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Optimal composition and position of histidine-containing tags improves biodistribution of Tc-99m-labeled DARP in G3
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.ORCID iD: 0000-0002-4778-3909
Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.ORCID iD: 0000-0003-3425-0828
Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9405Article in journal (Refereed) Published
Abstract [en]

Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARP in G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)(3)) of histidine-containing tags would influence the biodistribution of [Tc-99m]Tc(CO)(3)-labeled DARP in G3. To test the hypothesis, G3 variants containing tags at N-terminus (H-6-G3 and (HE)(3)-G3) or at C-terminus (G3-H-6 and G3-(HE)(3)) were labeled with [Tc-99m]Tc(CO)(3). Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [Tc-99m]Tc(CO)(3)-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 9405
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Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
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URN: urn:nbn:se:uu:diva-390813DOI: 10.1038/s41598-019-45795-8ISI: 000473130000026PubMedID: 31253840OAI: oai:DiVA.org:uu-390813DiVA, id: diva2:1343505
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-08-16Bibliographically approved

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