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Abstract Background Radiopharmaceutical therapy with 225Ac- and 177Lu-PSMA has shown promising results for the treatment of prostate cancer. However, the distinct physical properties of alpha and beta radiation elicit varying cellular responses, which could be influenced by factors such as tumour morphology. In this study, we use simulations to examine how cell geometry, region of pharmaceutical uptake within the cell to model different internalization fractions, and the presence of tumour hypoxia and necrosis impact nucleus absorbed doses and dose heterogeneity with 225Ac and 177Lu. We also develop nucleus absorbed dose kernels for application to autoradiography images. Methods We used the GATE Monte Carlo software to simulate three geometries of LNCaP prostate cancer cells (spherical, cubic, and ovoid) with activity of 225Ac or 177Lu internalized in the cytoplasm or bound to the extracellular membrane. Nucleus S-values were calculated for each geometry, source region, and isotope. The cell models were used to create nucleus absorbed dose kernels for each source region describing the dose to each nucleus in a cell layer, which were applied to simulated tumours composed of normoxic, hypoxic, or necrotic cancer cells to obtain dose rate maps. Absorbed doses within the tumours and dose heterogeneity were analyzed for each tumour morphology and isotope. Cell geometry made a minimal impact on S-values to the nucleus, however internalization resulted in higher nucleus doses. Applying the kernels to the simulated tumour maps showed that doses to each cell type varied between 225Ac and 177Lu depending on tumour morphology. Dose heterogeneity within tumours was slightly higher with 225Ac, however the tumour morphology made a larger impact on dose heterogeneity compared to the choice of isotope, with hypoxic and necrotic tumours having very heterogeneous dose distributions. Conclusions Cell geometry simplifications may still allow robust results in simulation studies. Furthermore, the morphology of the tumour itself may make a larger impact on treatment response compared to other variables such as ratio of internalization. Finally, nucleus absorbed dose kernels were created that could enable microdosimetric studies with autoradiography.

Abstract Background Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70 mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0 keV, 86.6 keV, and 105.3 keV for 155Tb and 48.9 keV and 74.6 keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. Results Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10 mm for 161Tb and ≥ 1.30 mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. Conclusions Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves

Abstract Background Radiopharmaceutical therapy (RPT) with alpha-emitting radionuclides has shown great promise in treating metastatic cancers. The successive emission of four alpha particles in the 225Ac decay chain leads to highly targeted and effective cancer cell death. Quantifying cellular dosimetry for 225Ac RPT is essential for predicting cell survival and therapeutic success. However, the leading assumption that all 225Ac 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 225Ac’s progeny radionuclides with GATE Monte Carlo simulations. Methods 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 221Fr (t 1/2 = 4.80 m) and 213Bi (t 1/2 = 45.6 m). Results For the cumulative 225Ac 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 225Ac decay chain self-dose S-values increased from 0.167 to 0.364 GyBq−1 s−1 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 221Fr and 213Bi retention, respectively. Conclusions Our GATE Monte Carlo simulations resulted in cellular S-values in agreement with existing MIRD S-values for the alpha-emitting radionuclides in the 225Ac decay chain. To obtain accurate absorbed dose estimates in 225Ac 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.

Terbium radioisotopes (149Tb, 152Tb, 155Tb, 161Tb) offer a unique class of radionuclides which encompass all four medicinally relevant nuclear decay modalities (α, β+, γ, β−/e−), and show high potential for the development of element-matched theranostic radiopharmaceuticals. The goal of this study was to design, synthesise, and evaluate the suitability of crown-TATE as a new peptide-conjugate for radiolabelling of [155Tb]Tb3+ and [161Tb]Tb3+, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice. [155Tb]Tb-crown-TATE and [161Tb]Tb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.5% RCP over 7 days). Longitudinal SPECT/CT images were acquired for 155Tb- and 161Tb- labelled crown-TATE in male NRG mice bearing AR42J tumours. The radiotracers, [155Tb]Tb-crown-TATE and [161Tb]Tb-crown-TATE, showed high tumour targeting (32.6 and 30.0 %ID/g, respectively) and minimal retention in non-target organs at 2.5 h post-administration. Biodistribution studies confirmed the SPECT/CT results, showing high tumour uptake (38.7 ± 8.0 %ID/g and 38.5 ± 3.5 %ID/g, respectively) and favourable tumour-to-background ratios. Blocking studies further confirmed SSTR2-specific tumour accumulation. Overall, these findings suggest that crown-TATE has great potential for element-matched molecular imaging and radionuclide therapy using 155Tb and 161Tb.