Novel direct alpha spectroscopy technique for²²⁵Ac radiopharmaceutical detection in cancer cells

Objective.Targeted Alpha Therapy (TAT) is a promising approach for treating metastatic cancers, utilizing alpha-emitting radionuclides conjugated to tumor-targeting molecules. Actinium-225 (²²⁵Ac) has emerged as a clinically relevant candidate due to its decay chain, which produces four successive alpha emissions, effectively damaging cancer cells. However, the nuclear recoil effect can lead to off-target redistribution of decay daughters, complicating dosimetry and increasing potential toxicity. This study aims to address these challenges by developing a direct alpha spectroscopy method forin vitroinvestigations of²²⁵Ac radiopharmaceuticals.Approach.We developed the Bio-Sample Alpha Detector (BAD), a silicon-based detector designed to operate under ambient conditions, enabling direct alpha spectroscopy of cell samples. AR42J rat pancreatic tumor cells, which express somatostatin receptor 2 (SSTR2), were incubated with [²²⁵Ac]Ac-crown-TATE, [²²⁵Ac]Ac-PSMA-617, and [²²⁵Ac]Ac³⁺. The BAD setup allowed radiolabeled cell samples to be positioned within 100µm of the detector for alpha spectra acquisition with statistical uncertainties of less than 1% in count rates. Geant4 Monte Carlo simulations were employed to validate the experimental results.Main results.Distinct spectral differences between radiolabeled cells and reference samples confirmed the uptake of [²²⁵Ac]Ac-crown-TATE by AR42J cells. Detection of²¹³Po, a decay daughter of²²⁵Ac, indicated partial retention and release of decay products from cells, providing insight into intracellular retention and radionuclide redistribution. Geant4 simulations confirmed the alignment of experimental data with theoretical predictions.Significance.This study introduces a novel method for directly measuring the behavior of²²⁵Ac and its decay daughters in biological samples using alpha spectroscopy. The BAD setup provides a valuable tool for investigating radionuclide retention, redistribution, and microdosimetry in radiopharmaceutical research.