Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death

Abstract

The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall Fe3O4 nanoparticles, Mn2+ ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/Fe3O4–Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (•OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

“…Mesoporous silica nanoparticles are another important platform as inorganic drug delivery carriers for tumor treatment. They have the advantages of low side effects, good biocompatibility and stability, relatively uniform size and a large specific surface area [ 307 , 308 ]. For example, Jang and colleagues developed hybrid mesoporous silica nanoparticles functionalized with β-cyclodextrin and 4-(phenylazo) benzoic acid for improved on-demand drug release.…”

NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

“…Ferroptosis, a newly defined type of programmed cell death, is closely related to oxidative stress and the disruption of redox homeostasis is also crucial for the chemoresistance of tumour cells ( 159 ). Wu et al ( 160 ) indicated that nanodrugs with silica particles used as carriers are able to dissolve and release Fe 3 O 4 particles and glutaminase inhibitors under acidic conditions, thus consuming glutathione in tumour cells and reversing the drug resistance of tumour cells to oxaliplatin by inducing ROS-dependent ferroptosis. Wang et al ( 161 ) indicated that ovarian tumour domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) and solute carrier family 7 member 11 (SLC7A11) directly bind to circ_BGN as RNA binding proteins, and circ_BGN significantly enhances OTUB1-mediated SLC7A11 deubiquitination, thereby suppressing ferroptosis.…”

Multivalent Polypeptide and Tannic Acid Cooperatively Iron-Coordinated Nanohybrids for Synergistic Cancer Photothermal Ferroptosis Therapy

“…CDT that employs the famous Fenton reaction to produce highly deleterious reactive oxygen species (ROS) in cancer cells has been increasingly investigated in the past decade, one of which is the so-called ferroptosis therapy (i.e., FT) based on iron nanoparticles. − As a peculiar modality for cancer treatment, ferroptosis is an oxidative stress-induced cell death marked by lethal lipid peroxide (LPO) that is different from apoptosis, necrosis, and autophagy. For example, ultrasmall Fe 3 O 4 and Mn 2+ co-loaded mesoporous silica nanoparticles have been constructed to achieve efficient ferroptosis by a peroxidase-like Fenton reaction . A high-performance self-cascade pyrite nanozyme has been fabricated for synergistic tumor ferroptosis–apoptosis, resulting in a thousand-fold catalytic activity compared to that of conventional Fe 3 O 4 .…”