Targeted Manganese doped silica nano GSH-cleaner for treatment of Liver Cancer by destroying the intracellular redox homeostasis

Abstract

Background: Glutathione (GSH), the primary antioxidant in cells, could fight against oxidative stress. Tumor cells display a higher GSH level than normal cells for coping with the hyperoxidative state, which meets the requirements of enhanced metabolism and vicious proliferation. Therefore, the consumption of GSH will lead to cell redox imbalance and impede life activities. Herein, targeted sorafenib (SFB) loaded manganese doped silica nanoparticle (FaPEG-MnMSN@SFB) was constructed, which could destroy the intracellular redox homeostasis by consuming GSH. Methods: In this study, MnMSN was prepared by an optimized one-pot Stober's method for loading SFB, and FaPEG chain was modified on the surface of MnMSN to achieve long circulation and targeted delivery. The anticancer efficacy and mechanism of the designed FaPEG-MnMSN@SFB were assessed both in vitro and in vivo. Results: FaPEG-MnMSN@SFB exhibited efficient antitumor activity by dual depleting intracellular GSH (the degradation of MnMSN would consume intracellular GSH and the SFB would inhibit the effect of X c - transport system to inhibit GSH synthesis). Moreover, disruption of redox balance would lead to apoptosis and reactive oxygen species (ROS)-dependent ferroptosis of tumor cells. Conclusion: Such a GSH-starvation therapeutic strategy would cause multi-path programmed cell death and could be a promising strategy for cancer therapy.

RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer

“…GSH is one of the most important antioxidants and protects cells against lipid peroxide damage [ 38 , 61 ]. By utilizing GSH, ferroptosis is antagonized because lipid peroxides are reduced to their corresponding alcohols [ 9 , 11 ].…”

“…By utilizing GSH, ferroptosis is antagonized because lipid peroxides are reduced to their corresponding alcohols [ 9 , 11 ]. It is also not difficult to understand that, exhausting GSH is a potential way to trigger ferroptosis [ 38 , 62 , 63 ]. GSH can be synthesized from three critical amino acids: cysteine, glutamate and glycine [ 64 , 65 ].…”

“…RRM2 antagonizes sorafenib, an FDA-approved multikinase inhibitor, to treat liver cancer, possibly due to its function to partially rescue liver cancer cells from sorafenib-induced long-term cytotoxicity [ 37 ]. Recently, the roles of sorafenib in triggering ferroptosis have been established in liver cancer cells [ 38 , 39 ]. However, whether and how RRM2 protects liver cancer cells against ferroptosis is still not known.…”

Vascular endothelial cell-secreted exosomes facilitate osteoarthritis pathogenesis by promoting chondrocyte apoptosis

“…ROS measurements further supported this conclusion. Studies have shown that oxidative stress is closely associated with apoptosis, and if the ability of cells to resist oxidative stress is diminished, intracellular ROS increase and lead to cell apoptosis [ 25 – 28 ]. Western blotting was used to detect the expression of apoptosis-associated proteins.…”

The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

“…In recent years, the advantages of various new materials in cancer prevention and treatment have gradually emerged. Previous studies demonstrated that manganese-doped silica nanoparticle (MnMSN) can deplete GSH, and on-demand drug release can be achieved by loading sorafenib into MnMSN, while dual induction of ferroptosis is achieved by depletion of GSH and inhibition of intracellular GSH synthesis, showing efficient anti-HCC activity ( 17 ). Jiang and colleagues observed that a platelet membrane-camouflaged magnetic nanoparticle could sensitize ferroptosis by inhibiting system Xc − , which lead to immunosuppressive M2 TAM reversely polarize to the anti-tumor M1 phenotype, further increasing response to immunotherapy ( 18 ).…”