Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice
Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice
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DOI：
10.1002/cmmi.408
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发表时间：
2011-03-01
影响因子：
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通讯作者：
Lahoutte, Tony
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文献类型：
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作者：
Gainkam, Lea Olive Tchouate;Caveliers, Vicky;Lahoutte, Tony
背景：纳米小体是从Camelidae中获得的功能重链抗体衍生的单域抗原结合片段。它们是放射免疫成像的有力探针，但它们的肾脏摄取相对较高。在这项研究中，我们评估了巨噬细胞苷对抗egfr Tc-99m-7C12纳米体肾脏摄取的作用，以及格洛夫辛和/或赖氨酸减少Tc-99m-7C12肾脏摄取的效力。方法：首先，我们使用针孔SPECT/微ct和离体分析比较巨噬细胞素缺乏和巨噬细胞素野生型小鼠Tc-99m-7C12的肾脏摄取。以CD-1小鼠为实验对象，分析gelofusine和赖氨酸给药对Tc-99m-7C12肾脏蓄积的影响，分为示剂注射前30 min赖氨酸预给药（LysPreload）、LysPreload + gelofusine共给药（LysPreload + GeloCoad）、赖氨酸共给药（LysCoad）、gelofusine共给药（GeloCoad）和LysCoad + GeloCoad。在小鼠异种移植物中检测了格洛夫辛和赖氨酸对肿瘤摄取的联合作用。结果：巨噬细胞激素缺乏小鼠Tc-99m-7C12的肾脏摄取比巨噬细胞激素野生型小鼠低44.22% +/- 3.46%。在CD-1小鼠中，赖氨酸预负荷对肾潴留没有影响，而赖氨酸或格洛夫辛与示踪剂共注射分别减少25.12 +/- 2.99和36.22 +/- 3.07%。格洛夫辛与赖氨酸联合用药效果最好，可使肾潴留减少45.24±2.09%。Gelofusine和赖氨酸共同给药可改善肿瘤摄取。结论：meggalin对Tc-99m-7C12在肾脏的蓄积有促进作用。Gelofusine和赖氨酸与示踪剂联合注射可减少肾脏摄取，而提高肿瘤摄取。尽管这种方法允许使用纳米体优化成像方案，但在使用这些分子进行放射性核素治疗之前，还需要进一步改进。版权所有John Wiley & Sons， Ltd。
Background: Nanobodies are single-domain antigen binding fragments derived from functional heavy-chain antibodies elicited in Camelidae. They are powerful probes for radioimmunoimaging, but their renal uptake is relatively high. In this study we have evaluated the role of megalin on the renal uptake of anti-EGFR Tc-99m-7C12 nanobody and the potency of gelofusine and/or lysine to reduce renal uptake of Tc-99m-7C12.Methods: First we compared the renal uptake of Tc-99m-7C12 in megalin-deficient and megalin-wild-type mice using pinhole SPECT/microCT and ex vivo analysis. The effect of gelofusine and lysine administration on renal accumulation of Tc-99m-7C12 was analyzed in CD-1 mice divided into lysine preload at 30 min before tracer injection (LysPreload), LysPreload + gelofusine coadministration (LysPreload + GeloCoad), lysine coadministration (LysCoad), gelofusine coadministration (GeloCoad) and LysCoad + GeloCoad. The combined effect of gelofusine and lysine on tumor uptake was tested in mice xenografts.Results: Renal uptake of Tc-99m-7C12 was 44.22 +/- 3.46% lower in megalin-deficient compared with megalin-wild-type mice. In CD-1 mice, lysine preload had no effect on the renal retention whereas coinjection of lysine or gelofusine with the tracer resulted in 25.12 +/- 2.99 and 36.22 +/- 3.07% reduction, respectively. The combined effect of gelofusine and lysine was the most effective, namely a reduction of renal retention of 45.24 +/- 2.09%. Gelofusine and lysine coadministration improved tumor uptake.Conclusion: Megalin contributes to the renal accumulation of Tc-99m-7C12. Gelofusine and lysine coinjection with the tracer reduces the renal uptake while tumor uptake is improved. Although this methodology allows for optimization of imaging protocol using nanobodies, further improvements are needed before using these molecules for radionuclide therapy. Copyright (C) 2010 John Wiley & Sons, Ltd.