Functionalized Tumor‐Targeting Nanosheets Exhibiting Fe(II) Overloading and GSH Consumption for Ferroptosis Activation in Liver Tumor

Abstract

incidences are increasing year by year. [2] As a newly discovered regulatory cell death, ferroptosis is a type of cell death caused by iron-dependent accumulation of lipid peroxides. [3][4][5] As we all known, normal liver is the important organ to store and metabolize iron. [6] Thus, inducing ferroptosis of liver tumor cells may be a new direction for specific treatment of liver tumors. Unfortunately, Sorafenib is currently the only anti-tumor chemotherapy drug that can treat liver tumors by inducing ferroptosis in clinical, but its drug resistance greatly affects the therapeutic effect. [7,8] Therefore, it is urgent to exploit novel strategies to induce ferroptosis in liver tumors.Briefly, ferroptosis is mainly induced in two modes: One is the classic ferroptosis induction mode, which destroys the membrane protective mechanism of tumor cells to activate ferroptosis by which is mainly managed by the GPX4 pathway. [9,10] GPX4 protein is considered the only glutathione peroxidase (GPXs) family molecule that protects biofilms from hydroperoxidation. [11] There are two main therapeutic methods targeting GPX4 pathway for inducing ferroptosis. The first one is the inactivation and depletion of GPX4 protein. [12] For example, (1S,3R)-RSL3 (RSL3) can covalently bind to the active site of GPX4, thereby mediating ferroptosis regulated by GPX4. [13,14] The second approach is to consume intracellular GSH content. [15] Reduced glutathione, a tripeptide form of antioxidant, can act as a synergistic molecule of GPX4 and assist GPX4 to eliminate lipid ROS. [16,17] Many nanomaterials with the ability to consume GSH have been demonstrated to activate ferroptosis, which provide additional strategies for inducing ferroptosis. [18][19][20] Cu(II) has been widely used for its excellent GSH consumption capacity. [21] Furthermore, another way to induce ferroptosis is named as nonclassical ferroptosis induction mode. Basically, the nonclassical mode is initiated by increasing the Fe 2+ content in tumor cells. [22] For instance, excessive activation of HMOX1 protein, down-regulated ferroportin expression and up-regulated transferrin expression could lead to overload Fe 2+ in tumor cells. [23][24][25] Some exogenous ironcontaining substances (hemin, FeCl 2 , and (NH 4 ) 2 Fe(SO 4 ) 2 ) can cause intracellular iron overloading, which can effectively Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX...

Cu-Hemin Nanosheets and Indocyanine Green Co-Loaded Hydrogel for Photothermal Therapy and Amplified Photodynamic Therapy

“…Cupric nitrate, PVP and hemin were mixed and stirred overnight, and the Cu-Hemin nanosheets were obtained by centrifugation ( 29 ). The transmission electron microscopy (TEM) images of Cu-Hemin are shown in Figure 1A , Cu-Hemin exhibits a random sheet-like structure with small nanoscale dimensions.…”

“…Thus, FeS 2 effectively depletes intracellular GSH, and at the same time produces a large amount of •OH to kill tumors. Cai et al developed novel Cu-Hemin-PEG-LA nanosheets to achieve synchronized GSH depletion and ferroptosis (29). As a new type of nanomaterial, Cu-Hemin has a good tumor killing effect, and the synthesis method is simple and convenient.…”

“…Cai et al. developed novel Cu-Hemin-PEG-LA nanosheets to achieve synchronized GSH depletion and ferroptosis ( 29 ). As a new type of nanomaterial, Cu-Hemin has a good tumor killing effect, and the synthesis method is simple and convenient.…”

Nanoprotection Against Retinal Pigment Epithelium Degeneration via Ferroptosis Inhibition

“…Measurement of ROS, LOS, and Ferrous Ions: Human ARPE-19 cells seeded in 24-well plates were incubated with compounds at determined times, and then intracellular levels of LOS, ROS, and ferrous ions were evaluated by C11-BODIPY (581/591) (5 µm), CM-H2DCFDA (5 µm) and FerroOrange fluorescent probe (10 µm), respectively, as previously described. [6,27] Cells were stained with these fluorescence probes in Hank's balanced salt solution (HBSS) for 30 min in an incubator. After washing with HBSS three times, FerroOrange and DCF fluorescence staining photos were imaged by fluorescence microscopy (Ex/Em = 488/525 nm).…”

Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM

“…Ferroptosis is a form of iron-dependent cell death. The essences of ferroptosis are the over-load of Fe 2+ , depletion of glutathione (GSH) and the decrease of glutathione peroxidase (GPX4) [ 17 , 18 ]. Lipid oxides cannot be metabolized through GPX4.…”