Dosimetry at cellular level for the alpha-emitting radionuclides actinium-225, astatine-211 and radium-223 for bone metastasis cells from castration resistant prostate cancer

Abstract Objectives
The aim is to evaluate energy deposition in the nucleus and cytoplasm in targeted alpha therapy of metastatic castration-resistant prostate cancer by modeling two cell lines, PC3 (osteolytic) and LNCaP C4-2 (osteoblastic), for actinium-225, astatine-211, and radium-223 and their progeny, using Monte Carlo simulations with the GATE/Geant4 code.
Approach
We developed single cell and cell clusters models and couple them to Monte Carlo simulations performed on the GATE platform version 9.3, setting the GEANT4-DNA physics list emstandard_opt3_mixed_dna for At-211, Ac-225 and Ra-223 progenies. We considered three radionuclide distributions as a sources: the nucleus, the cytoplasm and the whole cell.
Main Results
When the nucleus was considered as a target, the S-values (N←N) calculated for At-211, Ac-225 and Ra-223 progenies were significantly higher, within 60-90%, than S-values (N←Cy), demonstrating less influence of cytoplasm internalization. When the cytoplasm was considering as a target, the S-values (Cy←Cy) calculated for At-211, Ac-225 and Ra-223 progeny were significantly higher, within 30-90%, than the S-values (Cy←N). When no progeny migration occurs and the nucleus was considered as the target, the cumulative S-values (N←N) calculated for At-211, Ac-225 and Ra-223 were significantly higher, within 50- 70%, than the S-values (N←N) computed for At-211, Ac-225, and Ra-223. Comparing the cumulative S-values, Ac-225 and 
Ra-223 therapies is more effective, in terms of deposited energy in a target, than that with At-211.
Significance
The data presented in this research indicates that Ac-225 therapy may be theoptimum choice due to the energy deposited in the nucleus, as long as the recoil effects and redistribution of progeny are understood. In contrast, At-211 is an alternative to avoid progeny migration. However, to completely analyze the efficacy of radionuclide therapy, other parameters must be considered, such as biological half-life, stability of the transport molecule, progeny migration, excretion pathways, and uptake in different organs.