Ion Beam Imaging Shows Selective Thallium-201 Uptake in Cell Nuclei: Impact on Cellular Dosimetry and Radiotoxicity of Auger Electron Emitters

Thallium-201, a promising candidate for precise targeted radionuclide therapy, emits abundant, radiotoxic, short-range Auger and other secondary electrons, but its subcellular distribution, on which the delivered absorbed radiation dose depends, remains unknown. This study investigates the subcellular localization of unbound 201Tl+, for input into microdosimetry models. Methods: Prostate (DU145), ovarian (SKOV3), and lung (A549) cancer cells were exposed to nonradioactive TlCl and imaged using laser ablation-inductively coupled plasma-mass spectrometry, energy-dispersive X-ray spectroscopy combined with transmission electron microscopy, and ion beam analysis (IBA). Absorbed radiation doses to cell nuclei from intracellular 201Tl were calculated for geometries based on DU145 cells, applying the standard Medical Internal Radiation Dose formalism, and compared to those from 201Tl-labeled Prussian blue nanoparticles (PBNPs). Results: Only IBA successfully quantified thallium in both the nucleus and cytoplasm, showing selective uptake in the nucleus with nuclear:cytoplasmic concentration ratios of 1.8 ± 1.5 in DU145 cells and 1.8 ± 1.0 in SKOV3 cells. New dose calculations for 201Tl revealed that exclusively cytoplasmic localization of 201Tl activity, exemplified by 201Tl bound to chitosan-coated PBNPs in A549 cells, reduces the absorbed dose to the nucleus by 82%, compared to the observed distribution of unbound 201Tl+, providing a rationale for reduced cytotoxicity per decay for PBNPs compared to 201Tl+ observed previously. Conclusion: Thallium(I) ions show preferential accumulation in cell nuclei and this could account for the higher toxicity of [201Tl]TlCl than [201Tl]PBNPs per intracellular decay event.