College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Int J Pharm. 2023 Jul 25;642:123191. doi: 10.1016/j.ijpharm.2023.123191. Epub 2023 Jun 29.
Brain-targeted drug delivery has been a research hotspot, and substantial amount of related studies were already translated into standard therapy and put into clinical use. However, low effective rate retains a huge challenge for brain disease. Because, the blood-brain barrier (BBB) protects brain from pathogenic molecules and tightly controls the process of molecular transportation, which gives rise to poor-liposoluble drugs or molecules with high molecular weight cannot permeate the barrier to exert treating effect. There is an ongoing process to dig out more methods for efficient brain-targeted drug delivery. Besides modified chemical methods such as prodrugs design and brain-targeted nanotechnology, physical methods as a novel initiative could enhance the treatment effect for brain disease. In our study, the influence of low-intensity ultrasound on transient opening BBB and the related applications were explored. A medical ultrasound therapeutic device (1 MHz) was used on heads of mice at different intensities and for different treating time. Evans blue was used as a model to exhibit the permeability of the BBB after subcutaneous injection. Three types of intensities (0.6, 0.8, and 1.0 W/cm) and duration times (1, 3, and 5 min) of ultrasound were respectively investigated. It was found that the combinations of 0.6 W/cm/1 min, 0.6 W/cm/3 min, 0.6 W/cm/5 min, 0.8 W/cm/1 min, and 1.0 W/cm/1 min could open the BBB sufficiently with significant Evans blue staining in the brain. Brain pathological analysis showed structural change on moderate degree was found on cerebral cortex after ultrasound and could recovered rapidly. There are no obvious changes in the behavior of mice after ultrasound processing. More importantly, the BBB recovered quickly at 12 h after ultrasound application with complete BBB structure and unbroken tight junction, suggesting that ultrasound was safe to apply for brain-targeted drug delivery. Proper use of local ultrasound on the brain is a promising technique to open the BBB and enhance brain-targeted delivery.
脑靶向给药一直是研究热点，大量相关研究已转化为标准治疗并应用于临床。然而，低有效率仍然是脑疾病的巨大挑战。因为血脑屏障（BBB）保护大脑免受致病分子的侵害，并严格控制分子转运过程，导致脂溶性差的药物或分子量高的分子无法穿透屏障发挥治疗作用。人们一直在挖掘更多有效的脑靶向药物递送方法。除了前药设计和脑靶向纳米技术等改良的化学方法外，物理方法作为一种新的方法也可以增强脑疾病的治疗效果。在我们的研究中，我们探索了低强度超声对瞬时开放血脑屏障的影响及其相关应用。使用 1MHz 的医用超声治疗设备在不同强度和不同治疗时间下对小鼠头部进行处理。伊文思蓝被用作皮下注射后 BBB 通透性的模型。分别研究了三种强度（0.6、0.8 和 1.0 W/cm）和持续时间（1、3 和 5 分钟）的超声。结果发现，0.6 W/cm/1 min、0.6 W/cm/3 min、0.6 W/cm/5 min、0.8 W/cm/1 min 和 1.0 W/cm/1 min 的组合可以充分打开 BBB，大脑中有明显的伊文思蓝染色。脑病理分析显示，超声后大脑皮质出现中度结构变化，且可迅速恢复。超声处理后小鼠行为无明显变化。更重要的是，超声应用后 12 小时 BBB 迅速恢复，结构完整，紧密连接未破裂，提示超声应用于脑靶向药物递送是安全的。适当使用局部超声打开 BBB 并增强脑靶向递送是一种很有前途的技术。
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