期刊
ACS NANO
卷 16, 期 3, 页码 3647-3663出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c06777
关键词
nanomedicine; Fe3O4; GSH depletion; programmed cell death; oxaliplatin chemosensitivity
类别
资金
- National Natural Science Foundation of China [NSFC 51972075, 51772059, 81872427, 81872435, 81703000]
- Major Basic Research Project of Shandong Natural Science Foundation [ZR2019ZD29]
- Applied Technology Research and Development Program of Heilongjiang Province [GA19C002]
- Nn10 Excellent Discipline Construction Program
- Fundamental Research Funds for the Provincial Universities of Heilongjiang Province
The nanomedicine developed in this study integrates nanocarriers and clinical drugs, exhibiting peroxidase mimicking activities and depleting glutathione in the tumor microenvironment, promoting reactive oxygen species-mediated tumor catalytic therapy, and restoring the chemical sensitivity of oxaliplatin, playing an important role in apoptosis and ferroptosis of tumor cells.
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 nano-particles, 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.
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