From Radiation Track to DNA Damage: The Biophysics Behind Alpha- and Beta-Minus-Emitters in Targeted Radionuclide Therapy

Metastatic cancer remains a major challenge, necessitating innovative treatments like Targeted Radionuclide Therapy (TRT). Understanding the underlying radiobiological mechanisms influenced by radionuclide type, administered activity, and cellular localization is of utmost importance for optimizing TRT effectiveness and combating radioresistance. This study uses the prostate cancer-addressing radiopharmaceutical PSMA-617 to investigate how the physical differences between clinically-used alpha-emitter Ac-225 and beta-minus-emitter Lu-177 affect radiobiological efficacy and therapeutic outcome. Immunofluorescent gamma-H2AX staining of DNA double-strand breaks (DSBs) and cell proliferation assays demonstrated that the alpha-emitter outperformed the beta-minus-emitter, achieving a similar amount of DSBs with only 1 per cent of the activity. Notably, targeted internalization significantly enhanced therapeutic efficacy of short-range alpha-emitters (47–85 μm), while having negligible impact for longer-range beta-minus-emitters (1.5–1.7mm). Furthermore, the amount of alpha-induced DSBs remained high for up to 72 hours, while it decreased for beta-minus-exposure and external photon irradiation. Combining TRT with the DNA-PK inhibitor Nedisertib further enhanced treatment efficacy and demonstrated resistance-overcoming potential, allowing for a reduction in activity even at low inhibitor concentrations. These findings underscore the importance of radiobiology in TRT and highlight the relevance of alpha-emitters as well as combination strategies for more effective and well-tolerated cancer treatments.