Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity
Feng Wu1,2,3, Yaqian Du4, Jiani Yang1,2
1Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150001, People's Republic of China.
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.
Insights
This study developed a novel nanomedicine that depletes glutathione (GSH) to enhance cancer therapy. The nanomedicine restores oxaliplatin sensitivity by overcoming the antioxidant defense system, leading to tumor cell death.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Nanozymes show promise for tumor treatment but are limited by the tumor microenvironment's antioxidant defense system (ADS).
- Excessive glutathione (GSH) in tumors hinders nanozyme catalytic activity and contributes to drug resistance.
Purpose of the Study:
- To develop a nanomedicine that overcomes GSH-mediated limitations in the tumor microenvironment.
- To enhance the efficacy of cancer catalytic therapy and restore sensitivity to chemotherapy drugs like oxaliplatin.
Main Methods:
- Dendritic mesoporous silica nanoparticles (DMSNs) were engineered as nanocarriers.
- Ultrasmall Fe3O4 nanoparticles, Mn2+ ions, and the glutaminase inhibitor Telaglenastat (CB-839) were integrated into DMSNs, forming DMSN/Fe3O4-Mn@CB-839 (DFMC) nanomedicine.
- DFMC exhibits peroxidase-mimicking activity, depletes GSH, and inhibits its synthesis.
Main Results:
- DFMC catalyzes H2O2 decomposition into hydroxyl radicals, promoting ferroptosis.
- The nanomedicine effectively depletes GSH and blocks its endogenous synthesis, weakening the tumor's ADS.
- DFMC restores oxaliplatin sensitivity by reducing drug excretion and enhances tumor cell apoptosis and ferroptosis.
Conclusions:
- The developed DFMC nanomedicine offers a dual GSH depletion strategy to overcome tumor antioxidant defenses.
- This approach enhances ROS-mediated catalytic therapy and restores chemotherapy sensitivity, showing potential for improved cancer treatment.
