Intravital imaging of mouse colonic adenoma using MMP-based molecular probes with multi-channel fluorescence endoscopy

Abstract

Abstract:Intravital imaging has provided molecular, cellular and anatomical insight into the study of tumor. Early detection and treatment of gastrointestinal (GI) diseases can be enhanced with specific molecular markers and endoscopic imaging modalities. We present a wide-field multichannel fluorescence endoscope to screen GI tract for colon cancer using multiple molecular probes targeting matrix metalloproteinases (MMP) conjugated with quantum dots (QD) in AOM/DSS mouse model. MMP9 and MMP14 antibody (Ab)-QD conjugates demonstrate specific binding to colonic adenoma. The average target-to-background (T/B) ratios are 2.10 ± 0.28 and 1.78 ± 0.18 for MMP14 Ab-QD and MMP9 Ab-QD, respectively. The overlap between the two molecular probes is 67.7 ± 8.4%. The presence of false negative indicates that even more number of targeting could increase the sensitivity of overall detection given heterogeneous molecular expression in tumors. Our approach indicates potential for the screening of small or flat lesions that are precancerous. References and links1. G. Oh, E. Chung, and S. H. Yun, "Optical fibers for high-resolution in vivo microendoscopic fluorescence imaging," Opt. Fiber Technol. 19(6), 760-771 (2013). 2. J. C. van Rijn, J. B. Reitsma, J. Stoker, P. M. Bossuyt, S. J. van Deventer, and E. Dekker, "Polyp miss rate determined by tandem colonoscopy: a systematic review," Am. J. Gastroenterol. 101(2), 343-350 (2006). 3. C. A. Munroe, P. Lee, A. Copland, K. K. Wu, T. Kaltenbach, R. M. Soetikno, and S. Friedland, "A tandem colonoscopy study of adenoma miss rates during endoscopic training: a venture into uncharted territory," Gastrointest. Endosc. 75(3), 561-567 (2012 Rat, P. Roignot, J. Faivre, P. Laurent-Puig, and F. Piard, "Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers," Int.

A Clinical Wide-Field Fluorescence Endoscopic Device for Molecular Imaging Demonstrating Cathepsin Protease Activity in Colon Cancer

“…The importance of functional information to guide endoscopy has been noted by other investigators, and molecularly targeted fluorescent probes have been tested in both mouse models and humans [6, 9, 15, 41, 42, 45–47]. Fluorescence endoscopy can play an important role, because several tumor-targeting molecular probes like peptides, antibodies, activated probes, and nanoparticles can be conjugated with fluorescent dyes and localized using a fluorescence endoscope.…”

“…Bioconjugation of such probes with fluorescent dyes or nanoparticles has been used to target biomarkers that are overexpressed in colon cancers such as c-Met, VEGF, EGFR, or metalloproteinases [6, 9, 48–51]. The highly specific binding affinity provides an increased signal-to-noise ratio resulting in a visual contrast of the neoplastic lesion against the normal mucosal background.…”

Development and application of the near-infrared and white-light thoracoscope system for minimally invasive lung cancer surgery

“…[10][11][12] Different from the color imaging, NIR fluorescence imaging only illuminates certain regions inside the field-of-view (FoV) and provides pathological information several millimeters beneath the tissue surface, which results in many advantages in the intraoperative usage. 13 Some recent preclinical and clinical applications already proved the feasibility and benefits of NIR image-guided MIS, such as its application in colorectal surgery, [14][15][16][17] bladder cancer, 18,19 cholecystectomy, 20 liver cancer, 21 and gastric cancer. 22 Furthermore, NIR fluorescence imaging also showed its potential in minimally invasive lung cancer surgery (MILCS).…”

In vivo longitudinal cellular imaging of small intestine by side-view endomicroscopy

“…Endomicroscopy have been actively developed for minimally invasive visualization of internal organs of small animal models [10][11][12][13][14][15][16][17]. High-resolution confocal endomicroscopy relying on resonant single-mode fiber scanning has successfully visualized brain tumor in rat model [10], surgically exposed colorectal cancer [11] and infected small intestine [12] in mouse model, demonstrating its potential for a cellular-level diagnostic tool.…”

“…Although it is only demonstrated by using ex vivo tissue, spectrally encoded confocal microscopy [13] and three-photon microscopy [14] equipped with custom designed endoscopic probes have successfully obtained cellular-level images from swine esophagus and mouse lung respectively without any exogenous labeling, validating their clinical applicability. A commercial rigid endoscope modified for fluorescence imaging has applied to obtain a fisheye view image of colorectal cancer in mouse model in vivo [15]. Side-view confocal endomicroscopy [16,17] based on miniature GRIN lens and micro-prism has successfully demonstrated a repetitive cellular-level imaging of colorectal cancer development in mouse model.…”