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Order of amino acids in C-terminal cysteine-containing peptide-based chelators influences cellular processing and biodistribution of (99m)Tc-labeled recombinant Affibody molecules
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. (Vladimir Tolmachev)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. (Anna Orlova)ORCID-id: 0000-0001-6120-2683
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. (Vladimir Tolmachev)
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2012 (engelsk)Inngår i: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 42, nr 5, s. 1975-1985Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Affibody molecules constitute a novel class of molecular display selected affinity proteins based on non-immunoglobulin scaffold. Preclinical investigations and pilot clinical data have demonstrated that Affibody molecules provide high contrast imaging of tumor-associated molecular targets shortly after injection. The use of cysteine-containing peptide-based chelators at the C-terminus of recombinant Affibody molecules enabled site-specific labeling with the radionuclide (99m)Tc. Earlier studies have demonstrated that position, composition and the order of amino acids in peptide-based chelators influence labeling stability, cellular processing and biodistribution of Affibody molecules. To investigate the influence of the amino acid order, a series of anti-HER2 Affibody molecules, containing GSGC, GEGC and GKGC chelators have been prepared and characterized. The affinity to HER2, cellular processing of (99m)Tc-labeled Affibody molecules and their biodistribution were investigated. These properties were compared with that of the previously studied (99m)Tc-labeled Affibody molecules containing GGSC, GGEC and GGKC chelators. All variants displayed picomolar affinities to HER2. The substitution of a single amino acid in the chelator had an appreciable influence on the cellular processing of (99m)Tc. The biodistribution of all (99m)Tc-labeled Affibody molecules was in general comparable, with the main difference in uptake and retention of radioactivity in excretory organs. The hepatic accumulation of radioactivity was higher for the lysine-containing chelators and the renal retention of (99m)Tc was significantly affected by the amino acid composition of chelators. The order of amino acids influenced renal uptake of some conjugates at 1 h after injection, but the difference decreased at later time points. Such information can be helpful for the development of other scaffold protein-based imaging and therapeutic radiolabeled conjugates.

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2012. Vol. 42, nr 5, s. 1975-1985
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URN: urn:nbn:se:uu:diva-164422DOI: 10.1007/s00726-011-0927-xISI: 000302812700042PubMedID: 21573874OAI: oai:DiVA.org:uu-164422DiVA, id: diva2:525016
Tilgjengelig fra: 2012-05-04 Laget: 2011-12-20 Sist oppdatert: 2017-12-07bibliografisk kontrollert

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