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Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in α-emitter therapy for disseminated ovarian cancer

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Among gynecologic malignancies, ovarian cancer has the highest mortality due to rapid peritoneal dissemination. Treatment failure particularly arises from failure to eliminate disseminated cells. Our aim was to develop peptidic radioligands targeting tumour cell-associated urokinase receptor (uPAR, CD87) for α-emitter therapy for advanced ovarian cancer.

Methods

DOTA-conjugated, uPAR-directed ligands were synthesised on solid-phase. Binding of peptides to human cells expressing uPAR was assayed by flow cytofluorometry or, in case of 213Bi-labelled peptides, by measuring cell-bound radioactivity. Bio-distribution of the 213Bi-labelled peptide P-P4D was analysed in nude mice 28 days after intraperitoneal inoculation of OV-MZ-6 ovarian cancer cells in the absence or presence of the plasma expander gelofusine.

Results

uPAR-selective ligands were developed based on published high-affinity uPAR-binding peptides. For preparation of N-terminally cross-linked divalent ligands, a novel solid-phase procedure was developed. Specific binding of 213Bi-labelled peptides to monocytoid U937 and OV-MZ-6 cells was demonstrated using the natural ligand of uPAR, pro-uPA, or a soluble form of uPAR, suPAR, as competitors. The pseudo-symmetrical covalent dimer 213Bi-P-P4D displayed superior binding to OV-MZ-6 cells in vitro. Accumulation of 213Bi-P-P4D in tumour tissue was demonstrated by bio-distribution analysis in nude mice bearing intraperitoneal OV-MZ-6-derived tumours. Gelofusine reduced kidney uptake of 213Bi-P-P4D by half.

Conclusion

Ovarian cancer cells overexpressing uPAR were specifically targeted in vitro and in vivo by 213Bi-P-P4D. Kidney uptake of 213Bi-P-P4D was distinctly reduced using gelofusine. Thus, this radiopeptide may represent a promising option for therapy for disseminated ovarian cancer.

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Acknowledgements

We thank Birgit Pfost and Christel Schnelldorfer for excellent technical assistance in conducting the animal experiments and flow cytofluorometric analyses, respectively, and Nathalie Beaufort for helpful discussions. This study was supported by Deutsche Krebshilfe e.V., Germany (grant no. 106 185, V.M.) and by Deutsche Forschungsgemeinschaft (grants SE 962/2-4, R.S.-S.). H.K. thanks the Fonds der Chemischen Industrie for financial support.

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Authors and Affiliations

  1. Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany

    Sebastian Knör, Timo Huber & Horst Kessler

  2. Klinische Forschergruppe der Frauenklinik, Klinikum rechts der Isar der TU München, Ismaninger Str. 22, 81675, Munich, Germany

    Sumito Sato, Manfred Schmitt & Viktor Magdolen

  3. European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany

    Alfred Morgenstern & Frank Bruchertseifer

  4. Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar der TU München, Ismaninger Str. 22, 81675, Munich, Germany

    Reingard Senekowitsch-Schmidtke & Christof Seidl

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  1. Sebastian Knör
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Correspondence to Viktor Magdolen or Christof Seidl.

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Sebastian Knör and Sumito Sato contributed equally to the work.

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Knör, S., Sato, S., Huber, T. et al. Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in α-emitter therapy for disseminated ovarian cancer. Eur J Nucl Med Mol Imaging 35, 53–64 (2008). https://doi.org/10.1007/s00259-007-0582-3

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