2. Academic Validation
  3. Cyclic versus Noncyclic Chelating Scaffold for 89Zr-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression

Cyclic versus Noncyclic Chelating Scaffold for 89Zr-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression

  • Mol Pharm. 2018 Jan 2;15(1):175-185. doi: 10.1021/acs.molpharmaceut.7b00787.
Dominik Summer 1,  Javad Garousi 2,  Maryam Oroujeni 2,  Bogdan Mitran 3,  Ken G Andersson 4,  Anzhelika Vorobyeva 2,  John Löfblom 4,  Anna Orlova 3,  Vladimir Tolmachev 2,  Clemens Decristoforo 1
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, Medical University Innsbruck , Anichstrasse 35, A-6020 Innsbruck, Austria.
  • 2 Institute of Immunology, Genetic and Pathology, Uppsala University , SE-75185 Uppsala, Sweden.
  • 3 Division of Molecular Imaging, Department of Medicinal Chemistry, Uppsala University , SE-751 83 Uppsala, Sweden.
  • 4 Division of Protein Technology, KTH Royal Institute of Technology , SE-10691 Stockholm, Sweden.
PMID: 29160082 DOI: 10.1021/acs.molpharmaceut.7b00787
Abstract

Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow pharmacokinetics as due to its longer half-life, in comparison to fluorine-18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to-head as bifunctional Chelators for 89Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates.

Fsc-zegfr: 2377 and DFO-ZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 °C. Both 89Zr-FSC-ZEGFR:2377 and 89Zr-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 °C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89Zr-DFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of 89Zr-FSC-ZEGFR:2377 as well as 89Zr-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that 89Zr-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

Keywords

DFO; EGFR; FSC; PET; affibody; zirconium-89.

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