Effective tumor targeted gene transfer using PEGylated adenovirus vector via systemic administration
Effective tumor targeted gene transfer using PEGylated adenovirus vector via systemic administration
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DOI：
10.1016/j.jconrel.2007.06.010
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发表时间：
2007-09-11
影响因子：
10.8
通讯作者：
Nakagawa, Shinsaku
中科院分区：
文献类型：
--
作者：
Gao, Jian-Qing;Eto, Yusuke;Nakagawa, Shinsaku
聚乙二醇与蛋白质或颗粒的结合（PEG化）缩短了其血浆半衰期，并由于增强的渗透性和保留（EPR）效应而促进其在肿瘤中的蓄积。虽然腺病毒载体（Ads）的聚乙二醇化是一种有吸引力的策略来改善常规Ads的体内动力学，但聚乙二醇化的Ad（PEG-Ad）的EPR效应以前没有报道。在这项研究中，我们以不同的修饰比例制备了PEG-Ads，将其静脉注射到荷瘤小鼠体内，并分别测定了血液动力学、病毒分布和基因表达模式。此外，我们进行了编码肿瘤坏死因子（TNF）-α的PEG-Ad的癌症治疗研究。PEG-Ad的血浆半衰期比未修饰的Ad长，且随着PEG修饰比例的增加，PEG-Ad在肿瘤组织中的蓄积量增加。特别地，与未修饰的Ad相比，具有约90%修饰率的PEG-Ad在特纳中显示更高（35倍）的基因表达，而在肝脏中显示更低（6%）的基因表达。此外，与未修饰的Ad相比，编码TNF-α的PEG-Ad不仅表现出更强的肿瘤抑制活性，而且表现出更少的肝毒性副作用。PEG修饰的Ad通过EPR效应实现了更好的靶向性，这些属性表明全身注射PEG-Ad作为抗肿瘤治疗具有巨大的潜力。(c)2007 Elsevier B. V.保留所有权利。
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 turner 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 turner targeting through the EPR effect, and these attributes suggest that systemic injection of PEG-Ad has great potential as an anti-tumor treatment. (c) 2007 Elsevier B.V. All rights reserved.