title: Effective tumor targeted gene transfer using PEGylated adenovirus vector via systemic administration.
abstract: Conjugation of polyethylene glycol to protein or particles (PEGylation) prolongs their plasma half-lives and promotes their accumulation in tumors due to enhanced permeability and retention (EPR) effect. Although PEGylation of adenovirus vectors (Ads) is an attractive strategy to improve the in vivo kinetics of conventional Ads, the EPR effect of PEGylated Ad (PEG-Ad) had not previously been reported. In this study, we prepared PEG-Ads with PEG at various modification ratios, injected them intravenously into tumor-bearing mice, and determined the blood kinetics, viral distribution, and gene expression patterns, respectively. In addition, we conducted a cancer therapeutic study of PEG-Ad encoding tumor necrosis factor (TNF)-alpha. The plasma half-life of PEG-Ad was longer than that of unmodified-Ad, and accumulation of PEG-Ad in tumor tissue increased as the PEG modification ratio increased. In particular, PEG-Ad with about 90% modification ratio showed higher (35 times) gene expression in tumor and lower (6%) in liver, compared with values for unmodified Ad. Moreover, PEG-Ad encoding TNF-alpha demonstrated not only stronger tumor-suppressive activity but also fewer hepatotoxic side effects compared with unmodified-Ad. PEGylation of Ad achieved tumor targeting through the EPR effect, and these attributes suggest that systemic injection of PEG-Ad has great potential as an anti-tumor treatment.
authors.affiliation: Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Gao
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Eto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Kurachi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morishige
authors.forename: Xinglei
authors.initials: X
authors.lastname: Yao
authors.forename: Hikaru
authors.initials: H
authors.lastname: Watanabe
authors.forename: Ratima
authors.initials: R
authors.lastname: Asavatanabodee
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okada
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mukai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mayumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000493:pharmacokinetics*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D008156:Luciferases