title: Antitumor effect and safety profile of systemically delivered oncolytic adenovirus complexed with EGFR-targeted PAMAM-based dendrimer in orthotopic lung tumor model.
abstract: Adenovirus (Ad)-mediated cancer gene therapy has been proposed as a promising alternative to conventional therapy for cancer. However, success of systemically administered naked Ad has been limited due to the immunogenicity of Ad and the induction of hepatotoxicity caused by Ad's native tropism. In this study, we synthesized an epidermal growth factor receptor (EGFR)-specific therapeutic antibody (ErbB)-conjugated and PEGylated poly(amidoamine) (PAMAM) dendrimer (PPE) for complexation with Ad. Transduction of Ad was inhibited by complexation with PEGylated PAMAM (PP) dendrimer due to steric hindrance. However, PPE-complexed Ad selectively internalized into EGFR-positive cells with greater efficacy than either naked Ad or Ad complexed with PP. Systemically administered PPE-complexed oncolytic Ad elicited significantly reduced immunogenicity, nonspecific liver sequestration, and hepatotoxicity than naked Ad. Furthermore, PPE-complexed oncolytic Ad demonstrated prolonged blood retention time, enhanced intratumoral accumulation of Ad, and potent therapeutic efficacy in EGFR-positive orthotopic lung tumors in comparison with naked Ad. We conclude that ErbB-conjugated and PEGylated PAMAM dendrimer can efficiently mask Ad's capsid and retarget oncolytic Ad to be efficiently internalized into EGFR-positive tumor while attenuating toxicity induced by systemic administration of naked oncolytic Ad.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea.
authors.forename: A-Rum
authors.initials: AR
authors.lastname: Yoon
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea.
authors.forename: Dayananda
authors.initials: D
authors.lastname: Kasala
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea.
authors.forename: Wonsig
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea.
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Jung
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, South Korea. Electronic address: chaeok@hanyang.ac.kr.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000737:chemistry; D058575:Decorin / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry*; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011092:Polyethylene Glycols / Q000737:chemistry; D011485:Protein Binding; D013499:Surface Properties; D014018:Tissue Distribution; D014161:Transduction, Genetic
chemical_list: D058575:Decorin; D050091:Dendrimers; C104700:PAMAM Starburst; D011092:Polyethylene Glycols; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Adenovirus; Cancer; Cetuximab; Decorin; Dendrimer; EGFR; Erbitux; Gene therapy; Oncolytic adenovirus; PAMAM; PEGylation; c-Met; shRNA