Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates ${}^{225}$Ac- or ${}^{177}$Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or $\gamma$-ray, for the emitted $\alpha$ or $\beta$ particles the ionization of the DNA molecule is less dependent on the tissue oxygenation status. Furthermore, the diffusion range of electrons in a tumor is much larger than the volume typically spanned by hypoxic regions. Therefore, hypoxia is less investigated as an influential factor for PSMA-directed RLT, in particular with $\beta$ emitters. This study proposes an in silico approach to theoretically investigate the influence of tumor hypoxia on the PSMA-directed RLT. Based on mice histology images, the distribution of the radiopharmaceuticals was simulated with an in silico PBPK-based convection–reaction–diffusion model. Three anti-CD31 immunohistochemistry slices were used to simulate the tumor microenvironment. Ten regions of interest with varying hypoxia severity were analyzed. A kernel-based method was developed for dose calculation. The cell survival probability was calculated according to the linear-quadratic model. The statistical analysis performed on all the regions of interest (ROIs) shows more heterogeneous dose distributions obtained with ${}^{225}$Ac compared to ${}^{177}$Lu. The higher homogeneity of ${}^{177}$Lu-PSMA-ligand treatment is due to the larger range covered by the emitted $\beta$ particles. The dose-to-tissue histogram (DTH) metric shows that in poorly vascularized ROIs only 10% of radiobiological hypoxic tissue receives the target dose using ${}^{177}$Lu-PSMA-ligand treatment. This percentage drops down to 5% using ${}^{225}$Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the ${}^{177}$Lu and ${}^{225}$Ac-PSMA-ligands, respectively. The in silico study demonstrated that the reduced vascularization of the tumor strongly influences the dose delivered by PSMA-directed RLT, especially in hypoxic regions and consequently the treatment outcome.

Ziel/Aim Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates ²²⁵Ac- or ¹⁷⁷Lu-labeled ligands for the targeted killing of tumor cells. Differently from x- or gamma-ray, for the emitted α or β particles the ionization of the DNA molecule is less dependent on the tissue oxygenation status. Furthermore, the diffusion range of electrons in a tumor is much larger than the volume typically spanned by hypoxic regions. Therefore, hypoxia is less investigated as an influential factor for PSMA-directed RLT, in particular with β emitters. This study proposes an in-silico approach to theoretically investigate the influence of tumor hypoxia on the PSMA-directed RLT. Methodik/Methods Based on mice histology images, the distribution of the radio-pharmaceuticals was simulated with an in-silico PBPK-based convection-reaction-diffusion model. Three anti-CD31 immunohistochemistry slices were used to simulate the tumor microenvironment. Ten regions of interest with varying hypoxia severity have been analyzed. A kernel-based method was developed for dose calculation. The cell survival probability has been calculated accordingly to the linear-quadratic model. Ergebnisse/Results The statistical analysis performed on all the region-of-interests (ROI)s shows more heterogeneous dose distributions obtained with ²²⁵Ac compared to ¹⁷⁷Lu. The higher homogeneity of ¹⁷⁷Lu-PSMA-ligands treatment is due to the larger range covered by the emitted β particles. The dose-to-tissue histogram (DTH) metric shows that in poorly vascularized ROIs only 10\% of radiobiological hypoxic tissue receives the target dose using ¹⁷⁷Lu-PSMA-ligands treatment. This percentage drops down to 5\% using ²²⁵Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85\% and 65\% for the ¹⁷⁷Lu and ²²⁵Ac-PSMA-ligands respectively. Schlussfolgerungen/Conclusions The in-silico study demonstrated that the reduced vascularization of the tumor strongly influences the dose delivered by PSMA-directed RLT especially in hypoxic regions and consequently the treatment outcome. Publication Date: 14 April 2022 (online) © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany