Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy

Ferroptosis is a regulated cell death process caused by lipid peroxidation of membrane unsaturated fatty acids catalyzed by iron ions as defined in the review of Xiang et al. (2024). The rapid development of bio-nanotechnology has generated considerable interest in exploiting iron-induced cell death as a new therapeutic target against cancer. This article provides a comprehensive overview of recent advancements at the intersection of iron-induced cell death and bionanotechnology. In this respect, the mechanism of iron-induced cell death and its relation to cancer are summarized. Furthermore, the feasibility of a nano-drug delivery system based on iron-induced cell death for cancer treatment is introduced and analyzed. Secondly, strategies for inducing iron-induced cell death using nanodrug delivery technology are discussed, including promoting Fenton reactions, inhibiting glutathione peroxidase 4, reducing low glutathione levels, and inhibiting system Xc⁻. Additionally, the article explores the potential of combined treatment strategies involving iron-induced cell death and bionanotechnology. Finally, the application prospects and challenges of iron-induced nanoagents for cancer treatment are discussed.

 The occurrence and regulatory mechanisms of ferroptosis and the targets of nanoparticles intervention. (a) The schematic diagram of various nano delivery system carrier. (a-1) Nanoliposome. (a-2) Solid lipid nanoparticle. (a-3) Metal Organic Framework. (a-4) Exosome. (a-5) Hydrogel. (a-6) Polymeric micelle. (a-7) Dendrimer. (a-8) Gold nanoparticle. (b) The core network of ferroptosis regulation is roughly divided into three pathways. The first pathway involves iron metabolism, including iron import and export, storage or overload. The second pathway involves lipid metabolism including long-chain fatty acid CoA ligase 3/4 (ACSL3/4), and other enzymes. The third pathway involves amino acid metabolism, including the system Xc⁻/GSH/GPX4 pathway. [1]

Ferroptosis is quite novel in cyclodextrin research, too:

Xu et al. (2022) utilized pH-sensitive acetalated β-cyclodextrin (Ac-β-CD) to efficiently deliver dihydroartemisinin (DHA) for tumor ferroptosis therapy and chemodynamic therapy in a synergistic manner. The Ac-β-CD-DHA based nanoparticles are coated by an iron-containing polyphenol network. In response to the tumor microenvironment, Fe²⁺ /Fe³⁺ can consume glutathione (GSH) and trigger the Fenton reaction in the presence of hydrogen peroxide (H₂ O₂), leading to the generation of lethal reactive oxygen species (ROS). Meanwhile, the OO bridge bonds of DHA are also disintegrated to enable ferroptosis of cancer cells. 

Sun et al. (2023) studied the role of sterols including cholesterol in the ferroptosis. Forthese studies sterols dissolved in methyl-beta-cyclodextrin solution were used.

Deferoxamine (DFO) and deferiprone (DFP) are commonly used clinical iron chelators. The clinical efficacy of DFO in the treatment of Alzheimer disease is as high as 50%. However, the side effects, such as weight loss and loss of appetite limit its clinical application. Besides, DFO is difficult to pass through the blood-brain barrier (BBB), which could be solved by intranasal administration of DFO nanoparticles microparticles based on chitosan or methyl-beta-cyclodextrin (Rassu et al., 2015).

References

Rassu, G., Soddu, E., Cossu, M., Brundu, A., Cerri, G., Marchetti, N., et al. (2015). Solid microparticles based on chitosan or methyl-beta-cyclodextrin: A first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. J. Control. Release. 201, 68–77. doi: 10.1016/j.jconrel.2015.01.025

Sun, Q., Liu, D., Cui, W. et al. Cholesterol mediated ferroptosis suppression reveals essential roles of Coenzyme Q and squalene. Commun Biol 6, 1108 (2023). https://doi.org/10.1038/s42003-023-05477-8

Xiang D, Zhou L, Yang R, Yuan F, Xu Y, Yang Y, Qiao Y, Li X. Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy. Int J Nanomedicine. 2024;19:2091-2112
https://doi.org/10.2147/IJN.S448715

Xu M, Zha H, Han R, Cheng Y, Chen J, Yue L, Wang R, Zheng Y. Cyclodextrin-Derived ROS-Generating Nanomedicine with pH-Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy. Small. 2022 May;18(20):e2200330. doi: 10.1002/smll.202200330.