Targeted endoscopic imaging

Abstract

Endoscopy has undergone explosive technological growth in recent years, and with the emergence of targeted imaging, its truly transformative power and impact on medicine lies just over the horizon. Today, our ability to see inside the digestive tract with medical endoscopy is headed toward exciting crossroads. The existing paradigm of making diagnostic decisions based on observing structural changes and identifying anatomic landmarks may soon be replaced by visualizing functional properties and imaging molecular expression. In this novel approach, the presence of intracellular and cell surface targets unique to disease are identified and used to predict the likelihood of mucosal transformation and response to therapy. This strategy could result in the development of new methods for early cancer detection, personalized therapy, and chemoprevention. This targeted approach will require further development of molecular probes and endoscopic instruments, and will need support from the US Food and Drug Administration for streamlined regulatory oversight. Overall, this molecular imaging modality promises to significantly broaden the capabilities of the gastroenterologist by providing a new approach to visualize the mucosa of the digestive tract in a manner that has never been seen before.

Fig 1. Cancer transformation in the digestive tract

Progression from normal to malignant mucosa in the esophagus passes through histological stages of squamous, metaplasia, dysplasia, and carcinoma. Molecular variations occur well in advance of morphogical changes, providing a window of opportunity to perform earlier detection and therapy.

Fig 2. Near-infrared endoscopic imaging of protease activity in small animal model

Increase in near-infrared fluorescence intensity reveals protease activity from a colonic adenocarcinoma (bottom row) in comparison to normal colonic mucosa (top row) in an orthotopically implanted mouse model. (A,D) In vivo white light endoscopic images of normal and cancerous murine colonic mucosa, respectively. (B,E) Near-infrared fluorescence images following intravenous injection of Prosense 680, a protease activated probe sensitive to cathepsin B shows increased intensity at the site of the tumor but not in normal mucosa. (C,F) False color overlay of white light with fluorescence images show integration of structural and functional data. Used with permission [30].

Fig 3. In vivo localization of anti-CEA antibody binding to colonic adenoma on fluorescence endoscopy

(A) A conventional white light endoscopic image of a colonic adenoma reveals the presence of a mass lesion. (B) The corresponding fluorescence image collected in vivo after topical administration and incubation with the labeled anti-CEA antibody shows increased intensity at the site of the lesion. Used with permission [45].

Fig 4. In vivo localization of peptide binding to high grade dysplasia in Barrett’s esophagus on wide area endoscopy

(A) A conventional white light endoscopic image of Barrett’s esophagus shows no evidence of pre-malignant lesions. (B) Narrow band image (NBI) of same region shows improved contrast highlighting intestinal metaplasia but not dysplasia. (C) In vivo fluorescence image following topical administration and incubation with affinity peptide having sequence “ASYNYDA” reveals foci of high grade dysplasia.

Fig 5. In vivo validation of peptide binding to colonic adenoma on confocal microscopy

(A) Conventional white light endoscopic image of colonic adenoma. (B) In vivo confocal image following topical application and incubation of fluorescence-labeled affinity peptide with sequence “VRPMPLQ” shows binding to dysplastic (left half) and no binding to normal (right half) crypts. (C) Confocal image with control peptide (scrambled) with sequence “QLMRPPV” shows no binding to adenoma, scale bar 20 μm. Used with permission [44].