Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells
Abstract Background Beta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2023-12-01
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| Series: | EJNMMI Research |
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| Online Access: | https://doi.org/10.1186/s13550-023-01057-3 |
| _version_ | 1797388075885658112 |
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| author | Pierre Cheung Julia Thorngren Bo Zhang Svitlana Vasylovska Francesco Lechi Jonas Persson Stefan Ståhl John Löfblom Olle Korsgren Jonas Eriksson Joey Lau Olof Eriksson |
| author_facet | Pierre Cheung Julia Thorngren Bo Zhang Svitlana Vasylovska Francesco Lechi Jonas Persson Stefan Ståhl John Löfblom Olle Korsgren Jonas Eriksson Joey Lau Olof Eriksson |
| author_sort | Pierre Cheung |
| collection | DOAJ |
| description | Abstract Background Beta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-cell-derived islets have been suggested as an alternative source of beta cells, but face transplantation protocols optimization difficulties, mainly due to a lack of available methods and markers to directly monitor grafts survival, as well as their localization and function. Molecular imaging techniques and particularly positron emission tomography has been suggested as a tool for monitoring the fate of islets after clinical transplantation. The integral membrane protein DGCR2 has been demonstrated to be a potential pancreatic islet biomarker, with specific expression on insulin-positive human embryonic stem-cell-derived pancreatic progenitor cells. The candidate Affibody molecule ZDGCR2:AM106 was radiolabeled with fluorine-18 using a novel click chemistry-based approach. The resulting positron emission tomography tracer [18F]ZDGCR2:AM106 was evaluated for binding to recombinant human DGCR2 and cryosections of stem-cell-derived islets, as well as in vivo using an immune-deficient mouse model transplanted with stem-cell-derived islets. Biodistribution of the [18F]ZDGCR2:AM106 was also assessed in healthy rats and pigs. Results [18F]ZDGCR2:AM106 was successfully synthesized with high radiochemical purity and yield via a pretargeting approach. [18F]ZDGCR2:AM106 retained binding to recombinant human DCGR2 as well as to cryosectioned stem-cell-derived islets, but in vivo binding to native pancreatic tissue in both rat and pig was low. However, in vivo uptake of [18F]ZDGCR2:AM106 in stem-cell-derived islets transplanted in the immunodeficient mice was observed, albeit only within the early imaging frames after injection of the radiotracer. Conclusion Targeting of DGCR2 is a promising approach for in vivo detection of stem-cell-derived islets grafts by molecular imaging. The synthesis of [18F]ZDGCR2:AM106 was successfully performed via a pretargeting method to label a site-specific covalently bonded fluorine-18 to the Affibody molecule. However, the rapid washout of [18F]ZDGCR2:AM106 from the stem-cell-derived islets graft indicates that dissociation kinetics can be improved. Further studies using alternative binders of similar classes with improved binding potential are warranted. |
| first_indexed | 2024-03-08T22:35:30Z |
| format | Article |
| id | doaj.art-9bc788183687432ebdda01b90d26bed0 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-03-08T22:35:30Z |
| publishDate | 2023-12-01 |
| publisher | SpringerOpen |
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| spelling | doaj.art-9bc788183687432ebdda01b90d26bed02023-12-17T12:29:44ZengSpringerOpenEJNMMI Research2191-219X2023-12-0113111210.1186/s13550-023-01057-3Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cellsPierre Cheung0Julia Thorngren1Bo Zhang2Svitlana Vasylovska3Francesco Lechi4Jonas Persson5Stefan Ståhl6John Löfblom7Olle Korsgren8Jonas Eriksson9Joey Lau10Olof Eriksson11Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityDepartment of Medical Cell Biology, Uppsala UniversityScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityDepartment of Medical Cell Biology, Uppsala UniversityScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityDepartment of Protein Science, Division of Protein Engineering, KTH Royal Institute of TechnologyDepartment of Protein Science, Division of Protein Engineering, KTH Royal Institute of TechnologyDepartment of Protein Science, Division of Protein Engineering, KTH Royal Institute of TechnologyDepartment of Immunology, Genetics and Pathology, Uppsala UniversityScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityDepartment of Medical Cell Biology, Uppsala UniversityScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityAbstract Background Beta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-cell-derived islets have been suggested as an alternative source of beta cells, but face transplantation protocols optimization difficulties, mainly due to a lack of available methods and markers to directly monitor grafts survival, as well as their localization and function. Molecular imaging techniques and particularly positron emission tomography has been suggested as a tool for monitoring the fate of islets after clinical transplantation. The integral membrane protein DGCR2 has been demonstrated to be a potential pancreatic islet biomarker, with specific expression on insulin-positive human embryonic stem-cell-derived pancreatic progenitor cells. The candidate Affibody molecule ZDGCR2:AM106 was radiolabeled with fluorine-18 using a novel click chemistry-based approach. The resulting positron emission tomography tracer [18F]ZDGCR2:AM106 was evaluated for binding to recombinant human DGCR2 and cryosections of stem-cell-derived islets, as well as in vivo using an immune-deficient mouse model transplanted with stem-cell-derived islets. Biodistribution of the [18F]ZDGCR2:AM106 was also assessed in healthy rats and pigs. Results [18F]ZDGCR2:AM106 was successfully synthesized with high radiochemical purity and yield via a pretargeting approach. [18F]ZDGCR2:AM106 retained binding to recombinant human DCGR2 as well as to cryosectioned stem-cell-derived islets, but in vivo binding to native pancreatic tissue in both rat and pig was low. However, in vivo uptake of [18F]ZDGCR2:AM106 in stem-cell-derived islets transplanted in the immunodeficient mice was observed, albeit only within the early imaging frames after injection of the radiotracer. Conclusion Targeting of DGCR2 is a promising approach for in vivo detection of stem-cell-derived islets grafts by molecular imaging. The synthesis of [18F]ZDGCR2:AM106 was successfully performed via a pretargeting method to label a site-specific covalently bonded fluorine-18 to the Affibody molecule. However, the rapid washout of [18F]ZDGCR2:AM106 from the stem-cell-derived islets graft indicates that dissociation kinetics can be improved. Further studies using alternative binders of similar classes with improved binding potential are warranted.https://doi.org/10.1186/s13550-023-01057-3Affibody moleculeStem cellsDiabetesDGCR2PETFluorine-18 chemistry |
| spellingShingle | Pierre Cheung Julia Thorngren Bo Zhang Svitlana Vasylovska Francesco Lechi Jonas Persson Stefan Ståhl John Löfblom Olle Korsgren Jonas Eriksson Joey Lau Olof Eriksson Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells EJNMMI Research Affibody molecule Stem cells Diabetes DGCR2 PET Fluorine-18 chemistry |
| title | Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells |
| title_full | Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells |
| title_fullStr | Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells |
| title_full_unstemmed | Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells |
| title_short | Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells |
| title_sort | preclinical evaluation of affibody molecule for pet imaging of human pancreatic islets derived from stem cells |
| topic | Affibody molecule Stem cells Diabetes DGCR2 PET Fluorine-18 chemistry |
| url | https://doi.org/10.1186/s13550-023-01057-3 |
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