Radiotherapy-Activated Prodrug: Past, Present and Beyond

Abstract

Radiotherapy-activated prodrug (RAP) is defined as a type of prodrug that features low toxicity before activation, transforms into an active form upon ionizing radiation exposure, and exhibits targeted therapeutic effects within the irradiated area. In clinical practice, clear evidence demonstrates that the combination of radiotherapy and chemotherapy elicits a significant synergistic antitumor response, thereby enhancing patients’ overall survival rates. As a novel therapeutic modality, RAP has recently emerged as an active area of scientific research. The primary mechanism of RAP involves utilizing the reactive species from water radiolysis under ionizing radiation to trigger controlled cleavage of covalent bonds, enabling the controlled release of active drugs. In this Outlook, we summarize the advancements in the field of RAP, encompassing the types of ionizing radiation, novel chemical structures, and diverse prodrug formats. In addition, we discuss the current challenges and future directions of this promising field.

Radiotherapy-activated prodrug (RAP) exploits tumor-localized radicals (e⁻_aq/•OH/H•) generated from water radiolysis during radiotherapy to trigger spatiotemporally controlled drug release.