Format

Send to

Choose Destination
See comment in PubMed Commons below
Nucl Med Biol. 2012 Oct;39(7):962-9. doi: 10.1016/j.nucmedbio.2012.05.007. Epub 2012 Jun 26.

New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts.

Author information

1
The Danish-Chinese Center for Proteases and Cancer, Center for Diagnostic Investigations, Rigshospitalet, Copenhagen, Denmark.

Abstract

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 (64)Cu and (177)Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with (177)Lu-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 (177)Lu-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel (18)F-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 24h post injection of (177)Lu-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 (64)Cu-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using (177)Lu-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. (18)F-FLT PET/CT imaging study revealed a significant correlation between (18)F-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.

PMID:
22739362
DOI:
10.1016/j.nucmedbio.2012.05.007
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center