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Pre-clinical evaluation of [111In]-benzyl-DOTA-ZHER2:342, a potential agent for imaging of HER2 expression in malignant tumors

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Imaging of expression of human epidermal growth factor receptor type 2 (HER2) in breast carcinomas may help to select patients eligible for trastuzumab therapy. The Affibody molecule ZHER2:342 is a small (7-kDa) non-immunoglobulin affinity protein, which binds to HER2 with a picomolar affinity. Previously, a benzyl-DTPA conjugate of ZHER2:342 was labeled with 111In and demonstrated good targeting in murine xenografts. We considered that the use of the macrocyclic chelator DOTA could increase the label stability and enhance a choice of nuclides, which could be used as a label for ZHER2:342. The goal of this study was the preparation and pre-clinical evaluation of the indium-111- labeled DOTA-derivative of ZHER2:342. Isothiocyanate-benzyl-DOTA was coupled to recombinant ZHER2:342, and the conjugate was efficiently labeled with 111In at 60° C. The specificity of 111In-benzyl-DOTA-ZHER2:342 binding to HER2 was confirmed in vitro using HER2-expressing breast carcinoma BT474 and ovarian carcinoma SKOV-3 cell lines. Biodistribution of 111In-benzyl-DOTA-ZHER2:342 was performed in nude mice bearing LS174T xenografts and compared directly with the biodistribution of 111In-benzyl-DTPA-ZHER2:342. In vivo, 111In-benzyl-DOTA-ZHER2:342 demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of 111In-benzyl-DOTA-ZHER2:342 (4.4±1.0% IA/g) was specific and the tumor-to-blood ratio was 23. The use of benzyl-DTPA provided higher tumor-to-blood and tumor-to-liver ratios. γ-camera imaging showed clear visualization of HER2-expressing xenografts using 111In-benzyl-DOTA-ZHER2:342. 111In-benzyl-DOTA-ZHER2:342 has a potential for imaging of HER2 expression in malignant tumors.
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Document Type: Research Article

Affiliations: Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden

Publication date: September 1, 2007

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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