Birindelli, Gabriele; Drobnjakovic, Milos; Morath, Volker; Steiger, Katja; D'Alessandria, Calogero; Gourni, Eleni; Afshar-Oromieh, Ali; Weber, Wolfgang; Rominger, Axel; Eiber, Matthias; Shi, Kuangyu (2021). Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?-An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer. Cancers, 13(14) MDPI AG 10.3390/cancers13143429
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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 γ-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. 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 225Ac compared to 177Lu. The higher homogeneity of 177Lu-PSMA-ligand 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-ligand 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. 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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine |
UniBE Contributor: |
Birindelli, Gabriele, Gourni, Eleni, Afshar Oromieh, Ali, Rominger, Axel Oliver, Shi, Kuangyu |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2072-6694 |
Publisher: |
MDPI AG |
Language: |
English |
Submitter: |
Daria Vogelsang |
Date Deposited: |
05 Jan 2022 08:25 |
Last Modified: |
05 Dec 2022 15:55 |
Publisher DOI: |
10.3390/cancers13143429 |
PubMed ID: |
34298642 |
Uncontrolled Keywords: |
convection–reaction–diffusion models dosimetry hypoxia radiobiology radioligand therapy tumor microenvironment |
BORIS DOI: |
10.48350/161778 |
URI: |
https://boris.unibe.ch/id/eprint/161778 |
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