Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2018 Oct 17;9(1):4321. doi: 10.1038/s41467-018-06655-7.
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 Hf 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.
将光动力疗法（PDT）光敏剂选择性递送至癌细胞线粒体可增强 PDT 的疗效。虽然基于阳离子钌的光敏剂积聚在线粒体中，但它们需要使用穿透力较弱的短波长光子进行激发，这限制了它们在 PDT 中的应用。我们最近通过增强放射治疗（RT）并实现放射动力治疗（RDT），发现了基于纳米尺度金属有机骨架（nMOF）的 X 射线癌症治疗方法。在此，我们报告了 Hf-DBB-Ru 作为一种用于 RT-RDT 的靶向线粒体的 nMOF。该阳离子框架由基于钌的光敏剂构建，具有很强的靶向线粒体的特性。在 X 射线照射下，Hf-DBB-Ru 能够从 Hf SBUs 高效地产生羟基自由基，并从 DBB-Ru 光敏剂中产生单线态氧，从而导致 RT-RDT 效应。靶向线粒体的 RT-RDT 使线粒体膜去极化，引发癌细胞凋亡，导致小鼠模型中结直肠肿瘤的显著消退。我们的工作建立了一种有效的策略，通过低剂量穿透力强的 X 射线进行 RT-RDT，用阳离子 nMOF 选择性地靶向线粒体，以增强癌症治疗效果。
