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Optimized Molecular Design of ADAPT-Based HER2-Imaging Probes Labeled with 111In and 68Ga
School of Engineering in Chemistry, Biotechnology and Health (CBH), Division of Protein Science, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
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 Pharmacy, Department of Medicinal Chemistry, Theranostics.
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: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 7, p. 2674-2683Article in journal (Refereed) Published
Abstract [en]

Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE)3DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C59-DEAVDANS-ADAPT6-GSSC and DOTA-C61-(HE)3DANS-ADAPT6-GSSC) were stably labeled with 111In for SPECT and 68Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68Ga-labeled counterparts. The best performing variant was DOTA-C61-(HE)3DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111In and 68Ga labels, respectively.

Place, publisher, year, edition, pages
2018. Vol. 15, no 7, p. 2674-2683
Keywords [en]
ADAPT, DOTA, HER2, gallium-68, indium-111, radionuclide imaging
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-358055DOI: 10.1021/acs.molpharmaceut.8b00204ISI: 000448490100018PubMedID: 29865791OAI: oai:DiVA.org:uu-358055DiVA, id: diva2:1241575
Funder
Swedish Cancer Society, 2015/350Swedish Cancer Society, 2017/425VINNOVASwedish Research Council, 2015-02353Swedish Research Council, 2015-02509Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2019-01-18Bibliographically approved

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Garousi, JavadMitran, BogdanVorobyeva, AnzhelikaOroujeni, MaryamOrlova, AnnaTolmachev, Vladimir

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Garousi, JavadMitran, BogdanVorobyeva, AnzhelikaOroujeni, MaryamOrlova, AnnaTolmachev, Vladimir
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Molecular Pharmaceutics
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Radiology, Nuclear Medicine and Medical Imaging

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