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Order of amino acids in C-terminal cysteine-containing peptide-based chelators influences cellular processing and biodistribution of Tc-99m-labeled recombinant Affibody molecules
KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
Vise andre og tillknytning
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 Tc-99m. 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 Tc-99m-labeled Affibody molecules and their biodistribution were investigated. These properties were compared with that of the previously studied Tc-99m-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 Tc-99m. The biodistribution of all Tc-99m-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 Tc-99m 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.

sted, utgiver, år, opplag, sider
2012. Vol. 42, nr 5, s. 1975-1985
Emneord [en]
Affibody molecule, Technetium-99m, Molecular imaging, HER2, C-terminal cysteine, Peptide-based chelator
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-95083DOI: 10.1007/s00726-011-0927-xISI: 000302812700042PubMedID: 21573874Scopus ID: 2-s2.0-84862763098OAI: oai:DiVA.org:kth-95083DiVA, id: diva2:527688
Forskningsfinansiär
Swedish Research Council
Merknad
QC 20120522Tilgjengelig fra: 2012-05-22 Laget: 2012-05-14 Sist oppdatert: 2017-12-07bibliografisk kontrollert

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