Molecular Design of HER3-Targeting Affibody Molecules: Influence of Chelator and Presence of HEHEHE-Tag on Biodistribution of Ga-Labeled Tracers

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2019 Mar 6

PMID 30832342

Citations 14

Authors

Charles Dahlsson Leitao

Sara S Rinne

Bogdan Mitran

Anzhelika Vorobyeva

Ken G Andersson

Vladimir Tolmachev

Stefan Stahl

John Lofblom

Anna Orlova

Affiliations

Soon will be listed here.

Abstract

Affibody-based imaging of HER3 is a promising approach for patient stratification. We investigated the influence of a hydrophilic HEHEHE-tag ((HE)₃-tag) and two different gallium-68/chelator-complexes on the biodistribution of Z with the aim to improve the tracer for PET imaging. Affibody molecules (HE)₃-Z-X and Z-X (X = NOTA, NODAGA) were produced and labeled with gallium-68. Binding specificity and cellular processing were studied in HER3-expressing human cancer cell lines BxPC-3 and DU145. Biodistribution was studied 3 h p.i. in Balb/c nu/nu mice bearing BxPC-3 xenografts. Mice were imaged 3 h p.i. using microPET/CT. Conjugates were stably labeled with gallium-68 and bound specifically to HER3 in vitro and in vivo. Association to cells was rapid but internalization was slow. Uptake in tissues, including tumors, was lower for (HE)₃-Z-X than for non-tagged variants. The neutral [Ga]Ga-NODAGA complex reduced the hepatic uptake of Z compared to positively charged [Ga]Ga-NOTA-conjugated variants. The influence of the chelator was more pronounced in variants without (HE)tag. In conclusion, hydrophilic (HE)₃-tag and neutral charge of the [Ga]Ga-NODAGA complex promoted blood clearance and lowered hepatic uptake of Z. [Ga]Ga-(HE)₃-Z-NODAGA was considered most promising, providing the lowest blood and hepatic uptake and the best imaging contrast among the tested variants.

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