Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA School of Pharmacy, Fudan University, Shanghai, 201203, China.
Pharm Res. 2013 Oct;30(10):2538-48. doi: 10.1007/s11095-013-1004-9. Epub 2013 Mar 15.
To investigate the multivalent effect for up-regulating the intracerebral delivery of nanoparticles via receptor-mediated transcytosis.
Nanoparticles labeled with near-infrared (NIR) fluorophore and different numbers of angiopep-2 peptides that specifically target low-density lipoprotein receptor-related protein (LRP) on the brain capillary endothelial cells were developed. Bio-distribution studies quantified the intracerebral uptakes of these nanoparticles at 2 and 24 h after intravenous injection. In vivo NIR fluorescence imaging, ex vivo autoradiographic imaging and 3D reconstructed NIR fluorescence imaging revealed the nanoparticle distribution pattern in brain. Fluorescence microscopic imaging identified the nanoparticle locations at the cellular level.
The multimetirc association between the angiopep-2 peptides labeled on the nanoparticle and the LRP receptors on the brain capillary endothelial cells significantly increased the intracerebral uptake of the nanoparticles. Nanoparticle Den-Angio4 labeled four angiopep-2 peptides achieved the highest BBB traverse efficacy. After penetrating the BBB, Den-Angio4 distributed heterogeneously and mainly located at hippocampus, striatum and cerebellum in the brains.
The multivalent effect significantly enhances the BBB permeability of nanoparticles. Den-Angio4 as a nanoparticle prototype provides a two order targeted strategy for diagnosis or treatment of central nerver system diseases by first traversing the BBB via receptor-mediated endocytosis and secondly targeting the leisions with high receptor expression level.
通过受体介导的胞吞作用研究上调纳米颗粒脑内递送的多价效应。
制备了近红外（NIR）荧光标记并带有不同数量的能够特异地靶向脑毛细血管内皮细胞上低密度脂蛋白受体相关蛋白（LRP）的血管肽-2 肽的纳米颗粒。生物分布研究在静脉注射后 2 和 24 小时量化了这些纳米颗粒的脑内摄取量。体内近红外荧光成像、离体放射性自显影成像和 3D 重建近红外荧光成像揭示了纳米颗粒在脑内的分布模式。荧光显微镜成像确定了纳米颗粒在细胞水平上的位置。
标记在纳米颗粒上的血管肽-2 肽与脑毛细血管内皮细胞上的 LRP 受体之间的多价结合显著增加了纳米颗粒的脑内摄取量。标记有四个血管肽-2 肽的纳米颗粒 Den-Angio4 达到了最高的 BBB 穿透效果。穿透 BBB 后，Den-Angio4 呈不均匀分布，主要位于大脑中的海马体、纹状体和小脑。
多价效应显著增强了纳米颗粒的 BBB 通透性。Den-Angio4 作为纳米颗粒原型，通过受体介导的内吞作用首先穿透 BBB，其次靶向高受体表达水平的病变，为中枢神经系统疾病的诊断或治疗提供了一种两阶靶向策略。
