腺病毒载体的PEG修饰及其特性研究

PEGylation of adenovirus vectors and its features

目的:本研究通过对腺病毒载体(Adv)进行聚乙二醇(PEG)修饰,以达到改善Adv在体内免疫原性较强、血液半衰期短的不足。方法:使用活化的甲氧基PEG对Adv衣壳蛋白质进行修饰得到PEG化Adv(PEG-Adv),用A549细胞评价了PEG-Adv的抗体抵抗能力、基因转导能力,并以体内试验考察其半衰期。结果:用本实验方法可通过调整反应中的PEG量控制Adv的PEG修饰率,PEG-Adv的血液半衰期及抗体抵抗能力显著优于普通Adv。结论:Adv经PEG修饰后,可显著改善Adv血液半衰期短、易被抗体中和等缺点,对开发高效的、有理想药动学特征的Adv具有重要意义。

Objective： To enhanced the physical stability of adenovirus vectors （Adv） and ablated humoral immune responses by PEGylation of adenovirus with polyethylene glycols. Methods： PEGylated Adv （pEG-Adv） was constructed by PEGylated adenoviral capsid proteins with activated methoxypolyethylene glycols, and gene expression was evaluated using A549 cells. Furthermore, the plasma half life and the antibody evasion ability were also evaluated. Results： PEG-adv could be protected from antibody neutralization in the high antibody titers to adenovirus, suggesting that PEGylation improve of the ability to administer Adv on a repeated basis. Conclusion： PEGylated Adv can maintain strong protective activity against antibodies. The approach described here could form the basis for further development of adenoviral gene therapy vectors with improved pharmacokinetics and increased efficiency of therapeutic gene transfer in disease.