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Improved contrast of affibody-mediated imaging of HER3 expression through co-injection of affibody trimer for in vivo blocking of hepatic uptake
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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(English)Manuscript (preprint) (Other academic)
Keywords [en]
HER3, affibody molecule, molecular imaging, imaging contrast
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-360288OAI: oai:DiVA.org:uu-360288DiVA, id: diva2:1247516
Available from: 2018-09-12 Created: 2018-09-12 Last updated: 2018-09-20
In thesis
1. Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
Open this publication in new window or tab >>Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The HER3 receptor plays a strong role in disease progression and resistance to therapies in several cancer types. Due to its endogenous expression and low overexpression in malignant tumours, it is a particularly challenging target. The primary aim of this thesis project was to develop, evaluate and characterize affibody molecules for theranostic applications in HER3-expressing malignant tumours.

Paper I investigated the in vivo targeting properties and therapeutic efficacy of a bivalent affibody construct fused with an albumin binding domain, ZHER3-ABD-ZHER3. This construct could slow down the growth of HER3-expressing tumour xenografts without causing health problems or side effects in mice.

Paper II compared the in vitro and in vivo properties of two HER3-targeting affibody molecules (Z08698 and Z08699) to select an imaging probe for HER3 diagnostics. While the two constructs had similar properties, Z08698 demonstrated better blood clearance and better radioactivity retention in tumours.

Paper III and IV present the development of a HER3 imaging probe for PET using gallium and cobalt isotopes. We demonstrated that imaging of HER3 expression could be obtained as soon as 3 h pi using gallium-68. Additionally, we demonstrated that affibody molecules labelled with a neutral cobalt-NOTA complex had a lower radioactivity uptake in the liver than molecules radiolabelled with a positive gallium-NOTA complex. Imaging contrast increased over time. As the dose of the injected protein increased, the activity uptake in normal organs decreased, whereas the tumour uptake remained the same, which improved the imaging contrast and allowed discrimination between xenografts with high and low HER3 expression. This modification did not influence tumour activity uptake.

Paper V presents the HER3-targeting affibody molecule trimer as a tool to block hepatic uptake in order to increase the imaging contrast in the liver. The trimer demonstrated its ability to bind to endogenous receptors in the liver, which decreased the hepatic uptake of the radiolabelled monomer. This phenomenon enabled the monomer to pass the liver barrier, which increased tumour radioactivity uptake and improved imaging contrast.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 258
Keywords
affibody molecules, theranostics, HER3, molecular imaging
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-360973 (URN)978-91-513-0449-6 (ISBN)
Public defence
2018-11-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
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Supervisors
Available from: 2018-10-17 Created: 2018-09-20 Last updated: 2018-11-19

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