Synthetic affibody molecules:: A novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors
Synthetic affibody molecules:: A novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors
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DOI：
10.1158/0008-5472.can-06-2887
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Feldwisch, Joachim
中科院分区：
文献类型：
--
作者：
Orlova, Anna;Tolmachev, Vladimir;Feldwisch, Joachim
亲和体分子Z（HER 2：342-pep 2），与1，4，7，10-四氮杂环十二烷-N，N '，N”，N“”-四乙酸（DOTA）螯合剂位点特异性且均匀地缀合，通过肽合成在单一化学过程中产生。DOTA-Z（HER 2：342-pep 2）自发折叠，并以65 pmol/L亲和力结合HER 2。在低温（室温）和高温（高达90摄氏度）下，30分钟内即可实现In-111掺入率> 95%的高效放射性标记。In-111-DOTA-Z（HER 12：342-pep 2）的肿瘤摄取对HER 2阳性异种移植物具有特异性。在注射后1小时已经获得了每克组织23%注射活性的高肿瘤摄取、> 7.5的肿瘤与血液比和高对比度伽马照相机图像。赫赛汀预处理不干扰肿瘤靶向，而在In-111-DOTA-Z（HER 2：342-pep 2）给药前使用热休克蛋白90抑制剂17-烯丙基氨基-格尔德霉素降解HER 2可消除肿瘤图像。目前的结果表明，放射性标记的合成DOTA-Z（HER 2：342-pep 2）有可能成为临床上有用的放射性药物，用于HER 2表达癌的体内分子成像。
The Affibody molecule Z(HER2:342-pep2), site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N', N",N '''-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-Z(HER2:342-pep2) folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with > 95% incorporation of In-111 was achieved within 30 min at low (room temperature) and high temperatures (up to 90 degrees C). Tumor uptake of In-111-DOTA-Z(HER12:342-pep2) was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of > 7.5, and high-contrast gamma camera images were obtained already I h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of In-111-DOTA-Z(HER2:342-pep2) obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-Z(HER2:342-pep2) has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.