Abstract
Metabolic imaging of oral cavity mucosal surfaces could benefit early detection of oral squamous cell carcinoma (OSCC) and oral epithelial dysplasia (OED). Fluorescent deoxy-glucose agents provide contrast for glucose metabolism similar to 18FDG-PET imaging and allow use of optical imaging, which provides high resolution and lower potential cost. However, in-vivo topical mucosal delivery of fluorescent deoxy-glucose agents without injection or tissue resection has not been shown. We introduce in-vivo optical imaging of neoplasia following mucosal delivery of 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG) in an OSCC/OED hamster model and demonstrate uptake into epithelium across the mucosal surface without injection or disrupting the epithelium. 2-NBDG fluorescence intensity following 30-minutes topical application was 6-fold and 4-fold higher in OSCC and OED, respectively, compared to normal mucosa. Receiver operator characteristic analysis show 83% sensitivity and 73% specificity for detection of neoplasia vs benign (normal and inflammation). Faster 2-NBDG fluorescence temporal decay in neoplasia indicated higher uptake and glucose metabolic rate than normal mucosa. Mucosal delivery of 2-NBDG by topical application to the in-vivo oral surface is feasible and delineates neoplasia from normal mucosa, providing in-vivo noninvasive molecular imaging of dysregulated glucose metabolism, which could benefit preclinical studies of carcinogenesis or be developed for use in early detection.
Highlights
Incidence of Oral Squamous Cell Carcinoma (OSCC) (~90% of oral cancers), has increased over the past two decades with 640,000 new cases per year worldwide[1]
oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) show a broader distribution than normal. (c) Receiver operator characteristic (ROC) curves using ΔF2-NBDG with or without inflammation in the normal group; green: inflammation grouped with normal (Sensitivity: 83%, Specificity: 73%, area under the curve (AUC): 0.86); red: normal alone compared with OED and OSCC (Sensitivity: 90%, Specificity: 85%, AUC: 0.97). *p < 0.05, **p < 0.01
We investigated the potential of 2-NBDG in highlighting neoplastic regions in oral mucosa in a new in-vivo topical mucosal delivery approach. 2-NBDG applied directly to the fully intact mucosal surface in a living animal
Summary
2-NBDG topical application significantly increased fluorescence intensity in both normal (Fig. 2e) and DMBA (Fig. 2f) groups, implying buccal mucosal uptake of 2-NBDG. To spectrally characterize this signal as final validation of epithelial 2-NBDG uptake, biopsies from tissues with and without topical 2-NBDG were imaged using confocal microscopy with spectral capabilities. Normal and neoplastic tissue show a significant increase in 2-NBDG fluorescence after topical application compared to baseline autofluorescence, though this increase was significantly higher in neoplastic epithelium (Fig. 2). A high magnification white light image of a non-necrotic tumor (Fig. 7b), with 10, 90, and 120 minutes post 2-NBDG time-points shows temporal reduction of 2-NBDG fluorescence. Values of the slope in normal, OED, and OSCC areas in Fig. 7c are 0.39, 0.57, and 0.63, respectively, indicating faster 2-NBDG utilization of 2-NBDG by neoplastic epithelium.
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