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

Radiopharmaceutical therapy (RPT) with alpha-emitting radionuclides has shown great promise in treating metastatic cancers. The successive emission of four alpha particles in the ²²⁵Ac decay chain leads to highly targeted and effective cancer cell death. Quantifying cellular dosimetry for ²²⁵Ac RPT is essential for predicting cell survival and therapeutic success. However, the leading assumption that all ²²⁵Ac 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 ²²⁵Ac's progeny radionuclides with GATE Monte Carlo simulations.

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 ²²¹Fr (t_1/2 = 4.80 m) and ²¹³Bi (t_1/2 = 45.6 m).

For the cumulative ²²⁵Ac 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 ²²⁵Ac 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 ²²¹Fr and ²¹³Bi retention, respectively.

Our GATE Monte Carlo simulations resulted in cellular S-values in agreement with existing MIRD S-values for the alpha-emitting radionuclides in the ²²⁵Ac decay chain. To obtain accurate absorbed dose estimates in ²²⁵Ac 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.