title: Active targeting and safety profile of PEG-modified adenovirus conjugated with herceptin.
abstract: PEGylation of adenovirus (Ad) increases plasma retention and reduces immunogenicity, but decreases the accessibility of virus particles to target cells. We tested whether PEGylated Ad conjugated to Herceptin (Ad-PEG-HER) can be used to treat Her2/neu-positive cells in vitro and in vivo to demonstrate the therapeutic feasibility of this Ad formulation. Ad-PEG-HER transduced Her2/neu-overexpressing cancer cells through a specific interaction between Herceptin and Her2/neu. Ad-PEG-HER treatment resulted in higher plasma retention and lower neutralizing antibody and IL-6 production than naked Ad. This formulation was extended to generate a Her2/neu-targeted, PEGylated oncolytic Ad (DWP418-PEG-HER). DWP418-PEG-HER specifically killed Her2/neu-positive cells and performed better than non-targeted and naked Ad in vivo. DWP418-PEG-HER showed a 10(10)-fold increase in the liver to tumor biodistribution compared with naked Ad. Immunohistochemical staining confirmed accumulation of Ad E1A in tumors. These data suggest that targeted gene therapy with the PEGylated Ad conjugated with Herceptin might shed a light on its therapeutic application for metastatic cancer in the future.
authors.affiliation: Graduate Program for Nanomedical Science, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-749, South Korea.
authors.forename: Pyung-Hwan
authors.initials: PH
authors.lastname: Kim
authors.forename: Joo-Hyuk
authors.initials: JH
authors.lastname: Sohn
authors.forename: Joung-Woo
authors.initials: JW
authors.lastname: Choi
authors.forename: Yukyung
authors.initials: Y
authors.lastname: Jung
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Seungjoo
authors.initials: S
authors.lastname: Haam
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D050504:Oncolytic Viruses / Q000187:drug effects / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D014161:Transduction, Genetic; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab