Pre-clinical evaluation of [111In]-benzyl-DOTA-Z(HER2:342), a potential agent for imaging of HER2 expression in malignant tumors
2007 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 20, no 3, 397-404 p.Article in journal (Refereed) Published
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 Z(HER2:342) is a small (7-kDa) non-immunoglobulin affinity protein, which binds to HER2 with a picomolar affinity. Previously, a benzyl-DTPA conjugate of Z(HER2:342) 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 Z(HER2:342). The goal of this study was the preparation and pre-clinical evaluation of the indium-111- labeled DOTA-derivative of Z(HER2:342). Isothiocyanate-benzyl-DOTA was coupled to recombinant Z(HER2:342), and the conjugate was efficiently labeled with 111In at 60 degrees C. The specificity of 111In-benzyl-DOTA-Z(HER2:342) 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-Z(HER2:342) was performed in nude mice bearing LS174T xenografts and compared directly with the biodistribution of 111In-benzyl-DTPA-Z(HER2:342). In vivo, 111In-benzyl-DOTA-Z(HER2:342) demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of 111In-benzyl-DOTA-Z(HER2:342) (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. gamma-camera imaging showed clear visualization of HER2-expressing xenografts using 111In-benzyl-DOTA-Z(HER2:342). 111In-benzyl-DOTA-Z(HER2:342) has a potential for imaging of HER2 expression in malignant tumors.
Place, publisher, year, edition, pages
2007. Vol. 20, no 3, 397-404 p.
Animals, Breast Neoplasms/*genetics/metabolism/*radionuclide imaging, Cell Line; Tumor, Drug Evaluation; Preclinical, Female, Genes; erbB-2, Humans, Indium Radioisotopes/diagnostic use/pharmacokinetics, Mice, Mice; Inbred BALB C, Mice; Nude, Neoplasm Transplantation, Ovarian Neoplasms/*genetics/metabolism/*radionuclide imaging, Pentetic Acid/*analogs & derivatives/diagnostic use/pharmacokinetics, Radiopharmaceuticals/diagnostic use/pharmacokinetics, Receptor; erbB-2/metabolism, Tissue Distribution, Transplantation; Heterologous
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-17045ISI: 000248699900018PubMedID: 17671747OAI: oai:DiVA.org:uu-17045DiVA: diva2:44816