carbocyanines and Barrett-Esophagus

Topics: Aged; Aged, 80 and over; Barrett Esophagus; Carbocyanines; ErbB Receptors; Esophagoscopy; False Positive Reactions; Female; Fluorescent Dyes; Humans; Indoles; Male; Middle Aged; Molecular Imaging; Peptides; Pilot Projects; Proof of Concept Study; Receptor, ErbB-2

Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease that is rising rapidly in incidence and has poor prognosis. We developed a heterobivalent peptide to target detection of early Barrett's neoplasia by combining monomer heptapeptides specific for either EGFR or ErbB2 in a heterodimer configuration. The structure of a triethylene glycol linker was optimized to maximize binding interactions to the surface receptors on cells. The Cy5.5-labeled heterodimer QRH*-KSP*-E3-Cy5.5 demonstrated specific binding to each target and showed 3-fold greater fluorescence intensity and 2-fold higher affinity compared with those of either monomer alone. Peak uptake in xenograft tumors was observed at 2 h postinjection with systemic clearance by ∼24 h in vivo. Furthermore, ligand binding was evaluated on human esophageal specimens ex vivo, and 88% sensitivity and 87% specificity were found for the detection of either high-grade dysplasia (HGD) or EAC. This peptide heterodimer shows promise for targeted detection of early Barrett's neoplasia in clinical study.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Carbocyanines; Cell Line, Tumor; Drug Stability; ErbB Receptors; Esophageal Neoplasms; Female; Fluorescent Dyes; Humans; Mice, Nude; Microscopy, Confocal; Peptides; Protein Multimerization; Receptor, ErbB-2; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution; Xenograft Model Antitumor Assays