Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo.
Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo.
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DOI：
10.1016/j.ultrasmedbio.2009.08.006
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发表时间：
2010-01
影响因子：
2.9
通讯作者：
Konofagou, Elisa E.
中科院分区：
文献类型：
--
作者：
Choi, James J.;Wang, Shougang;Tung, Yao-Sheng;Morrison, Barclay, III;Konofagou, Elisa E.
关键词：
聚焦超声（FUS）在此显示出通过开放的血脑屏障（BBB）非侵入性地和选择性地递送与药物相关的分子量的化合物。使用荧光显微镜对FUS诱导的BBB开口的大小、递送的药剂的空间分布及其对药剂分子量的依赖性进行成像和定量。在全身施用微泡并随后通过完整的皮肤和颅骨将脉冲FUS（频率：1.525 MHz，原位峰值稀疏压力：569 kPa）应用于左侧小鼠海马体后，在体内实现小鼠（n=13）中的BBB开放。全身施用跨越几个数量级的三种不同分子量的BBB不渗透的荧光标记的葡聚糖，并作为模型治疗化合物。首先，3和70 kDa的右旋糖酐被递送trans-BBB，而2000 kDa的右旋糖酐则没有。其次，与70 kDa葡聚糖相比，更高浓度的3 kDa葡聚糖被递送通过开放的BBB。第三，3和70 kDa的葡聚糖都弥漫分布在整个目标脑区域。然而，高浓度的70 kDa葡聚糖在整个靶向区域中显得更点状。总之，与微泡组合的FUS充分打开BBB以允许至少70 kDa但不大于2000 kDa的化合物通过进入脑实质。因此，这种非侵入性和局部BBB开放技术可以提供一种独特的手段来递送几个kDa量级的化合物，其中包括在体外显示出治疗前景的药物，但其体内翻译已受到其相关BBB不渗透性的阻碍。
Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n=13) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525 MHz, peak-rarefactional pressure in situ: 569 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared to 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa, into the brain parenchyma. This noninvasive and localized BBB opening technique could thus provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro, but whose in vivo translation has been hampered by their associated BBB impermeability.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
影响因子：
2.4
作者：
Apfel, RE
通讯作者：
Apfel, RE
影响因子：
3
作者：
GREIG, NH;DALY, EM;RAPOPORT, SI
通讯作者：
RAPOPORT, SI
影响因子：
6.4
作者：
Treat, Lisa H.;McDannold, Nathan;Hynynen, Kullervo
通讯作者：
Hynynen, Kullervo
DOI：
10.1073/pnas.0509425103
发表时间：
2006-04-04
影响因子：
11.1
作者：
Thorne, RG;Nicholson, C
通讯作者：
Nicholson, C