Nanoscale Metal-Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy

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.

Automated summary

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.