Radiobiological effectiveness of varying Tb-161 and Lu-177 distributions in the nuclei of targeted cells

ABSTRACT This study investigates the radiobiological damage and microdosimetry of non-uniform distributions of 177Lu and 161Tb in the nucleus of targeted cell. The Geant4-DNA toolkit (version 11.3) was utilized to model PC-3 M prostate cancer cells. In these simulations, both uniform and non-uniform distributions of 177Lu and 161Tb within the cell nucleus were considered (10 MBq·s disintegrations were considered). To model the heterogeneity in radiopharmaceutical distribution at cellular scales, a Gaussian distribution function with a mean of zero and a standard deviation of 0.1–0.5 was used. Our simulations assess cell absorbed dose and direct and indirect DNA double-strand breaks (DSBs) based on the level of radionuclide heterogeneity. At a uniform radionuclide distribution, the number of DSBs and the absorbed dose from 161Tb were 0.035 decay−1 and 40.62 uGy/decay, respectively, while for 177Lu, they were 0.0093 decay−1 and 11.18 uGy/decay. As the heterogeneity of radionuclide distribution within the cell nucleus increased, the cell nucleus absorbed dose and the number of direct and indirect DSBs per cell nucleus absorbed dose remained constant for 177Lu, whereas the cell nucleus absorbed dose and the number of direct DSBs per cell nucleus absorbed dose decreased for 161Tb (P-value <0.05). Meanwhile, the radiobiological effectiveness of 161Tb is highly sensitive to its spatial distribution within the nucleus. Overall, our in silico study suggests that 161Tb is a highly promising radionuclide for radiopharmaceutical therapy, particularly when efficient nuclear targeting and a relatively uniform intranuclear distribution can be achieved. Accurately predicting the therapeutic efficacy of 161Tb-based agents requires careful consideration of their subcellular distribution.