McMahon Dallan, Jones Ryan M, Ramdoyal Rohan, Zhuang Joey Ying Xuan, Leavitt Dallas, Hynynen Kullervo
Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON M4N 3M5, Canada.
Pharmaceutics. 2024 Sep 30;16(10):1289. doi: 10.3390/pharmaceutics16101289.
Focused ultrasound (FUS) and microbubble (MB) exposure is a promising technique for targeted drug delivery to the brain; however, refinement of protocols suitable for large-volume treatments in a clinical setting remains underexplored. Here, the impacts of various sonication parameters on blood-brain barrier (BBB) permeability enhancement and tissue damage were explored in rabbits using a clinical-prototype hemispherical phased array developed in-house, with real-time 3D MB cavitation imaging for exposure calibration. Initial experiments revealed that continuous manual agitation of MBs during infusion resulted in greater gadolinium (Gd) extravasation compared to gravity drip infusion. Subsequent experiments used low-dose MB infusion with continuous agitation and a low burst repetition frequency (0.2 Hz) to mimic conditions amenable to long-duration clinical treatments. Key sonication parameters-target level (proportional to peak negative pressure), number of bursts, and burst length-significantly affected BBB permeability enhancement, with all parameters displaying a positive relationship with relative Gd contrast enhancement ( < 0.01). Even at high levels of BBB permeability enhancement, tissue damage was minimal, with low occurrences of hypointensities on T2*-weighted MRI. When accounting for relative Gd contrast enhancement, burst length had a significant impact on red blood cell extravasation detected in histological sections, with 1 ms bursts producing significantly greater levels compared to 10 ms bursts ( = 0.03), potentially due to the higher pressure levels required to generate equal levels of BBB permeability enhancement. Additionally, albumin and IgG extravasation correlated strongly with relative Gd contrast enhancement across sonication parameters, suggesting that protein extravasation can be predicted from non-invasive imaging. These findings contribute to the development of safer and more effective clinical protocols for FUS + MB exposure, potentially improving the efficacy of the approach.
聚焦超声（FUS）与微泡（MB）联合应用是一种很有前景的向脑内靶向给药技术；然而，适用于临床环境中大容量治疗的方案优化仍未得到充分探索。在此，我们使用自行研发的临床原型半球形相控阵，通过实时三维微泡空化成像进行暴露校准，在兔体内探讨了各种超声处理参数对血脑屏障（BBB）通透性增强和组织损伤的影响。初步实验表明，与重力滴注相比，输注过程中持续手动搅拌微泡会导致更大程度的钆（Gd）外渗。后续实验采用低剂量微泡输注并持续搅拌，以及低脉冲重复频率（0.2Hz）来模拟适合长时间临床治疗的条件。关键超声处理参数——靶点水平（与峰值负压成正比）、脉冲数和脉冲长度——显著影响血脑屏障通透性增强，所有参数与相对钆对比增强均呈正相关（<0.01）。即使在血脑屏障通透性大幅增强的情况下，组织损伤也最小，T2*加权磁共振成像上低信号出现的频率较低。在考虑相对钆对比增强时，脉冲长度对组织学切片中检测到的红细胞外渗有显著影响，1毫秒脉冲产生的红细胞外渗水平明显高于10毫秒脉冲（=0.03），这可能是由于产生同等程度血脑屏障通透性增强所需的压力水平较高。此外，在超声处理参数范围内，白蛋白和免疫球蛋白G外渗与相对钆对比增强密切相关，这表明可以通过非侵入性成像预测蛋白质外渗。这些发现有助于开发更安全、更有效的聚焦超声+微泡暴露临床方案，可能会提高该方法的疗效。
