Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles
Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles
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DOI：
10.1073/pnas.1105116108
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发表时间：
2011-10-04
影响因子：
11.1
通讯作者：
Konofagou, Elisa E.
中科院分区：
文献类型：
--
作者：
Choi, James J.;Selert, Kirsten;Konofagou, Elisa E.
聚焦超声激活全身给药微泡是一种非侵入性和局部给药方法，可以增加血管对大分子药物的渗透性。然而，负责药物递送的声学参数的范围仍然未知，因此，在不损害安全性的情况下增强递送特性已被证明是困难的。我们提出了一个新的基础，超声脉冲设计的药物输送通过血脑屏障（BBB），使用的原则，发生的概率和空间分布的空化，在对比常规应用的空化幅度。使用极短（2.3 μ s）脉冲的功效进行了评估，在27个不同的声学参数集在低峰值稀疏压力（0.51 MPa或更低）。在给予DehydrogenTM微泡后，对左侧海马和外侧丘脑进行无创超声处理。通过递送荧光标记的3-、10-或70-kDa葡聚糖证实BBB的破坏。在某些条件下，葡聚糖均匀分布在整个目标区域，并在特定的海马标志和神经元细胞和轴突积累。在最有效的参数设置下未观察到组织学损伤。我们的研究结果拓宽了参数的设计空间，使安全窗口更宽，这也可能增加血管通透性。该研究还发现了一组参数，可以增强分子递送的剂量和分布，克服了避免相关损伤的标准权衡。鉴于使用的短脉冲类似于诊断超声，还阐明了新的关键参数，以明确区分治疗超声和无干扰诊断超声。
Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 mu s) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.