ID 59979
Author
Nakamura, Shunsuke Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Matsuno, Aya Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Ueda, Masashi Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Abstract
Objective
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Since αvβ6 integrin has been reported as a promising target for PDAC diagnosis, we previously developed H-Cys(mal-NOTA-67Ga)-(Gly)6-A20FMDV2-NH2 ([67Ga]CG6) as an αvβ6 integrin-targeting probe. Although [67Ga]CG6 specifically binds to αvβ6 integrin-positive xenografts, the uptake of [67Ga]CG6 in the organs surrounding the pancreas, such as the liver and spleen, was comparable to that in the αvβ6 integrin-positive xenografts. We hypothesized that the undesirable accumulation of [67Ga]CG6 in those organs was caused by the positive charges of [67Ga]CG6 (+ 3). In this study, we aimed to decrease [67Ga]CG6 uptake in the liver and spleen by reducing the electric charges of the probe.
Methods
We synthesized H-Cys(mal-NOTA-67Ga)-(Asp)6-A20FMDV2-NH2 ([67Ga]CD6) and evaluated its affinity to αvβ6 integrin via in vitro competitive binding assay. Isoelectric points of the probes were determined by electrophoresis. Biodistribution study, autoradiography, and immunostaining for β6 integrin were conducted using αvβ6 integrin-positive and negative tumor-bearing mice.
Results
In vitro competitive binding assay showed that the alteration of the linker had a negligible impact on the affinity of [67Ga]CG6 to αvβ6 integrin. The results of electrophoresis revealed that [67Ga]CG6 was positively charged whereas [67Ga]CD6 was negatively charged. In the biodistribution study, the uptake of [67Ga]CD6 in the αvβ6 integrin-positive xenografts was significantly higher than that in the αvβ6 integrin-negative ones at 60 and 120 min. The uptake of [67Ga]CD6 in the liver and spleen was more than two-fold lower than that of [67Ga]CG6 at both time points. In the immunohistochemistry study, the radioactivity accumulated areas in the autoradiogram of the αvβ6 integrin-positive xenograft roughly coincided with β6 integrin-expressing areas.
Conclusion
We have successfully reduced the nonspecific uptake in the liver and spleen by altering the linker amino acid from G6 to D6. [67Ga]CD6 overcame the drawbacks of [67Ga]CG6 in its biodistribution.
Keywords
αvβ6 integrin
Pancreatic ductal adenocarcinoma (PDAC)
A20FMDV2
Aspartic acids
Electric charge
Note
This is a post-peer-review, pre-copyedit version of an article published in Annals of Nuclear Medicine. The final authenticated version is available online at: http://dx.doi.org/10.1007/s12149-020-01483-6.
This fulltext is available in June 2021.
Published Date
2020-06-08
Publication Title
Annals of Nuclear Medicine
Volume
volume34
Publisher
Springer
Start Page
575
End Page
582
ISSN
0914-7187
NCID
AA10708017
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
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DOI
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isVersionOf https://doi.org/10.1007/s12149-020-01483-6