Radiometal-labeled anti-VCAM-1 nanobodies as molecular tracers for atherosclerosis - impact of radiochemistry on pharmacokinetics

被引:21
作者
Bala, Gezim [1 ,2 ]
Crauwels, Maxine [1 ,3 ]
Blykers, Anneleen [1 ]
Remory, Isabel [1 ,4 ]
Marschall, Andrea L. J. [5 ]
Dubel, Stefan [5 ]
Dumas, Laurent [6 ]
Broisat, Alexis [6 ]
Martin, Charlotte [7 ]
Ballet, Steven [7 ]
Cosyns, Bernard [2 ]
Caveliers, Vicky [1 ,8 ]
Devoogdt, Nick [1 ]
Xavier, Catarina [1 ]
Hernot, Sophie [1 ]
机构
[1] Vrije Univ Brussel, ICMI BEFY, Lab Vivo Cellular & Mol Imaging, Laarbeeklaan 103, B-1090 Brussels, Belgium
[2] UZBrussel, Dept Cardiol, Laarbeeklaan 101, B-1090 Brussels, Belgium
[3] Vrije Univ Brussel, CMIM, Cellular & Mol Immunol, Pl Lann 2, B-1050 Brussels, Belgium
[4] UZBrussel, Dept Anesthesiol, Laarbeeklaan 101, B-1090 Brussels, Belgium
[5] Tech Univ Carolo Wilhelmina Braunschweig, Inst Biochem, Biotechnol & Bioinformat, Spielmannstr 7, D-38106 Braunschweig, Germany
[6] Univ Grenoble Alpes, INSERM, LRB, U1039, F-38700 La Tonche, France
[7] Vrije Univ Brussel, Res Grp Organ Chem, Pl Laan 2, B-1050 Brussels, Belgium
[8] UZBrussel, Dept Nucl Med, Laarbeeklaan 101, B-1090 Brussels, Belgium
关键词
mass effect; molecular imaging; single-domain antibody fragment; specific activity; VCAM-1 knock-down mice; vulnerable plaque; EXPRESSION; VCAM1; SPECT; SDAB; TOOL;
D O I
10.1515/hsz-2018-0330
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Radiolabeling of nanobodies with radiometals by chelation has the advantage of being simple, fast and easy to implement in clinical routine. In this study, we validated Ga-68/In-111-labeled anti-VCAM-1 nanobodies as potential radiometal-based tracers for molecular imaging of atherosclerosis. Both showed specific targeting of atherosclerotic lesions in ApoE(-/-) mice. Nevertheless, uptake in lesions and constitutively VCAM-1 expressing organs was lower than previously reported for the Tc-99m-labeled analog. We further investigated the impact of different radiolabeling strategies on the in vivo biodistribution of nanobody-based tracers. Comparison of the pharmacokinetics between Ga-68-, F-18-, In-111- and Tc-99m-labeled anti-VCAM-1 nanobodies showed highest specific uptake for Tc-99m-nanobody at all time-points, followed by the Ga-68-, In-111- and F-18- labeled tracer. No correlation was found with the estimated number of radioisotopes per nanobody, and mimicking specific activity of other radiolabeling methods did not result in an analogous biodistribution. We also demonstrated specificity of the tracer using mice with a VCAM-1 knocked-down phenotype, while showing for the first time the in vivo visualization of a protein knock-down using intrabodies. Conclusively, the chosen radiochemistry does have an important impact on the biodistribution of nanobodies, in particular on the specific targeting, but differences are not purely due to the tracer's specific activity.
引用
收藏
页码:323 / 332
页数:10
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