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Increase in negative charge of Ga-68/chelator complex reduces unspecific hepatic uptake but does not improve imaging properties of HER3-targeting affibody molecules
Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.ORCID iD: 0000-0002-9952-9814
Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 17710Article in journal (Refereed) Published
Abstract [en]

Upregulation of the human epidermal growth factor receptor type 3 (HER3) is a common mechanism to bypass HER-targeted cancer therapy. Affibody-based molecular imaging has the potential for detecting and monitoring HER3 expression during treatment. In this study, we compared the imaging properties of newly generated Ga-68-labeled anti-HER3 affibody molecules (HE)(3)-Z(HER3)-DOTA and (HE)(3)-Z(HER3)-DOTAGA with previously reported [Ga-68]Ga-(HE)(3)-Z(HER3)-NODAGA. We hypothesized that increasing the negative charge of the gallium-68/chelator complex would reduce hepatic uptake, which could lead to improved contrast of anti-HER3 affibody-based PET-imaging of HER3 expression. (HE)(3)-Z(HER3)-X (X = DOTA, DOTAGA) were produced and labeled with gallium-68. Binding of the new conjugates was specific in HER3 expressing BxPC-3 and DU145 human cancer cells. Biodistribution and in vivo specificity was studied in BxPC-3 xenograft bearing Balb/c nu/nu mice 3 h pi. DOTA- and DOTAGA-containing conjugates had significantly higher concentration in blood than [Ga-68]Ga-(HE)(3)-Z(HER3)-NODAGA. Presence of the negatively charged Ga-68-DOTAGA complex reduced the unspecific hepatic uptake, but did not improve overall biodistribution of the conjugate. [Ga-68]Ga-(HE)(3)-Z(HER3)-DOTAGA and [Ga-68]Ga-(HE)(3)-Z(HER3)-NODAGA had similar tumor-to-liver ratios, but [Ga-68]Ga-(HE)(3)-Z(HER3)-NODAGA had the highest tumor uptake and tumor-to-blood ratio among the tested conjugates. In conclusion, [Ga-68] Ga-(HE)(3)-Z(HER3)-NODAGA remains the favorable variant for PET imaging of HER3 expression.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 9, article id 17710
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Chemical Sciences
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URN: urn:nbn:se:kth:diva-265481DOI: 10.1038/s41598-019-54149-3ISI: 000499205900001PubMedID: 31776413Scopus ID: 2-s2.0-85075755842OAI: oai:DiVA.org:kth-265481DiVA, id: diva2:1378662
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QC 20191213

Available from: 2019-12-13 Created: 2019-12-13 Last updated: 2020-01-09Bibliographically approved

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Leitao, Charles DahlssonStåhl, StefanLöfblom, John

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