1. Targeting MMP-14 for dual PET and fluorescence imaging of glioma in preclinical models
- Author
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G. Yancey Gillespie, Tingting Dai, Guolan Lu, James M. Markert, Jason M. Warram, Jianghong Rao, Ke Jiang, Benjamin B. Kasten, Eben L. Rosenthal, Aditi Jani, Neha Udayakumar, and Denzel Cole
- Subjects
Fluorescence-lifetime imaging microscopy ,Biodistribution ,Peptide ,Article ,030218 nuclear medicine & medical imaging ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Positron Emission Tomography Computed Tomography ,Glioma ,Matrix Metalloproteinase 14 ,medicine ,Animals ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,chemistry.chemical_classification ,medicine.diagnostic_test ,Chemistry ,Optical Imaging ,General Medicine ,medicine.disease ,Positron emission tomography ,Positron-Emission Tomography ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Molecular imaging - 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 (68)Ga-binding peptide or (64)Cu-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.
- Published
- 2019