肽两亲性超分子组装体中较弱的疏水性坍塌增强了血脑屏障模型的渗透
Weaker Hydrophobic Collapse in Peptide Amphiphile Supramolecular Assemblies Enhances Permeation Across a Blood-Brain Barrier Model.
摘要(中文译文)
血脑屏障（BBB）阻止大多数分子从血管扩散进入脑组织，因此对于中枢神经系统的治疗性递送具有重大意义。我们利用肽两亲分子（PAs）研究了超分子组装体穿越血脑屏障的潜力，其中通过改变脂质尾链长度来调节超分子内聚力，同时保持相同的四肽序列VVEE不变。通过广角X射线散射和傅里叶变换红外光谱发现，所研究的PAs中含有16、14或12个碳原子的烷基尾链，其β-折叠二级结构含量依次递减。我们还发现随着脂质尾链缩短，pKa值逐渐降低，因此得出结论：较长的尾链形成内聚力最强的组装体。利用共聚焦显微镜和流式细胞术，我们证明尾链较长的PAs在脑内皮细胞中的蓄积显著更高，而体外血脑屏障Transwell实验显示C12组装体虽被内吞，但也能最有效地从细胞融合层中外排。活细胞成像表明所有组装体均进入溶酶体，但跨细胞转运在C12组装体中发生程度最大，在C14 PA中程度较小。我们得出结论：强疏水塌缩结合高pKa值形成稳定的纳米结构，这些结构被隔离在脑内皮细胞内而无法渗透。我们的工作还表明，PA超分子纳米结构在跨细胞转运后仍保留重新组装的能力，因此具有开发为脑部治疗性递送平台的潜力。
Abstract
The blood-brain barrier (BBB) prevents diffusion of most molecules from the vasculature into the brain tissue, and therefore is of great interest for therapeutic delivery into the central nervous system. We investigated the potential of supramolecular assemblies to cross the BBB using peptide amphiphiles (PAs) in which the lipid tail length was varied to modify supramolecular cohesion but maintaining the same tetrapeptide sequence VVEE. Alkyl tails containing 16, 14, or 12 carbon atoms in the PAs studied were found to contain decreasing amounts of β-sheet secondary structure by wide-angle X-ray scattering and Fourier transform infrared spectroscopy. We also found diminishing pKa values as the lipid tails were shortened, and therefore concluded that longer tails resulted in the most cohesive assemblies. Using confocal microscopy and flow cytometry, we demonstrated that PAs with longer tails had significantly higher accumulation in brain endothelial cells, whereas an in vitro BBB transwell assay showed that C12 assemblies were endocytosed but were also able to exocytose most efficiently from confluent layers of the cells. Live cell imaging demonstrated that all assemblies entered lysosomes, but transcytosis occurred to the greatest extent in C12 assemblies and to a lesser degree in the C14 PA. We conclude that strong hydrophobic collapse, combined with high pKa values, creates stable nanostructures that remain sequestered within brain endothelial cells without the possibility of permeation. Our work also indicates that PA supramolecular nanostructures retain the capacity to reassemble after transcytosis, thus offering potential for their development into therapeutic delivery platforms to the brain.
如何引用
AMA
Zijun Gao, Laura B DeOliveira, Amena Khatun, Ya Li, Zhiwei Li, Dhwanit R Dave, et al. Weaker Hydrophobic Collapse in Peptide Amphiphile Supramolecular Assemblies Enhances Permeation Across a Blood-Brain Barrier Model.. ACS nano. 2026; doi:10.1021/acsnano.6c01585.
APA
Zijun Gao, Laura B DeOliveira, Amena Khatun, Ya Li, Zhiwei Li, Dhwanit R Dave, et al (2026). Weaker Hydrophobic Collapse in Peptide Amphiphile Supramolecular Assemblies Enhances Permeation Across a Blood-Brain Barrier Model.. ACS nano. https://doi.org/10.1021/acsnano.6c01585
GB/T 7714
Zijun Gao, Laura B DeOliveira, Amena Khatun, Ya Li, Zhiwei Li, Dhwanit R Dave, et al. Weaker Hydrophobic Collapse in Peptide Amphiphile Supramolecular Assemblies Enhances Permeation Across a Blood-Brain Barrier Model.[J]. ACS nano, 2026 doi:10.1021/acsnano.6c01585.
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