Abstract:
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.
摘要:
气泡增强的冲击波诱导血脑屏障(BBB)的短暂开放,为脑肿瘤治疗的靶向药物递送提供了独特的优势。但是对这个过程的分子细节知之甚少。基于我们的BBB模型,包括28000脂质和280紧密连接蛋白和粗粒度动力学模拟,我们首次提供了三种典型药物的分子水平递送机制,包括亲脂性紫杉醇,亲水性吉西他滨,和包裹在脂质体中的siRNA,穿过BBB。结果表明,与人脑质膜(PM)相比,BBB更难被冲击诱导射流穿孔,需要更高的冲击波速度。对于形成的孔隙,BBB比PM表现出更大的自愈能力。疏水性紫杉醇可以穿过血脑屏障并被成功吸收,但金额仅为PM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。脂质体加载的siRNA仅停留在BBB的第一层中。机理分析表明,增加气泡大小可以促进药物吸收,同时降低较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,可以扩展到实验的微泡尺度。计算的超压与实验结果一致。这些关于休克辅助BBB开放用于靶向药物递送的分子尺度细节将指导和辅助实验尝试,以促进该策略在脑肿瘤临床治疗中的应用。