Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence
| Autor: | Torun Engfeldt, Alexander Bruskin, Anna Orlova, Thuy A Tran, Amelie Eriksson Karlström, Charles Widström, Vladimir Tolmachev |
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| Rok vydání: | 2006 |
| Předmět: |
Spectrometry
Mass Electrospray Ionization Biodistribution Phage display Receptor ErbB-2 Peptide Biosensing Techniques Antibodies Technetium Tc 99m Mertiatide Mice chemistry.chemical_compound Cell Line Tumor Neoplasms Peptide synthesis Animals Humans Radiology Nuclear Medicine and imaging Radionuclide Imaging Receptor chemistry.chemical_classification Mice Inbred BALB C General Medicine chemistry Biochemistry Cell culture Immunology Female Affibody molecule Radiopharmaceuticals Peptides Neoplasm Transplantation Conjugate |
| Zdroj: | European Journal of Nuclear Medicine and Molecular Imaging. 34:722-733 |
| ISSN: | 1619-7089 1619-7070 |
| Popis: | Expression of human epidermal growth factor receptor type 2 (HER2) in malignant tumours possesses well-documented prognostic and predictive value. Non-invasive imaging of expression can provide valuable diagnostic information, thereby influencing patient management. Previously, we reported a phage display selection of a small (about 7 kDa) protein, the Affibody molecule Z(HER2:342), which binds HER2 with subnanomolar affinity, and demonstrated the feasibility of targeting of HER2-expressing xenografts using radioiodinated Z(HER2:342). The goal of this study was to develop a method for (99m)Tc labelling of Z(HER2:342) using the MAG3 chelator, which was incorporated into Z(HER2:342) using peptide synthesis, and evaluate the targeting properties of the labelled conjugate.MAG3-Z(HER2:342) was assembled using Fmoc/tBu solid phase peptide synthesis. Biochemical characterisation of the agent was performed using RP-HPLC, ESI-MS, biosensor studies and circular dichroism. A procedure for (99m)Tc labelling in the presence of sodium/potassium tartrate was established. Tumour targeting was evaluated by biodistribution study and gamma camera imaging in xenograft-bearing mice. Biodistribution of (99m)Tc-MAG3-Z(HER2:342) and (125)I-para-iodobenzoate -Z(HER2:342) was compared 6 h p.i.Synthetic MAG3-Z(HER2:342) possessed an affinity of 0.2 nM for HER2 receptors. The peptide was labelled with (99m)Tc with an efficiency of about 75-80%. Labelled (99m)Tc-MAG3-Z(HER2:342) retained capacity to bind specifically HER2-expressing SKOV-3 cells in vitro. (99m)Tc-MAG3-Z(HER2:342) showed specific tumour targeting with a contrast similar to a radioiodinated analogue in mice bearing LS174T xenografts. Gamma camera imaging demonstrated clear and specific visualisation of HER2 expression.Incorporation of a mercaptoacetyl-containing chelating sequence during chemical synthesis enabled site-specific (99m)Tc labelling of the Z(HER2:342) Affibody molecule with preserved targeting capacity. |
| Databáze: | OpenAIRE |
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