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A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy
Ying Huang1,2, Si Wu1,2, Lu Zhang1,2
1Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, PR China.
Abstract:
The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.
Insights
This study presents a novel nanomedicine that depletes glutathione (GSH) in tumor cells, enhancing chemodynamic therapy (CDT) effectiveness. The approach targets tumor metabolism for highly potent and specific cancer treatment.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanomedicine
Background:
- High glutathione (GSH) levels in tumors impede chemodynamic therapy (CDT) efficacy.
- Developing tumor-specific CDT that effectively depletes GSH remains a significant challenge.
Purpose of the Study:
- To create a multistage, tumor-specific CDT strategy for rapid and thorough GSH depletion.
- To enhance cancer cell sensitivity to CDT by targeting tumor-specific metabolic pathways.
Main Methods:
- Utilized a nanocarrier system responsive to the tumor microenvironment.
- Incorporated a glycolysis inhibitor to block GSH synthesis and energy supply.
- Exploited metabolic differences between tumor and normal cells for selectivity.
Main Results:
- Achieved highly potent GSH exhaustion in tumor cells through multi-pronged inhibition.
- Demonstrated increased cancer cell sensitivity to CDT.
- Showcased tumor-specific therapeutic effects due to microenvironment responsiveness.
Conclusions:
- The developed nanomedicine effectively exhausts GSH, leading to potent CDT.
- Exploiting metabolic vulnerabilities and tumor microenvironment provides a strategy for tumor-specific therapy.
