99mTc-maEEE-ZHER2:342, an affibody molecule-based tracer for the detection of HER2 expression in malignant tumors
99mTc-maEEE-ZHER2:342, an affibody molecule-based tracer for the detection of HER2 expression in malignant tumors
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DOI：
10.1021/bc7002617
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发表时间：
2007-11-01
影响因子：
4.7
通讯作者：
Karlstroem, Amelie Eriksson
中科院分区：
文献类型：
--
作者：
Tran, Thuy;Engfeldt, Torun;Karlstroem, Amelie Eriksson
检测肿瘤和转移瘤中HER2的过度表达对于选择将受益于曲妥珠单抗治疗的患者很重要。早期的研究表明，在使用铟或镓标记的亲和分子的患者中，成功地对HER2阳性肿瘤进行了成像。本研究的目的是评价用99m标记的亲和分子检测HER2的表达。用多肽合成法合成了具有巯基乙酰-甘氨酸-谷氨酸-甘氨酸(MaGEG)和巯基乙酰-谷氨酸-谷氨酸(MaEEE)两种配基序列的亲和分子Z(HER2：342)，并用~(99m)Tc标记。考察了其结合特异性、细胞保留率和体外稳定性。比较了99m-MAGEG-Z(HER2：342)和Tc99m-MAEEE-Z(HER2：342)在正常小鼠体内的分布，并测定了Tc99m-MAEEE-Z(HER2：342)在SKOV-3裸鼠体内的靶向性。结果表明，~(99m)Tm能有效地标记亲和体分子。标记的偶联物在体外高度稳定，保留了HER2的结合能力。在~(99m)T标记Z(HER2：342)的螯合剂序列中使用谷氨酸，单次Gly-to-Glu取代可使肝胆排泄量减少3倍，3次Gly-to-Glu取代可使肝胆排泄量减少10倍。TC-99m-MAEEE-Z(HER2：342)显示受体特异性的肿瘤摄取率为7.9+/-1.0%IA/g，4hpi时肿瘤与血液的比率为38。99mTC-MAEEE-Z(HER2：342)伽玛摄像可在1hpi的异种移植瘤中检测到HER2表达的肿瘤。结论：将螯合剂序列偶联到亲和体分子上的多肽合成是修正体内动力学的有效途径。亲水性增加，再加上巯基乙酰-三聚氰胺螯合剂稳定性的提高，导致了良好的生物分布，使Tc-99m-maEEE-Z(HER2：342)成为一种有希望的肿瘤HER2过表达的临床显像剂。
Detection of HER2-overexpression in tumors and metastases is important for the selection of patients who will benefit from trastuzumab treatment. Earlier investigations showed successful imaging of HER2-positive tumors in patients using indium- or gallium-labeled Affibody molecules. The goal of this study was to evaluate the use of Tc-99m-labeled Affibody molecules for the detection of HER2 expression. The Affibody molecule Z(HER2:342) with the chelator sequences mercaptoacetyl-Gly-Glu-Gly (maGEG) and mercaptoacetyl-Glu-Glu-Glu (maEEE) was synthesized by peptide synthesis and labeled with technetium-99m. Binding specificity, cellular retention, and in vitro stability were investigated. The biodistribution of Tc-99m-maGEG-Z(HER2:342) and Tc-99m-maEEE-Z(HER2:342) was compared with Tc-99m-maGGG-Z(HER2:342) in normal mice, and the tumor targeting properties of Tc-99m-maEEE-Z(HER2:342) were determined in SKOV-3 xenografted nude mice. The results showed that the Affibody molecules were efficiently labeled with technetium-99m. The labeled conjugates were highly stable in vitro with preserved HER2-binding capacity. The use of glutamic acid in the chelator sequences for Tc-99m-labeling Of Z(HER2:342) reduced the hepatobiliary excretion 3-fold with a single Gly-to-Glu substitution and 10-fold with three Gly-to-Glu substitutions. Tc-99m-maEEE-Z(HER2:342) showed a receptor-specific tumor uptake of 7.9 +/- 1.0 %IA/g and a tumor-to-blood ratio of 38 at 4 h pi. Gamma-camera imaging with 99mTc-maEEE-Z(HER2:342) could detect HER2-expressing tumors in xenografts already at 1 h pi. It was concluded that peptide synthesis for the coupling of chelator sequences to Affibody molecules for Tc-99m labeling is an efficient way to modify the in vivo kinetics. Increased hydrophilicity, combined with improved stability of the mercaptoacetyl-triglutamyl chelator, resulted in favorable biodistribution, making Tc-99m-maEEE-Z(HER2:342) a promising tracer for clinical imaging of HER2 overexpression in tumors.