SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model
IntroductionPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes...
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.684713/full |
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| author | Sachindra Sachindra Teresa Hellberg Samantha Exner Sonal Prasad Sonal Prasad Nicola Beindorff Stephan Rogalla Richard Kimura Sanjiv Sam Gambhir Bertram Wiedenmann Carsten Grötzinger Carsten Grötzinger Carsten Grötzinger Carsten Grötzinger |
| author_facet | Sachindra Sachindra Teresa Hellberg Samantha Exner Sonal Prasad Sonal Prasad Nicola Beindorff Stephan Rogalla Richard Kimura Sanjiv Sam Gambhir Bertram Wiedenmann Carsten Grötzinger Carsten Grötzinger Carsten Grötzinger Carsten Grötzinger |
| author_sort | Sachindra Sachindra |
| collection | DOAJ |
| description | IntroductionPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin αvβ6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin αvβ6-specific knottin molecular probe containing the therapeutic radionuclide 177Lu for targeting of PDAC.MethodsThe expression of integrin αvβ6 in PDAC cell lines BxPC-3 and Capan-2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC-3 and Capan-2 cell lines as well as the maximum number of binding sites in these cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan-2 xenograft tumor mouse model.ResultsRT-qPCR and immunofluorescence results showed high expression of integrin αvβ6 in BxPC-3 and Capan-2 cells. A competition binding assay revealed high affinity of the tracer with IC50 values of 1.69 nM and 9.46 nM for BxPC-3 and Capan-2, respectively. SPECT/CT and biodistribution analysis of the conjugate 177Lu-DOTA-integrin αvβ6 knottin demonstrated accumulation in Capan-2 xenograft tumors (3.13 ± 0.63%IA/g at day 1 post injection) with kidney uptake at 19.2 ± 2.5 %IA/g, declining much more rapidly than in tumors.Conclusion177Lu-DOTA-integrin αvβ6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy. |
| first_indexed | 2024-12-21T22:10:15Z |
| format | Article |
| id | doaj.art-18078cbd95024e42825a22c9aa53eef7 |
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| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T22:10:15Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-18078cbd95024e42825a22c9aa53eef72022-12-21T18:48:35ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-05-011110.3389/fonc.2021.684713684713SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft ModelSachindra Sachindra0Teresa Hellberg1Samantha Exner2Sonal Prasad3Sonal Prasad4Nicola Beindorff5Stephan Rogalla6Richard Kimura7Sanjiv Sam Gambhir8Bertram Wiedenmann9Carsten Grötzinger10Carsten Grötzinger11Carsten Grötzinger12Carsten Grötzinger13Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, GermanyBerlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Berlin, GermanyBerlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United StatesDepartment of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United StatesDepartment of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, CA, United StatesDepartment of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, GermanyMolecular Cancer Research Center (MKFZ), Charité – Universitätsmedizin Berlin, Berlin, GermanyGerman Cancer Consortium (DKTK), Berlin, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyIntroductionPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin αvβ6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin αvβ6-specific knottin molecular probe containing the therapeutic radionuclide 177Lu for targeting of PDAC.MethodsThe expression of integrin αvβ6 in PDAC cell lines BxPC-3 and Capan-2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC-3 and Capan-2 cell lines as well as the maximum number of binding sites in these cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan-2 xenograft tumor mouse model.ResultsRT-qPCR and immunofluorescence results showed high expression of integrin αvβ6 in BxPC-3 and Capan-2 cells. A competition binding assay revealed high affinity of the tracer with IC50 values of 1.69 nM and 9.46 nM for BxPC-3 and Capan-2, respectively. SPECT/CT and biodistribution analysis of the conjugate 177Lu-DOTA-integrin αvβ6 knottin demonstrated accumulation in Capan-2 xenograft tumors (3.13 ± 0.63%IA/g at day 1 post injection) with kidney uptake at 19.2 ± 2.5 %IA/g, declining much more rapidly than in tumors.Conclusion177Lu-DOTA-integrin αvβ6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy.https://www.frontiersin.org/articles/10.3389/fonc.2021.684713/fulltumor targetingintegrin αvβ6radioligand therapyknottin peptidepancreatic ductal adenocarcinomadosimetry |
| spellingShingle | Sachindra Sachindra Teresa Hellberg Samantha Exner Sonal Prasad Sonal Prasad Nicola Beindorff Stephan Rogalla Richard Kimura Sanjiv Sam Gambhir Bertram Wiedenmann Carsten Grötzinger Carsten Grötzinger Carsten Grötzinger Carsten Grötzinger SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model Frontiers in Oncology tumor targeting integrin αvβ6 radioligand therapy knottin peptide pancreatic ductal adenocarcinoma dosimetry |
| title | SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model |
| title_full | SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model |
| title_fullStr | SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model |
| title_full_unstemmed | SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model |
| title_short | SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model |
| title_sort | spect ct imaging biodistribution and radiation dosimetry of a 177lu dota integrin αvβ6 cystine knot peptide in a pancreatic cancer xenograft model |
| topic | tumor targeting integrin αvβ6 radioligand therapy knottin peptide pancreatic ductal adenocarcinoma dosimetry |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.684713/full |
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