Quantifying DNA strand breaks from targeted alpha emitters ²²⁵Ac and ²²⁷Th via Geant4-DNA: implications for RBE and...

Targeted alpha therapy (TAT) utilizing high-LET alpha particles from radionuclides like ²²⁵Ac and ²²⁷Th shows promise in cancer treatment due to their ability to induce dense, localized DNA damage. This study uses the Geant4-DNA Monte Carlo toolkit to simulate DNA damage and evaluate the radiobiological effects of ²²⁵Ac and ²²⁷Th.

The simulations revealed that both ²²⁵Ac and ²²⁷Th induce significant DNA damage, particularly complex double-strand breaks (DSBs), with ²²⁷Th producing slightly more clustered damage due to its longer decay chain and higher alpha energy. The study also found that both radionuclides exhibited elevated Relative Biological Effectiveness (RBE), especially for complex DSBs. Cell survival analysis showed a sharp decline in viability, consistent with the clustered damage patterns induced by alpha emissions.

These findings underscore the potential of ²²⁵Ac and ²²⁷Th in targeted radionuclide therapy, particularly for tumors resistant to conventional treatments. The high RBE and complex DNA damage induced by these radionuclides suggest they could enhance therapeutic efficacy when combined with other treatment modalities, such as chemotherapy or immunotherapy, and may benefit patients with tumors exhibiting high DNA repair capacity. This study provides valuable insights for optimizing TAT protocols and advancing the clinical translation of ²²⁵Ac and ²²⁷Th therapies.