT3: lysophosphatidylcholine acyltransferase 3, xCT: cystine/glutamate antiporter, GSH: reduced glutathione, GSSG: oxidised glutathione, GPX4: glutathione peroxidase 4, BH4: tetrahydrobiopterin. Created using BioRender (https://www.biorender.com/).

Figure 2

Schematic representation of the molecular mechanisms of ferroptosis inducers and repressors in head and neck cancer cell models. The inducers are represented in green and include artesunate (indirectly increases ROS production), salinomycin (silences transporter DMT1) and erastin or sulfasalazine (inhibit transporter xCT). Knockdown of PCBP1 stimulates ferritinophagy. Cells undergoing epithelial–mesenchymal transition (EMT) seem to be more sensitive to ferroptosis inducers. The inhibitors are represented in red and include the activation of NRF2 and stimulation of iron storage through ferritin. RSL3: RAS-selective lethal small molecule 3. Created using BioRender (https://www.biorender.com/).

Figure 3

Main pathways identified leading to ferroptosis after radiotherapy, predominantly through lipid peroxidation or the suppression of the antiporter SLC7A11. xCT: cystine/glutamate antiporter, ER stress response: endoplasmic reticulum stress response, p53: tumour protein p53, PUFAs: polyunsaturated fatty acids, ACSL4: acyl-CoA synthetase long-chain family member 4, GSH: glutathione, GPX4: glutathione peroxidase 4, ROS: reactive oxygen species, cGAS: cyclic GMP–AMP synthase, STING: stimulator of interferon genes, ATM: protein kinase ataxia–telangiectasia mutated. Created using BioRender (https://www.biorender.com/).

Figure 4

Comparison of the XRD spectra of maghemite (a) and magnetite (b). Maghemite is known to present two additional peaks (in red; 210 and 211) in comparison to the magnetite. Reprinted with permission from [127].