start-ver=1.4 cd-journal=joma no-vol=34 cd-vols= no-issue= article-no= start-page=575 end-page=582 dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200608 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Improvement of biodistribution profile of a radiogallium-labeled, ƒ¿vƒÀ6 integrin-targeting peptide probe by incorporation of negatively charged amino acids en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Since ƒ¿vƒÀ6 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 ƒ¿vƒÀ6 integrin-targeting probe. Although [67Ga]CG6 specifically binds to ƒ¿vƒÀ6 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 ƒ¿vƒÀ6 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 ƒ¿vƒÀ6 integrin via in vitro competitive binding assay. Isoelectric points of the probes were determined by electrophoresis. Biodistribution study, autoradiography, and immunostaining for ƒÀ6 integrin were conducted using ƒ¿vƒÀ6 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 ƒ¿vƒÀ6 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 ƒ¿vƒÀ6 integrin-positive xenografts was significantly higher than that in the ƒ¿vƒÀ6 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 ƒ¿vƒÀ6 integrin-positive xenograft roughly coincided with ƒÀ6 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. en-copyright= kn-copyright= en-aut-name=NakamuraShunsuke en-aut-sei=Nakamura en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsunoAya en-aut-sei=Matsuno en-aut-mei=Aya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UedaMasashi en-aut-sei=Ueda en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil= Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=ƒ¿vƒÀ6 integrin kn-keyword=ƒ¿vƒÀ6 integrin en-keyword=Pancreatic ductal adenocarcinoma (PDAC) kn-keyword=Pancreatic ductal adenocarcinoma (PDAC) en-keyword=A20FMDV2 kn-keyword=A20FMDV2 en-keyword=Aspartic acids kn-keyword=Aspartic acids en-keyword=Electric charge kn-keyword=Electric charge END