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Comparative evaluation of Affibody molecules for radionuclide imaging of in vivo expression of carbonic anhydrase IX
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. (Anna Orlova)
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2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392Article in journal (Refereed) Accepted
Abstract [en]

Overexpression of the enzyme carbonic anhydrase IX (CAIX) is documented for chronically hypoxic malignant tumors as well as for normoxic renal cell carcinoma. Radionuclide molecular imaging of CAIX would be useful for detection of hypoxic areas in malignant tumors, for patients' stratification of CAIX-targeted therapies and for discrimination of primary malignant and benign renal tumors. Earlier, we have reported feasibility of in vivo radionuclide based imaging of CAIX expressing tumors using Affibody molecules, small affinity proteins based on a non-immunoglobulin scaffold. In this study, we compared imaging properties of several anti-CAIX Affibody molecules having identical scaffold parts and competing for the same epitope on CAIX, but having different binding paratopes. Four variants were labeled using residualizing 99mTc and non-residualizing 125I labels. All radiolabeled variants demonstrated high-affinity detection of CAIX-expressing cell line SK-RC-52 in vitro and specific accumulation in SK-RC-52 xenografts in vivo. 125I-labeled conjugates demonstrated much lower radioactivity uptake in kidneys but higher radioactivity concentration in blood compared with 99mTc-labed counterparts. Although all variants cleared rapidly from blood and non-specific compartments, there was noticeably difference in their biodistribution. The best variant for imaging of expression of CAIX- in disseminated cancer was 99mTc-(HE)3-ZCAIX:2 providing tumor uptake of 16.3±0.9 %ID/g and tumor-to-blood ratio of 44±7 at 4 h after injection. For primary renal cell carcinoma, the most promising imaging candidate was 125I-ZCAIX:4 providing tumor-kidney ratio of 2.1±0.5. In conclusion, several clones of scaffold proteins should be evaluated to select the best variant for development of an imaging probe with optimal sensitivity for the intended application.

Place, publisher, year, edition, pages
2016.
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-302639DOI: 10.1021/acs.molpharmaceut.6b00502PubMedID: 27529191OAI: oai:DiVA.org:uu-302639DiVA: diva2:962982
Available from: 2016-09-07 Created: 2016-09-07 Last updated: 2016-09-09Bibliographically approved

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Garousi, JavadHonarvar, HadisMitran, BogdanOrlova, AnnaFrejd, Fredrik YTolmachev, Vladimir
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Medical Radiation ScienceDivision of Molecular ImagingDepartment of Immunology, Genetics and Pathology
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Molecular Pharmaceutics
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