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

Abstract

Purpose Early and effective detection of cancers of the gastrointestinal tract will require novel molecular probes and advances in instrumentation that can reveal functional changes in dysplastic and malignant tissues. Here, we describe adaptation of a wide-field clinical fiberscope to perform wide-field fluorescence imaging while preserving its white-light capability for the purpose of providing wide-field fluorescence imaging capability to point-of-care microscopes. Procedures We developed and used a fluorescent fiberscope to detect signals from a quenched probe, BMV109, that becomes fluorescent when cleaved by, and covalently bound to, active cathepsin proteases. Cathepsins are expressed in inflammation- and tumor-associated macrophages as well as directly from tumor cells and are a promising target for cancer imaging. The fiberscope has a 1-mm outer diameter enabling validation via endoscopic exams in mice, and therefore we evaluated topically applied BMV109 for the ability to detect colon polyps in an azoxymethane-induced colon tumor model in mice. Results This wide-field endoscopic imaging device revealed consistent and clear fluorescence signals from BMV109 that specifically localized to the polypoid regions as opposed to the normal adjacent colon tissue (p < 0.004) in the murine colon carcinoma model. Conclusions The sensitivity of detection of BMV109 with the fluorescence fiberscope suggested utility of these tools for early detection at hard-to-reach sites. The fiberscope was designed to be used in conjunction with miniature, endoscope-compatible fluorescence microscopes for dual wide-field and microscopic cancer detection.

Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment

“…Cuneo et al found that the same probe could differentiate normal and tumor tissues following radiation therapy in mice and canines [ 148 ]. Further similar clinical applied probes include cathepsin/MMP-sensitive poly-lysine-based near-infrared fluorescence (NIRF) probes [ 149 , 150 ] for the early and effective detection of cancers of the gastrointestinal tract [ 151 ] and pan-cathepsin-sensitive PEG-based probe for the detection of STS and breast cancer [ 129 , 152 ].…”

Design and Synthesis of Luminescent Lanthanide-Based Bimodal Nanoprobes for Dual Magnetic Resonance (MR) and Optical Imaging

“…The emitted light has been collected by means of an intensified CCD camera, connected to the image beam of an endoscope. Optical imaging devices using endoscopic pathways and allowing the measurement of the autofluorescence of some endogenous porphyrins have been also proposed for urology, gynecology, and otorhinolaryngology [ 98 , 99 , 100 ]. More recently, two low energy photon excitation technology has been developed, in replacement of the conventional single high energy photon excitation one, making the dye photoexcitation less-harmful and deep-penetrating, even carried out outside the body [ 101 ].…”

A protease-activated, near-infrared fluorescent probe for early endoscopic detection of premalignant gastrointestinal lesions

“…1). Because these proteases are overexpressed by tumor-associated macrophages (TAM) that infiltrate the colorectal tumor microenvironment, their activity is an ideal biomarker for cancer as well as various types of pathogenic inflammation (14,15). Here we demonstrate that 6QC-ICG is an effective contrast agent that enables endoscopic detection of adenomas with high signal-to-background ratios in small animal models, a human-scale spontaneous large animal model, and in a mouse model of inflammation-induced colorectal carcinogenesis.…”