Estimation of relative biological effectiveness of ²²⁵Ac compared to ¹⁷⁷Lu during [²²⁵Ac]Ac-PSMA and [¹⁷⁷Lu]Lu-PSMA radiopharmaceutical therapy using TOPAS/TOPAS-nBio/MEDRAS

Aim: Over recent years, [²²⁵Ac]Ac-PSMA and [¹⁷⁷Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of ²²⁵Ac compared to ¹⁷⁷Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered.

Methods: This study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies.

Results: Based on the simulated dose-effect curves, the RBE of ²²⁵Ac compared to ¹⁷⁷Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for ²²⁵Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively.

Conclusion: In this work, the consideration of DNA repair of the damage from [²²⁵Ac]Ac-PSMA and [¹⁷⁷Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.