Background and study aims
To demonstrate the clinical use of a multimodal endoscope with a targeted fluorescently labeled peptide for quantitative detection of Barrett’s neoplasia.
Patients and methods
We studied 50 patients with Barrett’s esophagus using a prototype multimodal endoscope with a fluorescently labeled peptide. Co-registered fluorescence and reflectance images were converted to ratios to correct for differences in distance and geometry over the image field of view. The ratio images were segmented using a unique threshold that maximized the variance between high and low intensities to localize regions of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC).
Results
Early neoplasia (HGD and EAC) was identified with 94% specificity and 96% positive predictive value at a threshold of 1.49. The mean results for HGD and EAC were significantly greater than those for squamous/Barrett’s esophagus and low grade dysplasia by one-way analysis of variance (ANOVA). The receiver operator characteristic curve for detection of early neoplasia had an area under the curve of 0.884. No adverse events associated with the endoscope or peptide were found.
Conclusion
A multimodal endoscope can quantify fluorescence images from targeted peptides to localize early Barrett’s neoplasia. (ClinicalTrials.gov number NCT01630798.)
Background & Aims
Conventional white light colonoscopy aims to reduce the incidence and mortality of colorectal cancer (CRC). CRC has been found to arise from missed polypoid and flat pre-cancerous lesions. We aim to establish proof-of-concept for real time endoscopic imaging of colonic adenomas using a near-infrared peptide that is specific for claudin-1.
Methods
We used gene expression profiles to identify claudin-1 as a promising early CRC target, and performed phage display against the extracellular loop of claudin-1 (amino acids 53–80) to identify the peptide RTSPSSR. With a Cy5.5 label, we characterized binding parameters and demonstrated specific binding to human CRC cells. We collected in vivo near-infrared fluorescence images endoscopically in the CPC;Apc mouse that develops colonic adenomas spontaneously. With immunofluorescence, we validated specific peptide binding to adenomas from proximal human colon.
Results
We found a 2.5-fold increase in gene expression for claudin-1 in human colonic adenomas compared with normal. We demonstrated specific binding of RTSPSSR to claudin-1 in knockdown and competition studies, and measured an affinity of 42 nM and time constant of 1.2 minutes to SW620 cells. In the mouse, we found a significantly higher target-to-background ratio for both polypoid and flat adenomas compared to normal with in vivo images. On immunofluorescence, we found significantly greater intensity (mean±std) for human adenomas (25.5±14.0) versus normal (9.1±6.0) and hyperplastic polyps (3.1±3.7), P=10−5 and 8×10−12, respectively, and for sessile serrated adenomas (20.1±13.3) versus normal and hyperplastic polyps, P=0.02 and 3×10−7, respectively.
Conclusions
Claudin-1 is overexpressed in pre-malignant colonic lesions, and can be detected endoscopically in vivo with a near-infrared labeled peptide.
Many powerful drugs have limited clinical utility because of poor water solubility and high systemic toxicity. Here, we formulated a targeted nanomedicine, rapamycin encapsulated in pegylated octadecyl lithocholate micelles labeled with a new ligand for colorectal neoplasia, LTTHYKL peptide. CPC;Apc mice that spontaneously develop colonic adenomas were treated with free rapamycin, plain rapamycin micelles, and peptide-labeled rapamycin micelles via intraperitoneal injection for 35 days. Endoscopy was performed to monitor adenoma regression in vivo. We observed complete adenoma regression at the end of therapy. The mean regression rate for peptide-labeled rapamycin micelles was significantly greater than that for plain rapamycin micelles, P<0.01. On immunohistochemistry, we observed a significant reduction in phospho-S6 but not β-catenin expression and reduced tumor cell proliferation, suggesting greater inhibition of downstream mTOR signaling. We observed significantly reduced renal toxicity for peptide-labeled rapamycin micelles compared to that of free drug, and no other toxicities were found on chemistries. Together, this unique targeted micelle represents a potential therapeutic for colorectal neoplasia with comparable therapeutic efficacy to rapamycin free drug and significantly less systemic toxicity.
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