The high energy X-rays used for radiotherapy (RT) kill cancer cells by penetrating tumors and generating highly reactive oxygen species (ROS) to damage their DNA. This destruction induces and is aided by the recruitment of immune cells to the irradiated site. The poor absorption of X-rays and generation of ROS can therefore significantly diminish the efficacy of RT, as does the frequent activation of immunosuppressive factors in the tumor microenvironment (TME). Researchers led by Ludwig Chicago’s Wenbin Lin reported in a September publication in Advanced Materials the design and preclinical evaluation of a nanoscale metal-organic framework (nMOF) that takes on these challenges. Targeted to mitochondria, the nanoparticles—named Th-Ir-DBB/Dig, if you’re wondering—are loaded with digitonin, which binds cholesterol and permeabilizes cell membranes. Its components include photosensitizing molecules that enhance ROS emission in response to even low-dose radiation. The nMOF also releases digitonin in acidic TMEs to trigger disulfidptosis—a type of programmed cell death—of cancer cells and, additionally, sensitizes them to RT-radiodynamic therapy. The released digitonin also enhances immune responses: it simultaneously downregulates multiple immune checkpoints in cancer cells (PD-L1 and CD47) and T cells (TIM3 and 2B4), mainly via cholesterol depletion. Wenbin and his team showed that low-dose radiotherapy in combination with their nMOFs induces sufficiently potent immune responses to inhibit tumor growth in mouse models of colon and breast cancer.
Digitonin-Loaded Nanoscale Metal-Organic Framework for Mitochondria-Targeted Radiotherapy-Radiodynamic Therapy and Disulfidptosis
Advanced Materials, 2024 September 10