99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule
2007 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, no 11, 1843-1853 p.Article in journal (Refereed) Published
PURPOSE: Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z(HER2:342) binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z(HER2:342) with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with (99m)Tc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z(HER2:342) can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. METHODS: The Affibody molecule Z(HER2:342), carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D: -seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with (99m)Tc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of (99m)Tc-maSSS-Z(HER2:342) was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z(HER2:342). RESULTS: A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of (99m)Tc-maSSS-Z(HER2:342) was 11.5 +/- 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z(HER2:342) were better than those of radioiodinated Z(HER2:342). CONCLUSION: The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z(HER2:342) compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.
Place, publisher, year, edition, pages
2007. Vol. 34, no 11, 1843-1853 p.
Animals, Chelating Agents/chemistry, Drug Delivery Systems/*methods, Female, Metabolic Clearance Rate, Mice, Inbred BALB C, Mice, Nude, Organ Specificity, Ovarian Neoplasms/*metabolism/radionuclide imaging, Radiopharmaceuticals/chemistry/diagnostic use/pharmacokinetics, Recombinant Fusion Proteins/chemistry/diagnostic use/*pharmacokinetics, Technetium/chemistry/diagnostic use/*pharmacokinetics, Tissue Distribution
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-17041DOI: 10.1007/s00259-007-0474-6ISI: 000250205400017PubMedID: 17565496OAI: oai:DiVA.org:uu-17041DiVA: diva2:44812