European Journal of Nuclear Medicine and Molecular Imaging

, Volume 35, Issue 1, pp 53–64

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

Authors

  • Sebastian Knör
    • Department Chemie, Lehrstuhl II für Organische ChemieTechnische Universität München
  • Sumito Sato
    • Klinische Forschergruppe der FrauenklinikKlinikum rechts der Isar der TU München
  • Timo Huber
    • Department Chemie, Lehrstuhl II für Organische ChemieTechnische Universität München
  • Alfred Morgenstern
    • European Commission, Joint Research CentreInstitute for Transuranium Elements
  • Frank Bruchertseifer
    • European Commission, Joint Research CentreInstitute for Transuranium Elements
  • Manfred Schmitt
    • Klinische Forschergruppe der FrauenklinikKlinikum rechts der Isar der TU München
  • Horst Kessler
    • Department Chemie, Lehrstuhl II für Organische ChemieTechnische Universität München
  • Reingard Senekowitsch-Schmidtke
    • Nuklearmedizinische Klinik und PoliklinikKlinikum rechts der Isar der TU München
    • Klinische Forschergruppe der FrauenklinikKlinikum rechts der Isar der TU München
    • Nuklearmedizinische Klinik und PoliklinikKlinikum rechts der Isar der TU München
Original article

DOI: 10.1007/s00259-007-0582-3

Cite this article as:
Knör, S., Sato, S., Huber, T. et al. Eur J Nucl Med Mol Imaging (2008) 35: 53. doi:10.1007/s00259-007-0582-3

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.

Keywords

N-terminally cross-linked peptide dimerN-terminal dimerization on solid-phaseOV-MZ-6 ovarian cancer cellsPeritoneal carcinomatosis modelα-emitter 213Bi

Copyright information

© Springer-Verlag 2007