Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo
| Autor: | Mengdi Lv, Chenggen Qian, Jing Zhao, Jingwen Dong, Qin Tao, Zijian Guo, Zhi Su, Xuling Xue, Yong Qian, Hong-Ke Liu, Yuanxin Dai |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
Reactive oxygen species Multidisciplinary AcademicSubjects/SCI00010 Chemistry Autophagy Endogeny Synthetic lethality Mitochondrion In vitro Cell biology bio-orthogonal reaction chemistry.chemical_compound In vivo cancer therapy bio-orthogonally catalyzed lethality Azide mitochondrial targeting AcademicSubjects/MED00010 metallodrug Research Article |
| Zdroj: | National Science Review |
| ISSN: | 2053-714X 2095-5138 |
| Popis: | Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two non-toxic species Ru-N3 and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The non-toxic species Ru-arene complex Ru-N3 and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (>83%) and showed high anti-tumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two non-toxic species into a targeting anti-cancer metallodrug both in vitro and in vivo, while the product Ru-rhein was non-toxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anti-cancer drugs for cancer treatment. The anti-cancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generating targeting metallodrugs in vivo via the BCL strategy from non-toxic species in metal-based chemotherapy. This work established a 'bioorthogonally catalyzed lethality' strategy to generate tumor-targeting metallodrugs both in vitro and in vivo. |
| Databáze: | OpenAIRE |
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