Optical Imaging with a Cathepsin B Activated Probe for the Enhanced Detection of Esophageal Adenocarcinoma by Dual Channel Fluorescent Upper GI Endoscopy

1. Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital.
Theranostics (Impact Factor: 8.02). 02/2012; 2(2):227-34. DOI: 10.7150/thno.4088
Source: PubMed


Despite significant advances in diagnosis and treatment, the prognosis of esophageal adenocarcinoma remains poor highlighting the importance of early detection. Although white light (WL) upper endoscopy can be used for screening of the esophagus, it has limited sensitivity for early stage disease. Thus, development of new imaging technology to improve the diagnostic capabilities of upper GI endoscopy for early detection of esophageal adenocarcinoma is an important unmet need. The goal of this study was to develop a method for the detection of malignant lesions in the esophagus using WL upper endoscopy combined with near infrared (NIR) imaging with a protease activatable probe (Prosense750) selective for cathepsin B (CTSB). An orthotopic murine model for distal esophageal adenocarcinoma was generated through the implantation of OE-33 and OE-19 human esophageal adenocarcinoma lines in immunocompromised mice. The mice were imaged simultaneously for WL and NIR signal using a custom-built dual channel upper GI endoscope. The presence of tumor was confirmed by histology and target to background ratios (TBR) were compared for both WL and NIR imaging. NIR imaging with ProSense750 significantly improved upon the TBRs of esophageal tumor foci, with a TBR of 3.64±0.14 and 4.50±0.11 for the OE-33 and OE-19 tumors respectively, compared to 0.88±0.04 and 0.81±0.02 TBR for WL imaging. The combination of protease probes with novel imaging devices has the potential to improve esophageal tumor detection by fluorescently highlighting neoplastic regions.

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    • "This is the first demonstration of a novel NIRF imaging agent specific for CB that can localize and detect ESCC xenografts. Similarly, fluorescent imaging probes in combination with near-infrared optical imaging has been applied to more sensitive detection of a series of cancers including pancreas, hypopharynx, ovary, and lung cancers [24]–[29]. Proteases activatable NIRF probes enabled detection of molecules or biologic activities of tumors in real time [30], [31]. "
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    ABSTRACT: Despite great progress in treatment, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) remains poor, highlighting the importance of early detection. Although upper endoscopy can be used for the screening of esophagus, it has limited sensitivity for early stage disease. Thus, development of new diagnosis approach to improve diagnostic capabilities for early detection of ESCC is an important need. The aim of this study was to assess the feasibility of using cathepsin B (CB) as a novel imaging target for the detection of human ESCC by near-infrared optical imaging in nude mice. Initially, we examined specimens from normal human esophageal tissue, intraepithelial neoplasia lesions, tumor in situ, ESCC and two cell lines including one human ESCC cell line (Eca-109) and one normal human esophageal epithelial cell line (HET-1A) for CB expression by immunohistochemistry and western blot, respectively. Next, the ability of a novel CB activatable near-infrared fluorescence (NIRF) probe detecting CB activity presented in Eca-109 cells was confirmed by immunocytochemistry. We also performed in vivo imaging of tumor bearing mice injected with the CB probe and ex vivo imaging of resected tumor xenografts and visceral organs using a living imaging system. Finally, the sources of fluorescence signals in tumor tissue and CB expression in visceral organs were identified by histology. CB was absent in normal human esophageal mucosa, but it was overexpressed in ESCC and its precursor lesions. The novel probe for CB activity specifically detected ESCC xenografts in vivo and in vitro. CB was highly upregulated in human ESCC and its precursor lesions. The elevated CB expression in ESCC allowed in vivo and in vitro detection of ESCC xenografts in nude mice. Our results support the usefulness of CB activity as a potential imaging target for the detection of human ESCC.
    PLoS ONE 03/2014; 9(3):e92351. DOI:10.1371/journal.pone.0092351 · 3.23 Impact Factor
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    • "The probe is also designed for prolonged circulation by attaching several polyethylene-glycol side chains to the polymer. A commercially available probe, ProSense, is preferentially hydrolyzed by cathepsin B but can also be activated through proteolysis by other cathepsins, such as cathepsin L and cathepsin S. ProSense has been shown to detect a variety of experimentally induced tumors of the colon, ovary, mammary gland, pancreas, and esophagus [12] [13] [14] [15] [16]. However, the mechanisms underlying the tumor specificity of ProSense signals are still unclear because this probe is exposed to numerous complex in vivo processes. "
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    ABSTRACT: This study evaluated the detection of tumors using in vivo imaging with a commercially available and systemically administered protease-activatable fluorescent probe, ProSense. To this end, we analyzed the delivery and uptake of ProSense as well as the target protease and its cellular source in a mouse xenograft tumor model. In vivo and ex vivo multi wavelength imaging revealed that ProSense signals accumulated within tumors, with preferential distribution in the vascular leakage area that correlates with vasculature development at the tumor periphery. Immunohistochemically, cathepsin B, which is targeted by ProSense, was specifically localized in macrophages. The codistribution of tenascin C immunoreactivity and gelatinase activity provided evidence of tissue-remodeling at the tumor periphery. Furthermore, in situ zymography revealed extracellular ProSense cleavage in such areas. Colocalization of cathepsin B expression and ProSense signals showing reduction by addition of cathepsin B inhibitor was confirmed in cultured macrophage-derived RAW264.7 cells. These results suggest that increased tissue-remodeling activity involving infiltration of macrophages is a mechanism that may be responsible for the tumor accumulation of ProSense signals in our xenograft model. We further confirmed ProSense signals at the tumor margin showing cathepsin B(+) macrophage infiltration in a rat colon carcinogenesis model. Together, these data demonstrate that systemically administered protease-activatable probes can effectively detect cancer invasive fronts, where tissue-remodeling activity is high to facilitate neoplastic cell invasion.
    Translational oncology 12/2013; 6(6):628-37. DOI:10.1593/tlo.13430 · 2.88 Impact Factor
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    ABSTRACT: This themed issue provides up-to-date review and research articles covering the theranostic applications in the combined fields of protease research, diagnostics and drug development.
    Theranostics 02/2012; 2(2):125-6. DOI:10.7150/thno.4129 · 8.02 Impact Factor
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