Monte Carlo-Based Nanoscale Dosimetry Holds Promise for Radiopharmaceutical Therapy Involving Auger Electron Emitters

Simple Summary In contrast to external beam radiation therapy, our understanding of the dose-response relationship in radiopharmaceutical therapy (RPT) remains limited. Given that the estimation of radiation-induced deoxyribonucleic acid (DNA) damage can correlate with various biological responses, nanoscale dosimetry emerges as a critical tool in lighting this intricate relationship. In this study, we developed a novel simulation-based nanoscale dosimetry platform by identifying optimal DNA physics models and benchmarking against existing data. Leveraging this platform, we conducted a case study to estimate DNA damage, thereby enhancing our comprehension of RPT effects at nanoscales. This research serves as a foundation for future studies on how RPT affects DNA at the nano-level, potentially improving cancer treatment strategies.Abstract Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose-response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT.