Radiation Biology of Radiopharmaceuticals: Beyond External Beam Radiation Therapy

The dynamic field of radiopharmaceuticals is currently experiencing an explosion of growth due in part to excitement over the emerging field of theranostics (therapy and diagnostics). Radiopharmaceuticals use physiological targeting methods to deliver radionuclides with medically relevant decay properties to disease biomarkers for diagnosis and treatment, offering opportunities for early disease imaging and radiation therapy treatment in disease pathologies that are inoperable or refractory to other forms of radiotherapy. Sustaining this rapidly growing field depends heavily on the continued design and production of novel, effective radiopharmaceuticals. Effective therapeutic radiopharmaceuticals cause complex and varied cellular responses, and to choose radionuclides that maximize therapeutic response, researchers must understand radiation biology. Cellular radiation response depends heavily on factors including linear energy transfer (LET), dose, dose rate, targeted location, direct or indirect energy deposition mechanisms, the broader cellular matrix, cellular stress signaling pathways, and endogenous radiation protection mechanisms. Because of the extensive application of low-LET external beam radiation on clinical cancer treatments, biological responses to low-LET form the basis of radiation biology and are generally considered transferable to high-LET radiopharmaceuticals. However, increased focus on high-LET, radiopharmaceutical therapy-specific radiation biology is motivated by differences between low- and high-LET radiation, external beam versus radiopharmaceutical therapy-induced biological response, and the observed varied clinical responses to radiopharmaceutical therapies. This review article summarizes historical understanding of low- and high-LET radiation responses within cells, with emphasis on radiopharmaceutical-specific responses when available, and discusses current gaps in understanding in the radiation biology of radiotheranostic pharmaceuticals.