uPAR targeted radionuclide therapy with (177)Lu-DOTA-AE105 inhibits dissemination of metastatic prostate cancer.

Abstract

The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe ((177)Lu-DOTA-AE105) and a nonbinding control ((177)Lu-DOTA-AE105mut). Both uPAR flow cytometry and ELISA confirmed high expression levels of the target uPAR in PC-3M-LUC2.luc cells, and cell binding studies using (177)Lu-DOTA-AE105 resulted in a specific binding with an IC50 value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted (177)Lu groups (p < 0.05) using bioluminescence imaging. Moreover, we found a significantly longer metastatic-free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p = 0.047). In contrast, only 30% of all mice in the combined control groups treated with (177)Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induced toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using (64)Cu-DOTA-AE105 detected all small, disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of metastatic lesions in a human metastatic prostate cancer model. Furthermore, we have provided the first evidence of the potential for identification of small metastatic lesions using uPAR PET imaging in disseminated prostate cancer, illustrating the promising strategy of uPAR theranostics in prostate cancer.

• Authors: Morten Persson, Karina Juhl, Palle Rasmussen, Malene Brandt-Larsen, Jacob Madsen, Michael Ploug, Andreas Kjaer
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 11 Issue 8 Pg. 2796-806 (Aug 04 2014) ISSN: 1543-8392 [Electronic] United States
• PMID: 24955765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 177Lu-DOTA-AE105
• Coordination Complexes
• Ligands
• Oligopeptides
• Radioisotopes
• Receptors, Urokinase Plasminogen Activator
• Recombinant Proteins
• Lutetium

Topics

• Animals
• Cell Line, Tumor
• Coordination Complexes (chemistry)
• Disease-Free Survival
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Humans
• Inhibitory Concentration 50
• Ligands
• Lutetium (chemistry)
• Male
• Mice
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Oligopeptides (chemistry)
• Positron-Emission Tomography
• Prostatic Neoplasms (diagnostic imaging, radiotherapy)
• Protein Binding
• Radioisotopes (therapeutic use)
• Receptors, Urokinase Plasminogen Activator (chemistry)
• Recombinant Proteins (chemistry)
• Treatment Outcome
• X-Ray Microtomography