Targeted exosome‐encapsulated erastin induced ferroptosis in triple negative breast cancer cells

Abstract

Ferroptosis is an iron‐dependent, lipid peroxide‐driven cell death caused by inhibition of the cystine/glutamate transporter, which is of importance for the survival of triple‐negative breast cancer (TNBC) cells. Erastin is a low molecular weight chemotherapy drug that induces ferroptosis; however, poor water solubility and renal toxicity have limited its application. Exosomes, as drug delivery vehicles with low immunogenicity, high biocompatibility and high efficiency, have attracted increasing attention in recent years. Herein, we developed a formulation of erastin‐loaded exosomes labeled with folate (FA) to form FA‐vectorized exosomes loaded with erastin (erastin@FA‐exo) to target TNBC cells with overexpression of FA receptors. The characterization, drug release, internalization and anti–tumor effect in vitro of erastin@FA‐exo were determined. Erastin@FA‐exo could increase the uptake efficiency of erastin into MDA‐MB‐231 cells; compared with erastin@exo and free erastin, erastin@FA‐exo has a better inhibitory effect on the proliferation and migration of MDA‐MB‐231 cells. Furthermore, erastin@FA‐exo promoted ferroptosis with intracellular depletion of glutathione and reactive oxygen species overgeneration. Western blot analyses revealed that erastin@FA‐exo suppressed expression of glutathione peroxidase 4 (GPX4) and upregulated expression of cysteine dioxygenase (CDO1). We conclude that targeting and biocompatibility of exosome‐based erastin preparations provide an innovative and powerful delivery platform for anti–cancer therapy.

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

“…Ferroptosis is very important for the survival of TNBC cells; ferroptosis is an iron dependent non apoptotic cell death, which is closely related to GPX4 [28]. We rst found that compared with sh-NC group, the MDA level was signi cantly increased after GPX4 silencing (Fig.…”

“…After 8 hours, the cells were stained with 20 µM 2',7'-dichloro uorescein diacetates (Beyotime Biotechnology, Shanghai, China) in the dark at 37℃ for 30 minutes. The ROS level in the cells was observed by a uorescence microscope [28].…”

“…JC-1 mitoscreen assay 24 hours after transfection, mitochondrial membrane potential (MMP) assay kit with JC-1 (C2006, Beyotime) was used to detect the MMP. The cells were imaged with a uorescence microscope [28].…”

Ferroptosis: Final destination for cancer?

“…103,104 Recently, a great number of studies have found that exosomes have better advantages in drug delivery due to their low immunogenicity, high biocompatibility and high efficiency. 9 and PT greatly improved the treatment specificity, reduced the toxicity and enhanced the delivery efficiency. 106 One study reported that ultrasmall (<10 nm in diameter) silica nanoparticles can trigger ferroptosis in starved cancer cells and cancer-bearing mice.…”

“…In addition, some groups have tried to use nanoparticles and exosomes as carriers of erastin and drugs to precisely induce ferroptosis in tumour tissues. 9,10 These new findings and treatment attempts enrich the study of ferroptosis. Therefore, it is meaningful to review the main mechanisms underlying ferroptosis and their potential treatment value.…”