Understanding and Exploiting Biological Mechanisms of Radiosensitization Using High Atomic Mass Nanomaterials

Radiation therapy is an essential mode of treatment for cancer, but it is limited by resistance, potential damage to healthy tissue, and inefficacy in later-stage cancers. To overcome these limitations, nanoparticles made from high atomic number (Z) atoms, such as silver (AgNPs), gold (AuNPs), and hafnium oxide (HfONPs), have been investigated for their ability to increase radiation dose deposition in cancer cells. Historically, it is believed that radiation dose enhancement primarily is achieved by physical mechanisms like photoelectric and Compton effects. Based upon these mechanisms, the usage of high Z nanoparticles would be expected to have relatively small dose enhancements and a lack of selectivity towards cancer cells under most clinical irradiation conditions. However, high Z nanoparticles exhibit very promising radiosensitizing effects that cannot fully be accounted for by physical effects, suggesting underlying biological interactions with relevant cellular processes caused by the nanoparticles themselves. Specifically, high Z nanoparticles can directly damage proteins and vesicles involved in degradation pathways (e.g., lysosomes and autophagosomes) and induce lipid peroxidation. The observed radiosensitizing effects of high Z nanoparticles may be caused by the sublethal cytotoxic responses of cancer cells to the nanomaterials themselves and are significantly greater than expected, based upon the macroscale physical dose increases in radiation deposition due to the presence of nanomaterials. This review critically analyzes the underlying biological mechanisms that could contribute to the enhancement of radiation effects by these nanomaterials.