High‐Z metal‐based nanoscale metal–organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy‐radiodynamic therapy (RT‐RDT) process. Here we report Monte Carlo (MC) simulation‐guided design of a Th‐based nMOF built from Th6‐oxo secondary building units and 5,15‐di(p‐benzoato)porphyrin (DBP) ligands, Th‐DBP, for enhanced RT‐RDT. MC simulations revealed that the Th‐lattice outperformed the Hf‐lattice in radiation dose enhancement owing to its higher mass attenuation coefficient. Upon X‐ray or γ‐ray radiation, Th‐DBP enhanced energy deposition, generated more reactive oxygen species, and induced significantly higher cytotoxicity to cancer cells over the previously reported Hf‐DBP nMOF. With low‐dose X‐ray irradiation, Th‐DBP suppressed tumor growth by 88 % in a colon cancer and 97 % in a pancreatic cancer mouse model.
As heavy-metal-based nanoscale metal–organic frameworks
(nMOFs) are excellent radiosensitizers for radiotherapy via enhanced
energy deposition and reactive oxygen species (ROS) generation, we
hypothesize that nMOFs with covalently conjugated and X-ray triggerable
prodrugs can harness the ROS for on-demand release of chemotherapeutics
for 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. Upon
X-ray irradiation, electron-dense Hf12 secondary building
units serve as radiosensitizers to enhance hydroxyl radical generation
for the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzyl
carbonate followed by 1,4-elimination, leading to 5-fold higher release
of SN38 from Hf-TP-SN than its molecular counterpart. As a result,
Hf-TP-SN plus radiation induces significant cytotoxicity to cancer
cells and efficiently inhibits tumor growth in colon and breast cancer
mouse models.
High-Z metal-based nanoscale metal-organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process.Here we report Monte Carlo (MC) simulation-guided design of a Th-based nMOF built from Th 6 -oxo secondary building units and 5,15-di(p-benzoato)porphyrin (DBP) ligands, Th-DBP, for enhanced RT-RDT. MC simulations revealed that the Th-lattice outperformed the Hf-lattice in radiation dose enhancement owing to its higher mass attenuation coefficient. Upon X-ray or γray radiation, Th-DBP enhanced energy deposition, generated more reactive oxygen species, and induced significantly higher cytotoxicity to cancer cells over the previously reported Hf-DBP nMOF. With low-dose Xray irradiation, Th-DBP suppressed tumor growth by 88 % in a colon cancer and 97 % in a pancreatic cancer mouse model.
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