Radiometal-labeled anti-VCAM-1 nanobodies as molecular tracers for atherosclerosis - impact of radiochemistry on pharmacokinetics
Radiometal-labeled anti-VCAM-1 nanobodies as molecular tracers for atherosclerosis - impact of radiochemistry on pharmacokinetics
复制标题
DOI：
10.1515/hsz-2018-0330
复制
发表时间：
2019-03-01
影响因子：
3.7
通讯作者：
Hernot, Sophie
中科院分区：
文献类型：
--
作者：
Bala, Gezim;Crauwels, Maxine;Hernot, Sophie
通过螯合用放射性金属放射性标记纳米抗体具有简单、快速和易于在临床常规中实施的优点。在这项研究中，我们验证了Ga-68/In-111标记的抗VCAM-1纳米抗体作为动脉粥样硬化分子成像的潜在放射性示踪剂。两者均显示出对ApoE（-/-）小鼠动脉粥样硬化病变的特异性靶向作用。然而，病变和组成性VCAM-1表达器官的摄取低于以前报道的Tc-99 m标记的类似物。我们进一步研究了不同放射性标记策略对基于纳米抗体的示踪剂的体内生物分布的影响。Ga-68-、F-18-、In-111-和Tc-99 m-标记的抗VCAM-1纳米抗体之间的药代动力学的比较显示在所有时间点Tc-99 m-纳米抗体的最高特异性摄取，其次是Ga-68-、In-111-和F-18-标记的示踪剂。没有发现与每个纳米抗体的放射性同位素的估计数量的相关性，并且模拟其他放射性标记方法的比活性不会导致类似的生物分布。我们还使用具有VCAM-1敲低表型的小鼠证明了示踪剂的特异性，同时首次显示了使用胞内抗体的蛋白质敲低的体内可视化。总之，所选择的放射化学确实对纳米抗体的生物分布具有重要影响，特别是对特异性靶向，但差异并不纯粹是由于示踪剂的特异性活性。
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.