Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography
Abstract Background Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, inter...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2024-02-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41181-024-00241-7 |
| _version_ | 1797272741646172160 |
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| author | Lei Wang Hsiou-Ting Kuo Zhengxing Zhang Chengcheng Zhang Chao-Cheng Chen Devon Chapple Ryan Wilson Nadine Colpo François Bénard Kuo-Shyan Lin |
| author_facet | Lei Wang Hsiou-Ting Kuo Zhengxing Zhang Chengcheng Zhang Chao-Cheng Chen Devon Chapple Ryan Wilson Nadine Colpo François Bénard Kuo-Shyan Lin |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | Abstract Background Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [68Ga]Ga-TacBOMB2 (68Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-Thz14-NH2). Results Unnatural amino acid substitutions were conducted for Gln7, Trp8, Ala9, Val10, Gly11 and His12, either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu10 (Tle10) and NMe-His12 substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [68Ga]Ga-TacBOMB2, the Tle10 and NMe-His12 derived [68Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (Ki = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection). Conclusions Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [68Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle10,NMe-His12,Thz14]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents. |
| first_indexed | 2024-03-07T14:33:42Z |
| format | Article |
| id | doaj.art-24ff8b25475b4173968a9c483ac5e550 |
| institution | Directory Open Access Journal |
| issn | 2365-421X |
| language | English |
| last_indexed | 2024-03-07T14:33:42Z |
| publishDate | 2024-02-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj.art-24ff8b25475b4173968a9c483ac5e5502024-03-05T20:46:15ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2024-02-019111510.1186/s41181-024-00241-7Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomographyLei Wang0Hsiou-Ting Kuo1Zhengxing Zhang2Chengcheng Zhang3Chao-Cheng Chen4Devon Chapple5Ryan Wilson6Nadine Colpo7François Bénard8Kuo-Shyan Lin9Department of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteDepartment of Molecular Oncology, BC Cancer Research InstituteAbstract Background Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [68Ga]Ga-TacBOMB2 (68Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-Thz14-NH2). Results Unnatural amino acid substitutions were conducted for Gln7, Trp8, Ala9, Val10, Gly11 and His12, either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu10 (Tle10) and NMe-His12 substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [68Ga]Ga-TacBOMB2, the Tle10 and NMe-His12 derived [68Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (Ki = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection). Conclusions Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [68Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle10,NMe-His12,Thz14]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.https://doi.org/10.1186/s41181-024-00241-7Gastrin-releasing peptide receptorAgonistIn vivo stabilityPositron emission tomographyPancreas uptake |
| spellingShingle | Lei Wang Hsiou-Ting Kuo Zhengxing Zhang Chengcheng Zhang Chao-Cheng Chen Devon Chapple Ryan Wilson Nadine Colpo François Bénard Kuo-Shyan Lin Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography EJNMMI Radiopharmacy and Chemistry Gastrin-releasing peptide receptor Agonist In vivo stability Positron emission tomography Pancreas uptake |
| title | Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography |
| title_full | Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography |
| title_fullStr | Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography |
| title_full_unstemmed | Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography |
| title_short | Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography |
| title_sort | unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68ga labeled grpr targeted tacbomb2 derivatives for cancer imaging with positron emission tomography |
| topic | Gastrin-releasing peptide receptor Agonist In vivo stability Positron emission tomography Pancreas uptake |
| url | https://doi.org/10.1186/s41181-024-00241-7 |
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