Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Biomaterials. 2009 Dec;30(36):6976-85. doi: 10.1016/j.biomaterials.2009.08.049. Epub 2009 Sep 17.
Angiopep targeting to the low-density lipoprotein receptor-related protein-1 (LRP1) was identified to exhibit high transcytosis capacity and parenchymal accumulation. In this study, it was exploited as a ligand for effective brain-targeting gene delivery. Polyamidoamine dendrimers (PAMAM) were modified with angiopep through bifunctional PEG, then complexed with DNA, yielding PAMAM-PEG-Angiopep/DNA nanoparticles (NPs). The angiopep-modified NPs were observed to be internalized by brain capillary endothelial cells (BCECs) through a clathrin- and caveolae-mediated energy-depending endocytosis, also partly through marcopinocytosis. Also, the cellular uptake of the angiopep-modified NPs were competed by angiopep-2, receptor-associated protein (RAP) and lactoferrin, indicating that LRP1-mediated endocytosis may be the main mechanism of cellular internalization of angiopep-modified NPs. And the angiopep-modified NPs showed higher efficiency in crossing blood-brain barrier (BBB) than unmodified NPs in an in vitro BBB model, and accumulated in brain more in vivo. The angiopep-modified NPs also showed higher efficiency in gene expressing in brain than the unmodified NPs. In conclusion, PAMAM-PEG-Angiopep showed great potential to be applied in designing brain-targeting drug delivery system.
靶向低密度脂蛋白受体相关蛋白-1（LRP1）的血管肽被鉴定出具有高转胞作用和实质蓄积能力。在本研究中，它被用作有效脑靶向基因传递的配体。聚酰胺-胺树枝状大分子（PAMAM）通过双功能 PEG 与血管肽修饰，然后与 DNA 复合，得到 PAMAM-PEG-血管肽/DNA 纳米颗粒（NPs）。观察到血管肽修饰的 NPs 通过网格蛋白和小窝介导的能量依赖性内吞作用被脑毛细血管内皮细胞（BCECs）内化，也部分通过胞饮作用内化。此外，血管肽修饰的 NPs 的细胞摄取可被血管肽-2、受体相关蛋白（RAP）和乳铁蛋白竞争，表明 LRP1 介导的内吞作用可能是血管肽修饰的 NPs 细胞内化的主要机制。并且，在体外 BBB 模型中，与未修饰的 NPs 相比，血管肽修饰的 NPs 具有更高的穿越血脑屏障（BBB）效率，并且在体内更多地积累在脑中。血管肽修饰的 NPs 在脑内表达基因的效率也高于未修饰的 NPs。总之，PAMAM-PEG-血管肽具有很大的潜力可应用于设计脑靶向药物传递系统。
