Zhou Mi, Zhou Wenyu, Yang Hong, Cao Luoxia, Li Ming, Yin Ping, Zhou Yang
Institute of Chemical Materials, Chinese Academy of Engineering and Physics, Mianyang 621900, China.
School of Materials Science & Engineering, Beijing Institute of Technology, Beijing 100081, China.
ACS Appl Mater Interfaces. 2024 Apr 24;16(16):20212-20220. doi: 10.1021/acsami.4c00812. Epub 2024 Apr 15.
Bubble-enhanced shock waves induce the transient opening of the blood-brain barrier (BBB) providing unique advantages for targeted drug delivery of brain tumor therapy, but little is known about the molecular details of this process. Based on our BBB model including 28 000 lipids and 280 tight junction proteins and coarse-grained dynamics simulations, we provided the molecular-level delivery mechanism of three typical drugs for the first time, including the lipophilic paclitaxel, hydrophilic gemcitabine, and siRNA encapsulated in liposome, across the BBB. The results show that the BBB is more difficult to be perforated by shock-induced jets than the human brain plasma membrane (PM), requiring higher shock wave speeds. For the pores formed, the BBB exhibits a greater ability to self-heal than PM. Hydrophobic paclitaxel can cross the BBB and be successfully absorbed, but the amount is only one-third of that of PM; however, the absorption of hydrophilic gemcitabine was almost negligible. Liposome-loaded siRNAs only stayed in the first layer of the BBB. The mechanism analysis shows that increasing the bubble size can promote drug absorption while reducing the risk of higher shock wave overpressure. An exponential function was proposed to describe the relation between bubble and overpressure, which can be extended to the experimental microbubble scale. The calculated overpressure is consistent with the experimental result. These molecular-scale details on shock-assisted BBB opening for targeted drug delivery would guide and assist experimental attempts to promote the application of this strategy in the clinical treatment of brain tumors.
气泡增强的冲击波可诱导血脑屏障（BBB）短暂开放，为脑肿瘤治疗的靶向药物递送提供独特优势，但对此过程的分子细节知之甚少。基于我们包含28000种脂质和280种紧密连接蛋白的血脑屏障模型以及粗粒度动力学模拟，我们首次提供了三种典型药物（包括亲脂性紫杉醇、亲水性吉西他滨以及包裹在脂质体中的小干扰RNA）跨越血脑屏障的分子水平递送机制。结果表明，与人类脑细胞膜（PM）相比，血脑屏障更难被冲击诱导的射流穿孔，需要更高的冲击波速度。对于形成的孔，血脑屏障表现出比细胞膜更强的自我修复能力。疏水性紫杉醇可以穿过血脑屏障并被成功吸收，但其量仅为细胞膜的三分之一；然而，亲水性吉西他滨的吸收几乎可以忽略不计。负载小干扰RNA的脂质体仅停留在血脑屏障的第一层。机制分析表明，增加气泡大小可以促进药物吸收，同时降低更高冲击波超压的风险。提出了一个指数函数来描述气泡与超压之间的关系，该函数可扩展到实验微泡尺度。计算得到的超压与实验结果一致。这些关于冲击辅助血脑屏障开放用于靶向药物递送的分子尺度细节将指导并协助实验尝试，以促进该策略在脑肿瘤临床治疗中的应用。
