Abstract
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Objectives Despite aggressive treatment, the median survival of patients with glioblastoma multiforme (GBM) remains poor. Optimization of the initial cytoreductive surgery, using fluorescence imaging to highlight tumors has shown particular promise. We evaluated the applicability of utilizing a molecularly targeted optical imaging probe (GE-137) specific for c-Met to accurately delineate tumor in a murine model of GBM.
Methods Epifluorescence imaging was performed on mice (n=10) with subcutaneously implanted U87 xenografts injected with GE-137 to quantify target-to-background ratios (TBR). Binding specificity was evaluated by imaging GE-137 uptake in c-Met negative tumors and by blocking uptake with unlabeled peptide. Green fluorescent protein (GFP)-expressing U87 cells were implanted in cranial window chambers (n=5), and two-photon microscopy was performed to visualize the co-localization of GE-137 with tumor. Immunohistochemistry for c-Met was performed on a tissue array of astrocytic gliomas to assess the level of overexpression for various tumor grades.
Results We found GE-137 to bind avidly to U87 xenografts, with a TBR of 2.5 (SD ± 0.15). The optimal time for imaging was 45 minutes post-injection, with a washout over 3 hr. Uptake of GE-137 was decreased by >50% in animals pre-treated with 5 fold excess of unlabeled peptide, indicating specificity for receptor binding. No uptake above background was noted in c-Met negative tumors. Two photon imaging of intracranial GFP+ U87 tumors revealed a strong correlation between probe uptake and tumor tissue boundary. C-Met overexpression was present in the majority of high and medium grade gliomas, highlighting the broad applicability of the approach.
Conclusions Optical imaging of c-Met using GE-137 allows for specific delineation of GBM in brain tissue with a high TBR. This approach provides a clinically translatable molecular imaging approach with the potential to improve intraoperative glioblastoma identification and thereby maximize the extent of tumor resection.