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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.3c04602
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In this study, a novel nanoscale metal-organic framework (nMOF) Hf-TP-SN, containing an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin (SN38) prodrug, was designed for synergistic radiotherapy and chemotherapy. Upon X-ray irradiation, Hf-12 secondary building units served as radiosensitizers to enhance the generation of hydroxyl radicals, leading to the on-demand release of SN38. The Hf-TP-SN showed 5-fold higher release of SN38 compared to its molecular counterpart, resulting in significant cytotoxicity to cancer cells and efficient tumor growth inhibition in colon and breast cancer mouse models.
As heavy-metal-based nanoscale metal-organic frameworks(nMOFs) are excellent radiosensitizers for radiotherapy via enhancedenergy deposition and reactive oxygen species (ROS) generation, wehypothesize that nMOFs with covalently conjugated and X-ray triggerableprodrugs can harness the ROS for on-demand release of chemotherapeuticsfor chemoradiotherapy. Herein, we report the design of a novel nMOF,Hf-TP-SN, with an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin(SN38) prodrug for synergistic radiotherapy and chemotherapy. UponX-ray irradiation, electron-dense Hf-12 secondary buildingunits serve as radiosensitizers to enhance hydroxyl radical generationfor the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzylcarbonate followed by 1,4-elimination, leading to 5-fold higher releaseof SN38 from Hf-TP-SN than its molecular counterpart. As a result,Hf-TP-SN plus radiation induces significant cytotoxicity to cancercells and efficiently inhibits tumor growth in colon and breast cancermouse models.
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