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

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...

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Bibliographic Details
Published in:European journal of nuclear medicine and molecular imaging 2008, Vol.35 (1), p.53-64
Main Authors: Knör, Sebastian, Sato, Sumito, Huber, Timo, Morgenstern, Alfred, Bruchertseifer, Frank, Schmitt, Manfred, Kessler, Horst, Senekowitsch-Schmidtke, Reingard, Magdolen, Viktor, Seidl, Christof
Format: Article
Language:English
Subjects:
Alpha Particles - therapeutic use
Animals
Bismuth - chemistry
Cardiology
Cell Line, Tumor
Dimerization
Drug Discovery
Enzyme Inhibitors - chemistry
Female
Gene Expression Regulation, Neoplastic
Heterocyclic Compounds, 1-Ring - chemistry
Humans
Imaging
Kidney - drug effects
Kidney - metabolism
Ligands
Medicine
Medicine & Public Health
Mice
Neoplasm Metastasis
Nuclear Medicine
Oncology
Original Article
Orthopedics
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Ovarian Neoplasms - radiotherapy
Peptides - chemical synthesis
Peptides - chemistry
Peptides - metabolism
Peptides - pharmacokinetics
Polygeline - pharmacology
Radioisotopes
Radiology
Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors
Receptors, Urokinase Plasminogen Activator - chemistry
Receptors, Urokinase Plasminogen Activator - metabolism
Solubility
Substrate Specificity
Tissue Distribution
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Summary: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 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.
ISSN:1619-7070
1619-7089
DOI:10.1007/s00259-007-0582-3