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. 2018 Feb 12;8(7):1824–1849. doi: 10.7150/thno.22172

Figure 2.

Figure 2

Schematic illustration of metal-based NanoEnhancer radiosensitization process. (Upper-left) Following administration of NanoEnhancers, radiation therapy is carried out after a certain time interval. (Upper-right) Probable biological mechanisms include oxidative stress, cell cycle arrest, DNA repair inhibition, autophagy, ER stress, etc. Besides ionizing radiation-induced fluctuations in biological systems, the metal-based NanoEnhancers internalized by tumor cells can elicit significant cellular biochemical changes prior to, during, and following irradiation. (Lower-left) Classical radiosensitization process, which typically consists of physical dose enhancement, chemical contribution and biological phase, resulting in lethal cellular damage. The primary targets depending on cellular and subcellular distribution and location of metal-based NanoEnhancers include cell membrane, cytoplasm, nucleus, mitochondria, endoplasmic reticulum (ER), and other organelles. Specifically, photoelectrons and Auger electrons generated from the irradiated metal-based nanoparticles could contribute to the dose enhancement directly through the interactions with critical targets or indirectly through free radical production (mostly ROS (reactive oxygen species)), which can be assessed by DCFH-DA (2',7'-dichlorofluorescein diacetate) in living cell models and 3-CCA (coumarin-3-carboxylic acid) in aqueous buffered solutions. In addition, the production of hydroxyl radical in the radiosensitization processes of metal-based nanoparticles could be attributed to the catalytic-like mechanism/surface-catalyzed reaction (e.g., in IONs (iron oxide nanoparticles) this is the surface-catalyzed Haber-Weiss cycle and Fenton reaction). (Lower-right) Patterns of cell death in radiosensitization, such as apoptosis, necrosis, mitotic catastrophe, autophagic death, and senescence. Consequently, the enhanced cell-killing effects might result from the complicated physical, chemical and biological effects induced by the complex action of metal-based nanoparticles and ionizing radiation exposure.