Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques.
Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques.
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DOI：
10.1158/0008-5472.can-12-0128
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发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Livingstone MS
中科院分区：
文献类型：
--
作者：
McDannold N;Arvanitis CD;Vykhodtseva N;Livingstone MS
血脑屏障（BBB）阻止大多数药物进入大脑，是使用脑肿瘤和其他中枢神经系统疾病药物的主要障碍。在小动物中的工作已经表明，超声与静脉内循环微泡剂组合可以暂时透化BBB。在这里，我们评估了这种靶向给药方法是否可以安全，可靠地应用于恒河猴，并在一个可控的方式使用聚焦超声系统。我们确定了一个明确的安全窗口，在此期间可以产生BBB破坏而没有明显的组织损伤，并且发现BBB破坏概率为50%的声压幅度是将产生组织损伤的值的一半。声发射测量似乎有希望预测血脑屏障的破坏和损害。此外，我们在几周内对训练用于执行复杂视力任务的动物进行了对中央视野目标的重复BBB破坏。所有动物均从每次治疗中恢复，无行为缺陷、视觉缺陷或视力丧失。总之，我们的研究结果表明，在使用临床设备的临床相关动物模型中，可以可靠且重复地产生BBB破坏，而没有明显的组织学或功能损伤。因此，这些结果支持这种非侵入性靶向给药方法的临床试验。
The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% was found to be half of the value that would produce tissue damage. Acoustic emission measurements appeared promising for predicting BBB disruption and damage. In addition, we performed repeated BBB disruption to central visual field targets over several weeks in animals trained to perform complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings demonstrate that BBB disruption can be reliably and repeatedly produced without evident histological or functional damage in a clinically-relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive targeted drug delivery method.