Ion Beam Imaging Shows Selective Thallium-201 Uptake in Cell Nuclei: Impact on Cellular Dosimetry and Radiotoxicity...

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.

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).

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.

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.