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

Knör, Sebastian; Sato, Sumito; Huber, Timo; Morgenstern, Alfred; Bruchertseifer, Frank; Kessler, Horst; Senekowitsch–Schmidtke, Reingard; Magdolen, Viktor; Seidl, Christof

doi:10.1007/s00259-007-0582-3

Cited by 46 publications

(47 citation statements)

References 53 publications

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“…In addition, if a future uPAR-targeted therapy should be introduced into the clinic, identification of patients with local high uPAR expression levels in the tumor microenvironment could increase the chances for successful intervention. Such uPARtargeted therapies based on monoclonal antibodies, peptide antagonists, or protease-activated prodrugs are currently being investigated in several preclinical cancer models (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Persson¹,

Madsen²,

Østergaard³

et al. 2012

J Nucl Med

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Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expression levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy. Methods: To accomplish our objective, a linear, high-affinity uPAR peptide antagonist, AE105, was conjugated with DOTA and labeled with 64 Cu ( 64 Cu-DOTA-AE105). Small-animal PET was performed in 3 human cancer xenograft mice models, expressing different levels of human uPAR, and the tumor uptake was correlated with the uPAR expression level determined by uPAR enzyme-linked immunosorbent assay. The tumor uptake pattern of this tracer was furthermore compared with 18 F-FDG uptake, and finally the correlation between sensitivity toward 5-fluorouracil therapy and uPAR expression level was investigated. Results: The uPARtargeting PET tracer was produced in high purity and with high specific radioactivity. A significant correlation between tumor uptake of 64 Cu-DOTA-AE105 and uPAR expression was found (R 2 5 0.73; P , 0.0001) across 3 cancer xenografts, thus providing a strong argument for specificity. A significantly different uptake pattern of 64 Cu-DOTA-AE105, compared with that of 18 F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using 64 Cu-DOTA-AE105 PET. Furthermore, a significant correlation between baseline uPAR expression and sensitivity toward 5-fluorouracil was revealed, thus illustrating the possible potentials of uPAR PET in a clinical setting. Conclusion: Our results clearly demonstrate that the peptide-based PET tracer 64 Cu-DOTA-AE105 enables the noninvasive quantification of uPAR expression in tumors in vivo, thus emphasizing its potential use in a clinical setting to detect invasive cancer foci and for individualized cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Persson¹,

Madsen²,

Østergaard³

et al. 2012

J Nucl Med

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“…91 Disulfide cyclized GFD-derived peptide (amino acids 19-31)-DOTA conjugates bound to 213 Bi were cytotoxic to OV-MZ-6 ovarian cancer cells in vitro. 92 …”

Section: Peptidesmentioning

confidence: 99%

Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges

Toporkiewicz¹,

Meissner²,

Matusewicz³

et al. 2015

IJN

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There are many problems directly correlated with the systemic administration of drugs and how they reach their target site. Targeting promises to be a hopeful strategy as an improved means of drug delivery, with reduced toxicity and minimal adverse side effects. Targeting exploits the high affinity of cell-surface-targeted ligands, either directly or as carriers for a drug, for specific retention and uptake by the targeted diseased cells. One of the most important parameters which should be taken into consideration in the selection of an appropriate ligand for targeting is the binding affinity ( K D ). In this review we focus on the importance of binding affinities of monoclonal antibodies, antibody derivatives, peptides, aptamers, DARPins, and small targeting molecules in the process of selection of the most suitable ligand for targeting of nanoparticles. In order to provide a critical comparison between these various options, we have also assessed each technology format across a range of parameters such as molecular size, immunogenicity, costs of production, clinical profiles, and examples of the level of selectivity and toxicity of each. Wherever possible, we have also assessed how incorporating such a targeted approach compares with, or is superior to, original treatments.

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“…applications, or using pretargeting techniques, could however overcome this potential problem. A study using 213 Bi has been performed by Knör et al developing peptidic radioligands, which targets cancer cell urokinase receptors (uPAR, CD87) (Knör et al, 2008). DOTA-conjugated, uPAR-directed ligands were synthesised.…”

Section: 3mentioning

confidence: 99%

“…P-P4D is a targeting construct which is a pseudo-symmetrical covalent dimer of the monomeric peptide P-P4. It has been used in one animal study (Knör et al, 2008). PAI2 is a targeting construct that is a plasminogen activator inhibitor type 2 and which is a member of the serine protease inhibitor (Serpin) superfamily and forms SDS-stable 1:1 complexes with urokinase plasminogen activator (uPA) (Song et al, 2007).…”

Section: Targeting Constructsmentioning

confidence: 99%

Intraperitoneal Radionuclide Therapy – Clinical and Pre-Clinical Considerations

Elgqvist¹,

Lindegren²,

Albertsson³

2012

Ovarian Cancer - Clinical and Therapeutic Perspectives

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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

Abstract: 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.

Cited by 46 publications

References 53 publications

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges

Intraperitoneal Radionuclide Therapy – Clinical and Pre-Clinical Considerations

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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

Abstract: 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.

Cited by 46 publications

References 53 publications

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with 64Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with 64Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges

Intraperitoneal Radionuclide Therapy – Clinical and Pre-Clinical Considerations

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Product

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Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with ⁶⁴Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion