Department of Radiology, Columbia University, New York, NY, USA.
Curr Pharm Biotechnol. 2012 Jun;13(7):1332-45. doi: 10.2174/138920112800624364.
Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.
超过 400 万美国男性和女性患有阿尔茨海默病；100 万患有帕金森病；35 万患有多发性硬化症（MS）；2 万患有肌萎缩侧索硬化症（ALS）。在全球范围内，这四种疾病影响了超过 2000 万患者。此外，衰老大大增加了神经退行性疾病的风险。尽管近年来在理解这些疾病方面取得了巨大进展，但目前几乎没有有效的治疗方法，也没有治愈方法。这主要是由于血脑屏障（BBB）的不渗透性，该屏障仅允许 7000 种小分子药物中的 5%用于治疗这些疾病中的一小部分。另一方面，安全且局部的 BBB 开放已被证明是一个重大挑战。在已证明有效的 BBB 破坏方法中，与微泡结合使用的聚焦超声（FUS）是唯一可以非侵入性和区域性地诱导局部 BBB 开放的技术。因此，FUS 可能会对跨 BBB 脑内药物输送产生巨大影响。本文的主要目标是阐明 FUS 打开 BBB 过程中超声、微泡和局部微环境之间的相互作用，这些相互作用负责诱导 BBB 破坏。通过 MRI 和被动空化检测（PCD）监测体内 BBB 开放的机制，并在不同压力、脉冲长度和微泡直径下使用 H&E 组织学评估 BBB 破坏的安全性。结果表明，在特定声压（低于 0.45 MPa）和微泡（直径低于 8 μm）条件下，BBB 可以安全且短暂地破坏。
