Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)3-Conjugates in Important Organs
Pharmacokinetic Properties of Peptidic Radiopharmaceuticals: Reduced Uptake of (EH)3-Conjugates in Important Organs
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DOI：
10.2967/jnumed.112.114512
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发表时间：
2013-08-01
影响因子：
9.3
通讯作者：
Eisenhut, Michael
中科院分区：
文献类型：
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作者：
Eder, Matthias;Loehr, Thomas;Eisenhut, Michael
放射性标记的肿瘤靶向肽转化为临床常规常常受到排泄器官积累增强的阻碍。最近有报道称（EH）3纯化标签能够改善附着体分子的生物分布。因此，本研究的目的是证明（EH）3对2种肽性放射性药物gluu -urea- lys (Ahx)-HBED-CC和TATE-PEG(2)-HBED-CC （HBED-CC为N，N'-双[2-羟基-5（羧基乙基）苄基]乙二胺-N，N'-二乙酸，TATE为辛酸酯，PEG(2)为8-氨基-3,6-二恶辛酸间隔剂）的生物分布的积极影响。方法：将两种化合物与各自的（EH）(3)偶联变异体进行体外细胞检测和器官分布比较。结果：（EH）(3)的引入显著改变了HBED-CC的生物分布特征。在这两种情况下，几个器官的摄取减少，而肿瘤的摄取不受影响。最重要的是，（EH）(3)将肾脏和肝脏对前列腺特异性膜抗原抑制剂的摄取分别降低了2.8倍，在奥替酸的情况下，肝脏积累降低了51倍。结论：生物分布数据表明（EH）(3)能够改善肽类放射性药物的药代动力学特性，导致肝脏等器官的吸收减少，肝脏是转移性疾病的重要部位。
The translation of radiolabeled tumor-targeting peptides into clinical routine is often hampered by an enhanced accumulation into the excreting organs. It has recently been reported that the (EH)3 purification tag is able to improve the biodistribution of Affibody molecules. Therefore, the aim of this study was to prove the positive influence of (EH)3 on the biodistribution of 2 peptidic radiopharmaceuticals, Glu-urea-Lys(Ahx)-HBED-CC and TATE-PEG(2)-HBED-CC (HBED-CC is N,N'-bis [2-hydroxy-5(carboxyethyl)benzyl] ethylene-diamine-N,N'- diacetic acid, TATE is octreotate, and PEG(2) is 8-amino-3,6-dioxaoctanoic acid spacer). Methods: Both compounds were compared with their respective (EH)(3)-conjugated variants in cell-based in vitro assays and organ distribution. Results: The introduction of (EH)(3) to HBED-CC significantly changed the biodistribution profiles. In both cases, the uptake in several organs was reduced whereas tumor uptake was not affected. Most importantly, (EH)(3) lowered the kidney and liver uptake of the prostate-specific membrane antigen inhibitor each by a factor of 2.8 and, in the case of octreotate, the liver accumulation by a factor of 51. Conclusion: The biodistribution data suggest that (EH)(3) is able to improve the pharmacokinetic properties of peptidic radiopharmaceuticals, leading to reduced uptake in organs such as the liver, an important site of metastatic disease.