Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
School of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
J Control Release. 2014 Aug 28;188:78-86. doi: 10.1016/j.jconrel.2014.06.006. Epub 2014 Jun 14.
The possibility of using genes as medicines to treat brain diseases is currently limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier, thus resulting in a failure to reach the brain after intravenous administration. On the basis that iron can effectively reach the brain by using transferrin receptors for crossing the blood-brain barrier, we propose to investigate if a transferrin-bearing generation 3-polypropylenimine dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration. In vitro, the conjugation of transferrin to the polypropylenimine dendrimer increased the DNA uptake by bEnd.3 murine brain endothelioma cells overexpressing transferrin receptors, by about 1.4-fold and 2.3-fold compared to that observed with the non-targeted dendriplex and naked DNA. This DNA uptake appeared to be optimal following 2h incubation with the treatment. In vivo, the intravenous injection of transferrin-bearing dendriplex more than doubled the gene expression in the brain compared to the unmodified dendriplex, while decreasing the non-specific gene expression in the lung. Gene expression was at least 3-fold higher in the brain than in any tested peripheral organs and was at its highest 24h following the injection of the treatments. These results suggest that transferrin-bearing polypropylenimine dendrimer is a highly promising gene delivery system to the brain.
利用基因作为药物治疗脑部疾病的可能性目前受到限制，因为缺乏能够穿过血脑屏障的安全有效的递药系统，导致静脉给药后无法到达脑部。基于铁可以通过转铁蛋白受体有效地到达脑部，我们拟研究转铁蛋白结合的第三代聚丙稀亚胺树枝状聚合物是否可以在静脉给药后将质粒 DNA 递送到脑部。体外实验中，与非靶向的树枝状聚合物复合物和裸露 DNA 相比，转铁蛋白与聚丙稀亚胺树枝状聚合物的连接将转铁蛋白受体过表达的 bEnd.3 鼠脑内皮细胞瘤细胞摄取的 DNA 增加了约 1.4 倍和 2.3 倍。这种 DNA 摄取在与处理物孵育 2 小时后似乎达到最佳。在体内，与未经修饰的树枝状聚合物相比，转铁蛋白结合的树枝状聚合物复合物的静脉注射使脑部的基因表达增加了一倍以上，同时降低了肺部的非特异性基因表达。基因表达在脑部至少是任何测试的外周器官的 3 倍，并且在注射治疗后 24 小时达到最高。这些结果表明，转铁蛋白结合的聚丙稀亚胺树枝状聚合物是一种很有前途的脑部基因传递系统。
