The physicochemical and biochemical mechanisms of porphyrinoid-mediated radiodynamic therapy

Radiotherapy is the standard treatment for nearly 60 % of cancer patients. Despite advancements such as brachytherapy, stereotactic radiotherapy, and intensity-modulated radiotherapy, further improvements in efficacy and safety are needed. Radiodynamic therapy (RDT) is gaining attention, in which improved radiotherapy outcomes are achieved with the use of porphyrins such as protoporphyrin IX, verteporfin, Mn-porphyrins, and other porphyrinoids such as phthalocyanines and texaphyrins. While the light-based excitation mechanisms of these photosensitizing agents are widely established, their radiosensitization mechanisms remain unclear and underinvestigated. A comprehensive investigation into the observed physicochemical and biological effects of these compounds during radiotherapy enables the identification of several key underlying mechanisms to explain the radiocatalytic properties of porphyrins and porphyrin-related compounds. Porphyrin-like sensitizers can (1) be excited by Cherenkov radiation, (2) be ionized by secondary electrons, (3) initiate redox cycling reactions and enhance reactive oxygen species production, and (4) interfere with critical signaling pathways. These effects may synergistically combine to enhance the effects of ionizing radiation and boost the radiosensitivity of cancer cells, offering a powerful new direction for cancer treatment.