Biomimetic Activator of Sonodynamic Ferroptosis Amplifies Inherent Peroxidation for Improving the Treatment of Breast Cancer

Abstract

Unlike other common modes of cell death, such as apoptosis, necrosis, and autophagy, ferroptosis is triggered by iron-dependent accumulation of lipid peroxides (LPO), resulting in an oxidation-reduction imbalance in cells. [2] It has been reported that ferroptosis is closely associated with the occurrence and progression of malignant diseases and particularly plays a critical role in regulating the sensitivity of cancer cells to anticancer treatments, suggesting its importance in cancer treatment. [3] Recently, significant efforts have been devoted to revealing the anticancer role of ferroptosis and various ferroptosis-based cancer therapies have been proposed to inhibit tumor growth. [4] However, current ferroptosis strategy has failed to fulfill therapeutic promise due to the complex, heterogenous, and dynamic tumor microenvironment. [5] Particularly, a very high dose of Fe ions is needed to achieve oxidative stress to initiate the ferroptosis process, which always leads to unsatisfied therapeutic effects on alleviating the disease progression. [4,6] To enhance the therapeutic efficacy, some ferroptosis-inducing agents have been developed, [7] such as ferroptosis activators including erastin, [8] sulfasalazine, [9] and buthionine sulfoximine, [10] as well as glutathione peroxidase 4 (GPX4) inhibitors including Ras selective lethal 3 (RSL3). [11] Ferroptosis is a type of nonapoptotic cell death and is gradually emerging as an important anticancer treatment. However, its therapeutic efficacy is impaired by low intracellular levels of reactive oxygen species (ROS) and long-chain polyunsaturated fatty acids, significantly limiting its therapeutic potential. Herein, a multimodal strategy to improve ferroptosis is presented, in which a state-of-art engineered erythrocyte, termed as sonodynamic amplified ferroptosis erythrocyte (SAFE), is developed for simultaneously activating ferroptosis and oxygen-riched sonodynamic therapy (SDT). SAFE is composed of internalizing RGD peptide and red blood cell membrane hybrid camouflaged nanocomplex of hemoglobin, perfluorocarbon, ferroptosis activator (dihomo-γ-linolenic acid, DGLA), and sonosensitizer verteporfin. It is identified that SAFE, under ultrasound stimulation, can not only substantially supply oxygen to overcome tumor hypoxia associated therapeutic resistance, but effectively activate ferroptosis through the coeffect of SDT triggered ROS production and DGLA mediated lipid peroxidation. In vivo studies reveal that SAFE selectively accumulates in tumor tissues and induces desirable anticancer effects under mild ultrasound stimulation. Importantly, SAFE can effectively inhibit tumor growth with minimal invasiveness, resulting in a prolonged survival period of mice. Therefore, a multimodal ferroptosis therapy driven by oxygen-riched sonodynamic peroxidation of lipids, significantly advancing synergistic cancer treatment, is presented.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smll.202106568.

Synergistic therapy for orthotopic gliomas via biomimetic nanosonosensitizer-mediated sonodynamic therapy and ferroptosis

“…The accumulation of LPO is considered to be a particular biomarker of ferroptosis, which contributes to the imbalance of oxidation-reduction and the destruction of the structure and integrity in cells. 17,26,36 In order to determine whether PIOC@CM-US induced LPO, the LPO content was measured in treated cells by flow cytometry. Fig.…”

“…In recent years, the combined treatment strategy of SDT and ferroptosis has been used in research on breast cancer and liver cancer. 17,[23][24][25][26] However, its application in orthotopic brain tumors has not been studied.…”

“…16 Notably, considering that SDT is caused by the stimulation of sonosensitizers to produce ROS to kill tumor cells, glutathione (GSH) is negatively regulated by high levels of ROS, which causes lipid peroxidation (LPO), and SDT has the potential to improve ROS-mediated ferroptosis. 17 Ferroptosis, first reported in 2012, 18 is characterized by increased LPO and GSH inhibition and is known to selectively eliminate drug-resistant tumor cells. 19–21 Importantly, ferroptosis is a programed cell death mode dependent on iron, which can react with excess H 2 O 2 in tumors to generate hydroxyl radicals (˙OH) via the Fenton reaction, further oxidize polyunsaturated fatty acids, and produce LPO that induces oxidative damage in cells.…”

The Regulatory Role of Ferroptosis in Bone Homeostasis

“…System Xc − is embedded into the cell membrane and as an effective cystine/glutamate antiporter system regulates the transport of cysteine and glutamate [ 20 ]. Glutamate is transferred outside the cell, while simultaneously, cystine is imported into the cell where it participates in the generation of GSH and thereby prevents ferroptosis [ 21 ]. A recent study reported that IFN- γ was capable of suppressing the expression of SLC3A2 and SLC7A11 via activation of JAK/STAT signaling, and repression of system Xc − could induce ferroptosis in hepatocellular carcinoma cells [ 22 ].…”

A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma

“…Ferroptosis is a recently identified form of programmed cell death that is dependent on iron (13,14). It has been linked with the outcomes of several cancers, including hepatocellular carcinoma, breast cancer, renal cell carcinoma, lung squamous cell carcinoma, and pancreatic carcinoma (15)(16)(17)(18)(19). Invasive and metastatic tumor cells have been found to be susceptible to ferroptosis (20) suggesting that targeting the process may be useful for treating cancer.…”