Longguang Tang1,2, Chenyu Peng1, Bowen Tang3, Zijing Li1, Xiangyu Wang1, Jindian Li1, Fei Gao1, Lumei Huang1, Duo Xu1, Pu Zhang1, Rongqiang Zhuang1, Xinhui Su4, Xiaoyuan Chen2, Xianzhong Zhang5. 1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China. 2. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health, Bethesda, Maryland. 3. School of Pharmaceutical Science, Xiamen University, Xiamen, China; and. 4. Zhongshan Hospital, affiliated with Xiamen University, Xiamen, China. 5. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China zhangxzh@xmu.edu.cn.
Abstract
One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog (125/131I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. Methods: The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. 125/131I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of 131I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal 125I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of 125/131I-IBA-CP toward HER2 in vitro and in vivo. Additionally, 125/131I-ICP was prepared by direct radioiodination of CP724,714 for comparison with 125/131I-IBA-CP. Results: IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. 125/131I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of 125I-IBA-CP than of 125I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of 125I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. Conclusion: The radiolabeled HER2-selective inhibitor 125/131I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.
One of the most clinically relevant molecular aberrations in breast cancer is overexpression of humanepidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog (125/131I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous humanbreast cancer xenografts. Methods: The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. 125/131I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of 131I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal 125I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of 125/131I-IBA-CP toward HER2 in vitro and in vivo. Additionally, 125/131I-ICP was prepared by direct radioiodination of CP724,714 for comparison with 125/131I-IBA-CP. Results:IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. 125/131I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of 125I-IBA-CP than of 125I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of 125I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. Conclusion: The radiolabeled HER2-selective inhibitor 125/131I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.
Authors: Helen Su; Yann Seimbille; Gregory Z Ferl; Claudia Bodenstein; Barbara Fueger; Kevin J Kim; Yu-Tien Hsu; Steven M Dubinett; Michael E Phelps; Johannes Czernin; Wolfgang A Weber Journal: Eur J Nucl Med Mol Imaging Date: 2008-02-01 Impact factor: 9.236
Authors: Jitesh P Jani; Richard S Finn; Mary Campbell; Kevin G Coleman; Richard D Connell; Nicolas Currier; Erling O Emerson; Eugenia Floyd; Shawn Harriman; John C Kath; Joel Morris; James D Moyer; Leslie R Pustilnik; Kristina Rafidi; Sherry Ralston; Ann Marie K Rossi; Stefanus J Steyn; Larry Wagner; Steven M Winter; Samit K Bhattacharya Journal: Cancer Res Date: 2007-10-15 Impact factor: 12.701