Abstract：
Nanoparticles, in particular PEGylated, show great potential for in vivo brain targeted drug delivery. Nevertheless, how polyethylene glycol (PEG) length of nanoparticles affects their blood brain barrier (BBB) penetration or brain targeting is still unclear. In this study, we investigated the power of PEG chain-lengths (2, 3.4, 5, 10 kDa) in BBB penetration and brain targeting using Angiopep-2 peptide decorated liposomes. We found that PEG chain-length is critical, where the shorter PEG enabled the Angiopep-2 decorated liposomes to display more potent in vitro cell uptake via endocytosis. In contrast, their in vitro BBB penetration via transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the in vivo brain targeting aligns with the in vitro BBB penetration, as the long chain PEG-modified liposomes exerted superior brain accumulation both in normal or orthotropic glioblastoma (GBM) bearing mice, which could be ascribed to the combinational effect of prolonged circulation and enhanced BBB penetration of long chain PEG attached liposomes. These results demonstrate the crucial role of PEG length of nanoparticles for BBB penetration and brain targeting, providing guidance for PEG length selection in the design of nanocarrier for brain diseases treatment.
摘要：
纳米颗粒,特别是聚乙二醇化，在体内脑靶向药物递送方面显示出巨大的潜力。然而，聚乙二醇（PEG）长度的纳米颗粒如何影响其血脑屏障（BBB）渗透或脑靶向仍不清楚。在这项研究中,我们使用Angiopep-2肽修饰的脂质体研究了PEG链长（2,3.4,5,10kDa）在BBB渗透和脑靶向中的功效。我们发现PEG链长是关键的，其中较短的PEG使血管肽-2修饰的脂质体能够通过内吞作用显示更有效的体外细胞摄取。相比之下,相对于具有较长PEG链的脂质体，它们通过胞吞作用的体外BBB渗透要弱得多，这是由于它们无效的BBB胞吐作用。有趣的是,体内脑靶向与体外BBB渗透一致，因为长链PEG修饰的脂质体在正常或正交性胶质母细胞瘤（GBM）携带小鼠中都表现出优越的脑积累，这可以归因于长链PEG连接脂质体延长循环和增强BBB渗透的组合效应。这些结果证明了纳米颗粒的PEG长度对BBB渗透和脑靶向的关键作用，为脑疾病治疗纳米载体设计中PEG长度的选择提供指导。
