title: Selective targeting of liver cancer with the endothelial marker CD146.
abstract: Hepatocellular carcinomas are well-vascularized tumors; the endothelial cells in these tumors have a specific phenotype. Our aim was to develop a new approach for tumor-specific drug delivery with monoclonal antibody targeting of endothelial ligands. CD146, a molecule expressed on the endothelial surface of hepatocellular carcinoma, was identified as a promising candidate for targeting. In the present study, endothelial cells immediately captured circulating anti-CD146 (ME-9F1) antibody, while antibody binding in tumors was significantly higher than in hepatic endothelium. Macroscopically, after intravenous injection, there were no differences in the mean accumulation of anti-CD146 antibody in tumor compared to liver tissue , due to a compensating higher blood vessel density in the liver tissue. Additional blockade of nontumoral epitopes and intra-arterial administration, improved selective antibody capture in the tumor microvasculature and largely prevented antibody distribution in the lung and liver. The potential practical use of this approach was demonstrated by imaging of radionuclide-labeled ME-9F1 antibody, which showed excellent tumor-selective uptake. Our results provide a promising principle for the use of endothelial markers for intratumoral drug delivery. Tumor endothelium-based access might offer new opportunities for the imaging and therapy of hepatocellular carcinoma and other liver malignancies.
authors.affiliation: Department of Surgery, University of Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Thomann
authors.affiliation: Department of Pathology, University of Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Department of Surgery, University of Heidelberg, Germany.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Bazhin
authors.affiliation: Department of Nuclear Medicine, University of Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Surgery, University of Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Department of Surgery, University of Heidelberg, Germany.
authors.forename: Eduard
authors.initials: E
authors.lastname: Ryschich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000918:Antibody Specificity; D001682:Biological Availability; D051929:CD146 Antigen / Q000276:immunology / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000939:Epitopes; D006801:Humans; D007275:Injections, Intravenous; D008102:Liver Circulation; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008833:Microcirculation
chemical_list: D000911:Antibodies, Monoclonal; D051929:CD146 Antigen; D004337:Drug Carriers; D000939:Epitopes; C497902:MCAM protein, human