title: CD146-targeted immunoPET and NIRF Imaging of Hepatocellular Carcinoma with a Dual-Labeled Monoclonal Antibody.
abstract: Overexpression of CD146 has been correlated with aggressiveness, recurrence rate, and poor overall survival in hepatocellular carcinoma (HCC) patients. In this study, we set out to develop a CD146-targeting probe for high-contrast noninvasive in vivo positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of HCCs. YY146, an anti-CD146 monoclonal antibody, was employed as a targeting molecule to which we conjugated the zwitterionic near-infrared fluorescence (NIRF) dye ZW800-1 and the chelator deferoxamine (Df). This enabled labeling of Df-YY146-ZW800 with (89)Zr and its subsequent detection using PET and NIRF imaging, all without compromising antibody binding properties. Two HCC cell lines expressing high (HepG2) and low (Huh7) levels of CD146 were employed to generate subcutaneous (s.c.) and orthotopic xenografts in athymic nude mice. Sequential PET and NIRF imaging performed after intravenous injection of (89)Zr-Df-YY146-ZW800 into tumor-bearing mice unveiled prominent and persistent uptake of the tracer in HepG2 tumors that peaked at 31.65 ± 7.15 percentage of injected dose per gram (%ID/g; n=4) 72 h post-injection. Owing to such marked accumulation, tumor delineation was successful by both PET and NIRF, which facilitated the fluorescence image-guided resection of orthotopic HepG2 tumors, despite the relatively high liver background. CD146-negative Huh7 and CD146-blocked HepG2 tumors exhibited significantly lower (89)Zr-Df-YY146-ZW800 accretion (6.1 ± 0.5 and 8.1 ± 1.0 %ID/g at 72 h p.i., respectively; n=4), demonstrating the CD146-specificity of the tracer in vivo. Ex vivo biodistribution and immunofluorescent staining corroborated the accuracy of the imaging data and correlated tracer uptake with in situ CD146 expression. Overall, (89)Zr-Df-YY146-ZW800 showed excellent properties as a PET/NIRF imaging agent, including high in vivo affinity and specificity for CD146-expressing HCC. CD146-targeted molecular imaging using dual-labeled YY146 has great potential for early detection, prognostication, and image-guided surgical resection of liver malignancies.
authors: Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA;
authors: Reinier
authors: R
authors: Hernandez
authors: Department of Radiology, University of Wisconsin, Madison, WI 53705, USA;
authors: Haiyan
authors: H
authors: Sun
authors: Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA;
authors: Christopher G
authors: CG
authors: England
authors: Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA;
authors: Hector F
authors: HF
authors: Valdovinos
authors: Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA;
authors: Emily B
authors: EB
authors: Ehlerding
authors: Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA;
authors: Todd E
authors: TE
authors: Barnhart
authors: Department of Radiology, University of Wisconsin, Madison, WI 53705, USA;
authors: Yunan
authors: Y
authors: Yang
authors: Department of Medical Physics, University of Wisconsin, Madison, WI 53705, USA;; Department of Radiology, University of Wisconsin, Madison, WI 53705, USA;; University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA.
authors: Weibo
authors: W
authors: Cai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D051929:CD146 Antigen / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging*; D002460:Cell Line; D003676:Deferoxamine / Q000378:metabolism; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging*; D008819:Mice, Nude; D061848:Optical Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D017262:Siderophores / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods*; D013451:Sulfonic Acids / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D051929:CD146 Antigen; D005456:Fluorescent Dyes; C497902:MCAM protein, human; D000644:Quaternary Ammonium Compounds; D017262:Siderophores; D013451:Sulfonic Acids; C562069:ZW800-1 compound; D003676:Deferoxamine
keywords: 89Zr.; CD146; Positron emission tomography (PET); dual-modality imaging; hepatocellular carcinoma (HCC); near-infrared fluorescence (NIRF) imaging