Journal
NUCLEAR MEDICINE AND BIOLOGY
Volume 39, Issue 7, Pages 962-969Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.nucmedbio.2012.05.007
Keywords
uPAR; PRRT; in vivo; Lu-177; Imaging
Funding
- Danish National Research Foundation (Centre for Proteases and Cancer)
- Danish Medical Research Council
- Danish National Advanced Technology Foundation
- Novo Nordisk Foundation
- Lundbeck Foundation
- A.P. Moeller Foundation
- Svend Andersen Foundation
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The proposition of uPAR as a potential target in cancer therapy is advanced by its predominant expression at the invasive front of colorectal cancer (CRC) and its value as prognostic biomarker for poor survival in this disease. In this study, we provide the first in vivo proof-of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model. Methods: A DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with Cu-64 and Lu-177, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with Lu-177-DOTA-AE105 once a visible tumor had formed. To evaluate the true effect of the targeted radiotherapy, two controls groups were included in this study, one receiving a Lu-177-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel F-18-FLT PET/CT study was performed on day 0, 1, 3 and 6. Dosimetry calculations were based on a biodistribution study, where organs and tissue of interest were collected 0.5, 1.0, 2.0, 4.0 and 24 h post injection of Lu-177-DOTA-AE105. Toxicity was assessed by recording mouse weight and by H&E staining of kidneys in each treatment group. Results: uPAR-positive HT-29 xenograft was clearly visualized by PET/CT imaging using Cu-64-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using Lu-177-DOTA-AE105, where a significant effect on tumor size and the number of uPAR-positive cells in the tumor was found (p<0.05). Evaluations of biodistribution and dosimetry revealed highest accumulation of radioactivity in kidneys and tumor tissue. F-18-FLT PET/CT imaging study revealed a significant correlation between F-18-FLT tumor uptake and efficacy of the radionuclide therapy. A histological examination of the kidneys from one animal in each treatment group did not reveal any gross abnormalities and the general performance of all treated animals also showed no indications of radioactivity-induced toxicity. Conclusion: These findings document for the first time the in vivo efficacy of an uPAR-targeted radionuclide therapeutic intervention on both tumor size and its content of uPAR expressing cells thus setting the stage for future translation into clinical use. (c) 2012 Elsevier Inc. All rights reserved.
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