H2S-driven Chemotherapy and Mild Photothermal Therapy Induced Mitochondrial Reprogramming to Promote Cuproptosis
Abstract The high level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excess H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid to form TPZCu2Cl(OH)3-HA (TPZ@CuO) nanoparticles (NPs), demonstrated enhanced efficacy for H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis. The drug was injected through the caudal vein and concentrated in colon cancer through its enhanced permeability, retention effects, and active targeting. The photothermic agent copper sulfide (Cu9S8) was prepared in situ by reacting with excess H2S and near-infrared II, thereby releasing TPZ. When H2S content was sufficiently depleted, the induction of mitochondrial reprogramming stimulated oxygen consumption by colonic epithelial cells. Activation of the hypoxic prodrug TPZ yielded activated TPZ-ed for chemotherapeutic treatment of colon cancer. Further exacerbation of hypoxia inhibited the synthesis of adenosine triphosphate, leading to decreased expression of heat shock proteins and improving the effectiveness of mild photothermal therapy. Additionally, copper ions were enriched in colon cancer, and Cu2+ bound to lipoacylated dihydrolipoamide S-acetyltransferase (DLAT), inducing DLAT heteromerization. The increase in insoluble DLAT led to cytotoxicity and cell death, followed by cuproptosis. Simultaneously, Cu2+ generated highly catalytic Cu+ under conditions of increased GSH expression, which catalyzed H2O2 to produce highly toxic hydroxyl radicals (·OH) during chemodynamic therapy, inducing apoptosis. These results offer a new NP-based treatment modality that can promote copper-related synergistic combination therapy in various ways..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ResearchSquare.com - (2024) vom: 05. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qiao, Lihong [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-3993644/v1 |
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| PPN (Katalog-ID): |
XRA042806259 |
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| 520 | |a Abstract The high level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excess H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid to form TPZCu2Cl(OH)3-HA (TPZ@CuO) nanoparticles (NPs), demonstrated enhanced efficacy for H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis. The drug was injected through the caudal vein and concentrated in colon cancer through its enhanced permeability, retention effects, and active targeting. The photothermic agent copper sulfide (Cu9S8) was prepared in situ by reacting with excess H2S and near-infrared II, thereby releasing TPZ. When H2S content was sufficiently depleted, the induction of mitochondrial reprogramming stimulated oxygen consumption by colonic epithelial cells. Activation of the hypoxic prodrug TPZ yielded activated TPZ-ed for chemotherapeutic treatment of colon cancer. Further exacerbation of hypoxia inhibited the synthesis of adenosine triphosphate, leading to decreased expression of heat shock proteins and improving the effectiveness of mild photothermal therapy. Additionally, copper ions were enriched in colon cancer, and Cu2+ bound to lipoacylated dihydrolipoamide S-acetyltransferase (DLAT), inducing DLAT heteromerization. The increase in insoluble DLAT led to cytotoxicity and cell death, followed by cuproptosis. Simultaneously, Cu2+ generated highly catalytic Cu+ under conditions of increased GSH expression, which catalyzed H2O2 to produce highly toxic hydroxyl radicals (·OH) during chemodynamic therapy, inducing apoptosis. These results offer a new NP-based treatment modality that can promote copper-related synergistic combination therapy in various ways. | ||
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| 700 | 1 | |a Guo, Yanxian |4 aut | |
| 700 | 1 | |a Liu, Mu |4 aut | |
| 700 | 1 | |a Yu, Dongsheng |4 aut | |
| 700 | 1 | |a Chen, Qinghua |4 aut | |
| 700 | 1 | |a Yuan, Jianmin |4 aut | |
| 700 | 1 | |a Wei, Chuanqi |4 aut | |
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| 700 | 1 | |a Cheng, Du |4 aut | |
| 700 | 1 | |a Yu, Zhiqiang |4 aut | |
| 700 | 1 | |a Li, Zhongjun |4 aut | |
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