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Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging 6/2020

26.11.2019 | Original Article

Targeting MMP-14 for dual PET and fluorescence imaging of glioma in preclinical models

verfasst von: Benjamin B. Kasten, Ke Jiang, Denzel Cole, Aditi Jani, Neha Udayakumar, G. Yancey Gillespie, Guolan Lu, Tingting Dai, Eben L. Rosenthal, James M. Markert, Jianghong Rao, Jason M. Warram

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 6/2020

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Abstract

Purpose

There is a clinical need for agents that target glioma cells for non-invasive and intraoperative imaging to guide therapeutic intervention and improve the prognosis of glioma. Matrix metalloproteinase (MMP)-14 is overexpressed in glioma with negligible expression in normal brain, presenting MMP-14 as an attractive biomarker for imaging glioma. In this study, we designed a peptide probe containing a near-infrared fluorescence (NIRF) dye/quencher pair, a positron emission tomography (PET) radionuclide, and a moiety with high affinity to MMP-14. This novel substrate-binding peptide allows dual modality imaging of glioma only after cleavage by MMP-14 to activate the quenched NIRF signal, enhancing probe specificity and imaging contrast.

Methods

MMP-14 expression and activity in human glioma tissues and cells were measured in vitro by immunofluorescence and gel zymography. Cleavage of the novel substrate and substrate-binding peptides by glioma cells in vitro and glioma xenograft tumors in vivo was determined by NIRF imaging. Biodistribution of the radiolabeled MMP-14-binding peptide or substrate-binding peptide was determined in mice bearing orthotopic patient-derived xenograft (PDX) glioma tumors by PET imaging.

Results

Glioma cells with MMP-14 activity showed activation and retention of NIRF signal from the cleaved peptides. Resected mouse brains with PDX glioma tumors showed tumor-to-background NIRF ratios of 7.6–11.1 at 4 h after i.v. injection of the peptides. PET/CT images showed localization of activity in orthotopic PDX tumors after i.v. injection of 68Ga-binding peptide or 64Cu-substrate-binding peptide; uptake of the radiolabeled peptides in tumors was significantly reduced (p < 0.05) by blocking with the non-labeled-binding peptide. PET and NIRF signals correlated linearly in the orthotopic PDX tumors. Immunohistochemistry showed co-localization of MMP-14 expression and NIRF signal in the resected tumors.

Conclusions

The novel MMP-14 substrate-binding peptide enabled PET/NIRF imaging of glioma models in mice, warranting future image-guided resection studies with the probe in preclinical glioma models.
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Metadaten
Titel
Targeting MMP-14 for dual PET and fluorescence imaging of glioma in preclinical models
verfasst von
Benjamin B. Kasten
Ke Jiang
Denzel Cole
Aditi Jani
Neha Udayakumar
G. Yancey Gillespie
Guolan Lu
Tingting Dai
Eben L. Rosenthal
James M. Markert
Jianghong Rao
Jason M. Warram
Publikationsdatum
26.11.2019
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 6/2020
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-019-04607-x

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