Koniar Helena, Miller Cassandra, Rahmim Arman, Schaffer Paul, Uribe Carlos
Life Sciences Division, TRIUMF, Vancouver, BC, Canada.
Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.
EJNMMI Phys. 2023 Aug 1;10(1):46. doi: 10.1186/s40658-023-00564-5.
Radiopharmaceutical therapy (RPT) with alpha-emitting radionuclides has shown great promise in treating metastatic cancers. The successive emission of four alpha particles in the Ac decay chain leads to highly targeted and effective cancer cell death. Quantifying cellular dosimetry for Ac RPT is essential for predicting cell survival and therapeutic success. However, the leading assumption that all 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 Ac'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 Fr (t = 4.80 m) and Bi (t = 45.6 m).
For the cumulative 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 Ac decay chain self-dose S-values increased from 0.167 to 0.364 GyBq s 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 Fr and Bi 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 Ac decay chain. To obtain accurate absorbed dose estimates in 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.
使用发射α粒子的放射性核素进行放射性药物治疗（RPT）在治疗转移性癌症方面显示出巨大潜力。锕衰变链中连续发射四个α粒子会导致癌细胞高度靶向且有效地死亡。对锕RPT进行细胞剂量测定对于预测细胞存活和治疗成功至关重要。然而，所有锕子体都停留在其靶位点这一主要假设可能高估了癌细胞所吸收的剂量。为解决现有半解析方法的局限性，本研究利用蒙特卡罗模拟软件GATE评估锕子体放射性核素的S值。
所考虑的细胞几何形状包括单个细胞（直径10μm，细胞核直径8μm）和细胞簇（微转移灶），放射性核素定位于四个亚细胞区域：细胞膜、细胞质、细胞核或整个细胞。对细胞核所吸收的剂量进行评分，并得出自剂量和交叉剂量S值。我们还评估了不同程度的放射性药物内化以及子体放射性核素钫（t = 4.80分钟）和铋（t = 45.6分钟）保留情况下的总吸收剂量。
对于累积的锕衰变链，我们的自剂量和交叉剂量核S值与MIRDcell公布的S值均高度一致，不同放射性核素源位置的百分比差异范围为-2.7%至-8.7%。源位置对自剂量S值的影响大于细胞间交叉剂量S值。随着放射性核素从细胞表面内化进入细胞，累积的锕衰变链自剂量S值从0.167增加至0.364 GyBq⁻¹s⁻¹。当对子体从靶位点的迁移进行建模时，对于钫和铋的保留情况，细胞核的累积自剂量S值分别最多降低71%和21%。
我们的GATE蒙特卡罗模拟得出的细胞S值与锕衰变链中发射α粒子的放射性核素现有的MIRD S值一致。为在锕研究中获得准确的吸收剂量估计值，准确了解子体迁移对于优化注射活度至关重要。未来的工作将研究其他新型临床前发射α粒子的放射性核素，以评估治疗效力，并探索与靶向癌细胞系相对应的实际细胞几何形状。
