A GATE simulation study for dosimetry in cancer cell and micrometastasis from the (225)Ac decay chain

BACKGROUND: Radiopharmaceutical therapy (RPT) with alpha-emitting radionuclides has shown great promise in treating metastatic cancers. The successive emission of four alpha particles in the (225)Ac decay chain leads to highly targeted and effective cancer cell death. Quantifying cellular dosimetry for (225)Ac RPT is essential for predicting cell survival and therapeutic success. However, the leading assumption that all (225)Ac progeny remain localized at their target sites likely overestimates the absorbed dose to cancer cells. To address limitations in existing semi-analytic approaches, this work evaluates S-values for (225)Ac’s progeny radionuclides with GATE Monte Carlo simulations. METHODS: The cellular geometries considered were an individual cell (10 µm diameter with a nucleus of 8 µm diameter) and a cluster of cells (micrometastasis) with radionuclides localized in four subcellular regions: cell membrane, cytoplasm, nucleus, or whole cell. The absorbed dose to the cell nucleus was scored, and self- and cross-dose S-values were derived. We also evaluated the total absorbed dose with various degrees of radiopharmaceutical internalization and retention of the progeny radionuclides (221)Fr (t(1/2) = 4.80 m) and (213)Bi (t(1/2) = 45.6 m). RESULTS: For the cumulative (225)Ac decay chain, our self- and cross-dose nuclear S-values were both in good agreement with S-values published by MIRDcell, with per cent differences ranging from − 2.7 to − 8.7% for the various radionuclide source locations. Source location had greater effects on self-dose S-values than the intercellular cross-dose S-values. Cumulative (225)Ac decay chain self-dose S-values increased from 0.167 to 0.364 GyBq(−1) s(−1) with radionuclide internalization from the cell surface into the cell. When progeny migration from the target site was modelled, the cumulative self-dose S-values to the cell nucleus decreased by up to 71% and 21% for (221)Fr and (213)Bi retention, respectively. CONCLUSIONS: Our GATE Monte Carlo simulations resulted in cellular S-values in agreement with existing MIRD S-values for the alpha-emitting radionuclides in the (225)Ac decay chain. To obtain accurate absorbed dose estimates in (225)Ac studies, accurate understanding of daughter migration is critical for optimized injected activities. Future work will investigate other novel preclinical alpha-emitting radionuclides to evaluate therapeutic potency and explore realistic cellular geometries corresponding to targeted cancer cell lines.