Department of Biomedical Engineering, Columbia University, New York 10027, NY, USA.
J Control Release. 2013 Dec 28;172(3):795-804. doi: 10.1016/j.jconrel.2013.09.025. Epub 2013 Oct 2.
Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature.
聚焦超声（FUS）联合全身给药的微泡已被证明可局部、短暂且可逆地增加血脑屏障（BBB）的通透性，从而允许治疗剂靶向递送至大脑以治疗中枢神经系统疾病。目前，微泡是唯一已被用于促进 FUS 诱导的 BBB 开放的试剂。然而，由于其微米级直径，它们局限在血管内空间内，限制了在微血管附近或处的递送效果。在本研究中，声激活纳米液滴被用作一类新的造影剂来介导 FUS 诱导的 BBB 开放，以研究利用这些纳米级相移颗粒在大脑中进行靶向药物递送的可行性。在临床相关压力下，纳米液滴在小鼠海马体中实现了显著的葡聚糖递送。采用被动空化检测试图在大脑中递送的葡聚糖量与超声处理期间记录的声发射之间建立相关性。还使用与纳米液滴具有相同脂质壳组成和全氟丁烷核的常规微泡来比较 FUS 诱导的葡聚糖递送效率。结果发现，纳米液滴具有更高的 BBB 开放压力阈值，但比微泡具有更低的稳定空化阈值，表明需要依赖造影剂的声发射监测。使用纳米液滴在不引起惯性空化或损害安全性的情况下在靶向海马体中实现了更均匀的葡聚糖递送。我们的结果为开发 FUS 诱导的 BBB 开放技术以用于潜在的血管外靶向药物递送至大脑提供了新方法，将潜在的药物递送区域扩展至脑脉管系统之外。
