Abstract
Selective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT). Though cationic Ru-based photosensitizers accumulate in mitochondria, they require excitation with less penetrating short-wavelength photons, limiting their application in PDT. We recently discovered X-ray based cancer therapy by nanoscale metal–organic frameworks (nMOFs) via enhancing radiotherapy (RT) and enabling radiodynamic therapy (RDT). Herein we report Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT. Constructed from Ru-based photosensitizers, the cationic framework exhibits strong mitochondria-targeting property. Upon X-ray irradiation, Hf-DBB-Ru efficiently generates hydroxyl radicals from the Hf6 SBUs and singlet oxygen from the DBB-Ru photosensitizers to lead to RT-RDT effects. Mitochondria-targeted RT-RDT depolarizes the mitochondrial membrane to initiate apoptosis of cancer cells, leading to significant regression of colorectal tumors in mouse models. Our work establishes an effective strategy to selectively target mitochondria with cationic nMOFs for enhanced cancer therapy via RT-RDT with low doses of deeply penetrating X-rays.
Highlights
Selective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT)
Powder X-ray diffraction (PXRD) studies showed that Hf-DBB-Ru was stable in 0.6 mM PBS for 6 days owing to strong carboxylate coordination to the Hf6 clusters (Fig. 1c)
Upon X-ray irradiation, Hfporphyrin nanoscale metal–organic frameworks (nMOFs) enhance RT by generating hydroxyl radicals and enable radiodynamic therapy (RDT) by directly transferring energy from Hf-oxo SBUs to porphyrin ligands to sensitize the formation of 1O2 in a process termed RT-RDT35
Summary
Selective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT). Our work establishes an effective strategy to selectively target mitochondria with cationic nMOFs for enhanced cancer therapy via RT-RDT with low doses of deeply penetrating X-rays. Two-photon excitation can be used to activate Ru-based PSs for mitochondria-targeted PDT, the two-photon process has low photosensitizing efficiency[23,24,25]. Innovative strategies are needed to realize anti-cancer PDT treatment with mitochondria-targeted Ru-based PSs. As a new class of molecular nanomaterials, nanoscale metal–organic frameworks (nMOFs) have shown interesting potential in nanomedicine applications due to their synthetic tunability, multifunctionality, and biocompatibility[26,27,28,29]. We recently discovered efficient X-ray based cancer therapy by Hf-porphyrin nMOFs via enhancing radiotherapy (RT) and enabling radiodynamic therapy (RDT) using low doses of deeply penetrating X-rays[35,36]. Upon X-ray irradiation, Hf-porphyrin nMOFs efficiently generated hydroxyl radicals from the Hf SBUs and singlet oxygen from the porphyrin PSs to exert RT-RDT effects
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