Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer

SIMPLE SUMMARY: Tumor hypoxia is considered a critical factor associated with the resistance of conventional radiotherapy, where the X-ray-induced free radicals lead to DNA damage in a manner that is strongly dependent on the tissue oxygenation. The emerging PSMA-directed radioligand therapy (RLT) employs the [Formula: see text] or [Formula: see text] particles emitted by the radiopharmaceuticals to kill the tumor cells. In contrast to conventional therapy, the induced DNA damage is less dependent on the oxygenation status. Less attention has been paid to investigating whether tumor hypoxia will influence the efficacy of PSMA-directed RLT. We propose a histology-driven in silico model to quantitatively investigate the influence of tumor hypoxia on the treatment outcome for PSMA-directed RLT with [Formula: see text] Lu and [Formula: see text] Ac. Our finding suggests that hypoxia is a factor to be considered for the application of PSMA-directed RLT. ABSTRACT: Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates [Formula: see text] Ac- or [Formula: see text] Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or [Formula: see text]-ray, for the emitted [Formula: see text] or [Formula: see text] 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 [Formula: see text] 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 [Formula: see text] Ac compared to [Formula: see text] Lu. The higher homogeneity of [Formula: see text] Lu-PSMA-ligand treatment is due to the larger range covered by the emitted [Formula: see text] 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 [Formula: see text] Lu-PSMA-ligand treatment. This percentage drops down to 5% using [Formula: see text] Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the [Formula: see text] Lu and [Formula: see text] 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.