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

Eur J Nucl Med Mol Imaging. 2008 Jan;35(1):53-64. doi: 10.1007/s00259-007-0582-3. Epub 2007 Sep 22.


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 alpha-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 (213)Bi-labelled peptides, by measuring cell-bound radioactivity. Bio-distribution of the (213)Bi-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 (213)Bi-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 (213)Bi-P-P4D displayed superior binding to OV-MZ-6 cells in vitro. Accumulation of (213)Bi-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 (213)Bi-P-P4D by half.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha Particles / therapeutic use*
  • Animals
  • Bismuth / chemistry
  • Cell Line, Tumor
  • Dimerization
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Female
  • Gene Expression Regulation, Neoplastic
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Ligands
  • Mice
  • Neoplasm Metastasis
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / radiotherapy*
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / metabolism*
  • Peptides / pharmacokinetics
  • Polygeline / pharmacology
  • Radioisotopes
  • Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors
  • Receptors, Urokinase Plasminogen Activator / chemistry
  • Receptors, Urokinase Plasminogen Activator / metabolism*
  • Solubility
  • Substrate Specificity
  • Tissue Distribution


  • Enzyme Inhibitors
  • Heterocyclic Compounds, 1-Ring
  • Ligands
  • Peptides
  • Radioisotopes
  • Receptors, Urokinase Plasminogen Activator
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Polygeline
  • Bismuth