Modelling single cell dosimetry and DNA damage of targeted alpha therapy using Monte-Carlo techniques

Targeted alpha therapy (TαT) employs alpha particle-emitting radioisotopes conjugated to tumour-specific carriers to precisely irradiate tumour cells. Monte-carlo techniques have been used to accurately simulate absorbed dose and DNA damage for the four promising TαT radionuclides, Actinium-225 (²²⁵Ac), Radium-223, (²²³Ra), Lead-212 (²¹²Pb) and Astatine-211, (²¹¹At). TOPAS and TOPAS-nBio, based on the Geant4 and Geant4-DNA monte-carlo codes respectively, were used to model the radioactive decay and alpha particle transport within a simplified spherical cell model. Four different sites within the cell model were used for the initial radionuclide distributions: the cell membrane layer, within the cytoplasm volume, on the nucleus surface, and within the nucleus volume. Results indicate higher absorbed doses to the nucleus per decay when radionuclides are initially located on the nucleus wall or within the nucleus volume. ²²⁵Ac and ²²³Ra, with longer decay chains and higher alpha yields, exhibit higher doses to the nucleus per decay compared to ²¹²Pb and ²¹¹At. Notably, ²¹¹At, particularly when initially distributed within the nucleus volume or at its surface, demonstrates high relative efficacy, indicated by the absorbed dose to the nucleus per decay and number of single and double-strand breaks. These findings suggest that tumour-specific molecules should ideally target the nucleus to optimize efficacy.