Pre-clinical evaluation of -benzyl-DOTA-ZHER2: 3429 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 In-111 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(HIR2:342). 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 In-111 at 60 degrees C. The specificity of In-111-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 In-111-benzyl-DOTA-Z(HER2:342) was performed in nude mice bearinLy LS174T xenografts and compared directly with the biodistribution of In-111-benzyl-DTPA-Z(HR2:342). In vivo, In-111-benzyl-DOTA-Z(HER2:312) demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of In-111-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 In-111-benzyl-DOTA-Z(HER2:342). In-111-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.
affibody, human epidermal growth factor receptor type 2, tumor targeting, indium-111, benzyl-DOTA, disseminated peritoneal disease, breast-cancer xenografts, binding-proteins, in-vitro, affibody, antibody, trastuzumab, therapy, in-111, mice
IdentifiersURN: urn:nbn:se:kth:diva-16865ISI: 000248699900018PubMedID: 17671747ScopusID: 2-s2.0-35148899326OAI: oai:DiVA.org:kth-16865DiVA: diva2:334908
QC 201005252010-08-052010-08-052014-11-11Bibliographically approved