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Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
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2018 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 50, no 8, p. 981-994Article in journal (Refereed) Published
Abstract [en]

Epidermal growth factor receptor (EGFR) is overexpressed in a number of cancers and is the molecular target for several anti-cancer therapeutics. Radionuclide molecular imaging of EGFR expression should enable personalization of anti-cancer treatment. Affibody molecule is a promising type of high-affinity imaging probes based on a non-immunoglobulin scaffold. A series of derivatives of the anti-EGFR affibody molecule ZEGFR:2377, having peptide-based cysteine-containing chelators for conjugation of Tc-99m, was designed and evaluated. It was found that glutamate-containing chelators Gly-Gly-Glu-Cys (GGEC), Gly-Glu-Glu-Cys (GEEC) and Glu-Glu-Glu-Cys (EEEC) provide the best labeling stability. The glutamate containing conjugates bound to EGFR-expressing cells specifically and with high affinity. Specific targeting of EGFR-expressing xenografts in mice was demonstrated. The number of glutamate residues in the chelator had strong influence on biodistribution of radiolabeled affibody molecules. Increase of glutamate content was associated with lower uptake in normal tissues. The Tc-99m-labeled variant containing the EEEC chelator provided the highest tumor-to-organ ratios. In conclusion, optimizing the composition of peptide-based chelators enhances contrast of imaging of EGFR-expression using affibody molecules.

Place, publisher, year, edition, pages
2018. Vol. 50, no 8, p. 981-994
Keywords [en]
Affibody molecules, EGFR, Tc-99m, Peptide-based chelators, Glutamate
National Category
Cell and Molecular Biology Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-358029DOI: 10.1007/s00726-018-2571-1ISI: 000438425500002PubMedID: 29728916OAI: oai:DiVA.org:uu-358029DiVA, id: diva2:1241515
Funder
Swedish Society for Medical Research (SSMF)Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved

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Oroujeni, MaryamAltai, MohamedOrlova, AnnaMitran, BogdanVorobyeva, AnzhelikaGarousi, JavadTolmachev, Vladimir
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