TY - JOUR
T1 - Synthetic affibody molecules
T2 - A novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors
AU - Orlova, Anna
AU - Tolmachev, Vladimir
AU - Pehrson, Rikard
AU - Lindborg, Malin
AU - Tran, Thuy
AU - Sandström, Mattias
AU - Nilsson, Fredrik Y.
AU - Wennborg, Anders
AU - Abrahmsén, Lars
AU - Feldwisch, Joachim
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2007/3/1
Y1 - 2007/3/1
N2 - The Affibody molecule ZHER2:342-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-ZHER2:342-pep2 folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of 111In was achieved within 30 min at low (room temperature) and high temperatures (up to 90°C). Tumor uptake of 111In-DOTA-ZHER2:342-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 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylaminogeldanamycin before administration of 111In-DOTA-ZHER2:342-pep2 obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-ZHER2:342-pep2 has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.
AB - The Affibody molecule ZHER2:342-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-ZHER2:342-pep2 folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of 111In was achieved within 30 min at low (room temperature) and high temperatures (up to 90°C). Tumor uptake of 111In-DOTA-ZHER2:342-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 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylaminogeldanamycin before administration of 111In-DOTA-ZHER2:342-pep2 obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-ZHER2:342-pep2 has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.
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U2 - 10.1158/0008-5472.CAN-06-2887
DO - 10.1158/0008-5472.CAN-06-2887
M3 - Article
C2 - 17332348
AN - SCOPUS:33947193534
VL - 67
SP - 2178
EP - 2186
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 5
ER -