Effective tumor targeted gene transfer using PEGylated adenovirus vector via systemic administration.
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.
Gao
Jian-Qing
JQ
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Eto
Yusuke
Y
Yoshioka
Yasuo
Y
Sekiguchi
Fumiko
F
Kurachi
Shinnosuke
S
Morishige
Tomohiro
T
Yao
Xinglei
X
Watanabe
Hikaru
H
Asavatanabodee
Ratima
R
Sakurai
Fuminori
F
Mizuguchi
Hiroyuki
H
Okada
Yuka
Y
Mukai
Yohei
Y
Tsutsumi
Yasuo
Y
Mayumi
Tadanori
T
Okada
Naoki
N
Nakagawa
Shinsaku
S
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*
D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D008156:Luciferases