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Influence of an aliphatic linker between DOTA and synthetic Z(HER2:342) Affibody molecule on targeting properties of the (111)In-labeled conjugate
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
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2011 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 38, no 5, 697-706 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Affibody molecules are small (similar to 6.5 kDa) scaffold proteins suitable for radionuclide imaging of rumor-associated molecular targets. Site-specific labeling of Affibody molecules made by peptide synthesis can be achieved by coupling a chelator to N-terminus in the last synthesis step. The goal of this study was to evaluate the influence of a 6-aminohexanoic linker between DOTA and Z(HER2:342) on targeting properties of (111)In-labeled conjugate. Methods: A DOTA-conjugated 6-aminohexanoic linker-containing variant Of Z(HER2:342) (ABY-003) was produced by peptide synthesis, and the in vitro binding affinity, specificity and cellular processing were evaluated. The biodistribution of (111)In-ABY-003 in normal mice was compared to (111)In-ABY-002 (DOTA-Z(HER2:342-pep2)) lacking the linker. Tumor-targeting properties of (111)In-ABY-003 were evaluated in mice bearing HER2-expressing xenografts. Results: The dissociation constant of ABY-003 was in the low picomolar range, slightly higher than for ABY-002. (111)In-ABY-003 bound specifically to HER2-expressing cells in vitro. The cellular retention was efficient but slightly worse than for (111)In-ABY-002. In normal mice, the clearance of (111)In-ABY-003 from blood and other tissues was slightly but significantly faster compared to (111)In-ABY-002. Targeting of HER2-expressing xenografts by (111)In-ABY-003 was receptor-specific. Due to faster clearance, the tumor-to-blood ratio for (111)In-ABY-003 at 4 h postinjection was improved compared to (111)In-ABY-002. The capacity of (111)In-ABY-003 to visualize HER2-expressing tumors was confirmed by gamma camera imaging. Conclusions: A 6-aminohexanoic linker between the DOTA chelator and N-terminus of synthetic Z(HER2:342) had a measurable effect on affinity, cellular retention of radioactivity and blood clearance. The linker might be used for modulation of targeting properties of Affibody molecules.

Place, publisher, year, edition, pages
2011. Vol. 38, no 5, 697-706 p.
Keyword [en]
Affibody molecule, DOTA, Indium-111, Aminohexanoic acid, Linker, Targeting
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-156672DOI: 10.1016/j.nucmedbio.2010.11.013ISI: 000292671700012OAI: oai:DiVA.org:uu-156672DiVA: diva2:433394
Available from: 2011-08-09 Created: 2011-08-07 Last updated: 2017-12-08Bibliographically approved

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Tolmachev, VladimirOrlova, Anna

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