Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer
Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><s...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/14/3429 |
| _version_ | 1797527536183279616 |
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| author | Gabriele Birindelli Milos Drobnjakovic Volker Morath Katja Steiger Calogero D’Alessandria Eleni Gourni Ali Afshar-Oromieh Wolfgang Weber Axel Rominger Matthias Eiber Kuangyu Shi |
| author_facet | Gabriele Birindelli Milos Drobnjakovic Volker Morath Katja Steiger Calogero D’Alessandria Eleni Gourni Ali Afshar-Oromieh Wolfgang Weber Axel Rominger Matthias Eiber Kuangyu Shi |
| author_sort | Gabriele Birindelli |
| collection | DOAJ |
| description | Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>Ac- or <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>-ray, for the emitted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>α</mi></semantics></math></inline-formula> or <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>Ac compared to <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu. The higher homogeneity of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu-PSMA-ligand treatment is due to the larger range covered by the emitted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu-PSMA-ligand treatment. This percentage drops down to 5% using <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>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. |
| first_indexed | 2024-03-10T09:44:07Z |
| format | Article |
| id | doaj.art-7b037ef8b095407fac0c810ee5a6cbdb |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:44:07Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7b037ef8b095407fac0c810ee5a6cbdb2023-11-22T03:22:59ZengMDPI AGCancers2072-66942021-07-011314342910.3390/cancers13143429Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate CancerGabriele Birindelli0Milos Drobnjakovic1Volker Morath2Katja Steiger3Calogero D’Alessandria4Eleni Gourni5Ali Afshar-Oromieh6Wolfgang Weber7Axel Rominger8Matthias Eiber9Kuangyu Shi10Department of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, SwitzerlandDepartment of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, SwitzerlandDepartment of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 München, GermanyInstitute of Pathology, School of Medicine, Technical University of Munich, 81675 München, GermanyDepartment of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 München, GermanyDepartment of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, SwitzerlandDepartment of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, SwitzerlandDepartment of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 München, GermanyDepartment of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, SwitzerlandDepartment of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 München, GermanyDepartment of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, SwitzerlandRadioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>Ac- or <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>-ray, for the emitted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>α</mi></semantics></math></inline-formula> or <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>Ac compared to <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu. The higher homogeneity of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu-PSMA-ligand treatment is due to the larger range covered by the emitted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula> 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu-PSMA-ligand treatment. This percentage drops down to 5% using <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>177</mn></msup></semantics></math></inline-formula>Lu and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mn>225</mn></msup></semantics></math></inline-formula>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.https://www.mdpi.com/2072-6694/13/14/3429hypoxiaradioligand therapytumor microenvironmentconvection–reaction–diffusion modelsdosimetryradiobiology |
| spellingShingle | Gabriele Birindelli Milos Drobnjakovic Volker Morath Katja Steiger Calogero D’Alessandria Eleni Gourni Ali Afshar-Oromieh Wolfgang Weber Axel Rominger Matthias Eiber Kuangyu Shi Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer Cancers hypoxia radioligand therapy tumor microenvironment convection–reaction–diffusion models dosimetry radiobiology |
| title | Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer |
| title_full | Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer |
| title_fullStr | Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer |
| title_full_unstemmed | Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer |
| title_short | Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer |
| title_sort | is hypoxia a factor influencing psma directed radioligand therapy an in silico study on the role of chronic hypoxia in prostate cancer |
| topic | hypoxia radioligand therapy tumor microenvironment convection–reaction–diffusion models dosimetry radiobiology |
| url | https://www.mdpi.com/2072-6694/13/14/3429 |
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