Targeted alpha therapy with ²¹²Pb or ²²⁵Ac: Change in RBE from daughter migration

Targeted α-therapy (TAT) could be delivered early to patients who are at a high-risk for developing brain metastases, targeting the areas of the vasculature where tumor cells are penetrating into the brain. We have utilized a Monte Carlo model representing brain vasculature to calculate physical dose and DNA damage from the α-emitters ²²⁵Ac and ²¹²Pb. The micron-scale dose distributions from all radioactive decay products were modeled in Geant4, including the eV-scale interactions using the Geant4-DNA models. These interactions were then superimposed on an atomic-scale DNA model to estimate strand break yields. In addition to ²²⁵Ac having a higher dose per decay than ²¹²Pb, it also has a double strand break yield per decay that is 4.7 ± 0.5 times that of ²¹²Pb. However, the efficacy of both nuclides depends on retaining the daughter nuclei at the target location in the brain vasculature. The relative biological effectiveness (RBE) of ²²⁵Ac and ²¹²Pb are similar when the entire decay chains are included, with maxima of 2.7 ± 0.6 and 2.5 ± 0.5 (respectively), and RBE values of about 2 to a depth of 80 microm. If the initial daughter is lost, the RBE of ²¹²Pb is completely reduced to 1 or lower and the RBE of ²²⁵Ac is approximately 2 only for the first 40 microm.