Gao Jian-Qing, Eto Yusuke, Yoshioka Yasuo, Sekiguchi Fumiko, Kurachi Shinnosuke, Morishige Tomohiro, Yao Xinglei, Watanabe Hikaru, Asavatanabodee Ratima, Sakurai Fuminori, Mizuguchi Hiroyuki, Okada Yuka, Mukai Yohei, Tsutsumi Yasuo, Mayumi Tadanori, Okada Naoki, Nakagawa Shinsaku
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
J Control Release. 2007 Sep 11;122(1):102-10. doi: 10.1016/j.jconrel.2007.06.010. Epub 2007 Jun 21.
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.
将聚乙二醇与蛋白质或颗粒偶联（聚乙二醇化）可延长它们在血浆中的半衰期，并由于增强的渗透和滞留（EPR）效应促进它们在肿瘤中的蓄积。尽管腺病毒载体（Ads）的聚乙二醇化是改善传统腺病毒载体体内动力学的一种有吸引力的策略，但此前尚未报道聚乙二醇化腺病毒（PEG-Ad）的EPR效应。在本研究中，我们制备了具有不同修饰比例聚乙二醇的PEG-Ads，将它们静脉注射到荷瘤小鼠体内，并分别测定血液动力学、病毒分布和基因表达模式。此外，我们对编码肿瘤坏死因子（TNF）-α的PEG-Ad进行了癌症治疗研究。PEG-Ad的血浆半衰期比未修饰的腺病毒长，并且随着聚乙二醇修饰比例的增加，PEG-Ad在肿瘤组织中的蓄积增加。特别是，与未修饰的腺病毒相比，修饰比例约为90%的PEG-Ad在肿瘤中的基因表达更高（35倍），而在肝脏中的表达更低（6%）。此外，与未修饰的腺病毒相比，编码TNF-α的PEG-Ad不仅表现出更强的肿瘤抑制活性，而且肝毒性副作用更少。腺病毒的聚乙二醇化通过EPR效应实现肿瘤靶向，这些特性表明全身注射PEG-Ad作为一种抗肿瘤治疗具有巨大潜力。
