Nanoparticles, in particular PEGylated, show great potential for 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 cell uptake endocytosis. In contrast, their BBB penetration transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the brain targeting aligns with the 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.

中文翻译：

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肽功能脂质体的PEG长度对血脑屏障（BBB）穿透和脑靶向的影响


纳米颗粒，特别是聚乙二醇化纳米颗粒，在脑靶向药物输送方面显示出巨大的潜力。然而，纳米粒子的聚乙二醇（PEG）长度如何影响其血脑屏障（BBB）穿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、10 kDa）在 BBB 渗透和脑靶向中的作用。我们发现 PEG 链长至关重要，较短的 PEG 使 Angiopep-2 修饰的脂质体能够表现出更有效的细胞摄取内吞作用。相反，它们的 BBB 渗透转胞吞作用相对于具有较长 PEG 链的脂质体要弱得多，这是由于它们无效的 BBB 胞吐作用所致。有趣的是，脑靶向与 BBB 渗透一致，因为长链 PEG 修饰的脂质体在正常或正交向性胶质母细胞瘤 (GBM) 荷瘤小鼠中均发挥了优异的脑积聚作用，这可归因于延长循环和增强 BBB 渗透的组合效应长链 PEG 附着的脂质体。这些结果证明了纳米粒子的PEG长度对于BBB穿透和脑靶向的关键作用，为脑部疾病治疗的纳米载体设计中PEG长度的选择提供了指导。