Opening of the Blood Brain Barrier for Molecular Imaging

描述(由申请人提供)： 由于血脑屏障(BBB)保护脑组织免受外来分子的伤害，通过血液供应将大分子药物输送到中枢神经系统(CNS)通常是不可能的。决定物质从血液渗透到中枢神经系统的因素是脂类的溶解度、分子大小和电荷。BBB可防止分子量大于180道尔顿的电离水溶性物质的渗透。因此，大多数潜在的分子显像剂无法通过血液供应到达脑组织。一种允许这些药物到达脑组织的技术将为目前无法进行的脑部疾病的诊断和监测打开新的可能性之门。实验室实验表明，聚焦的超声束可以非侵入性地打开大脑深处高度局部化的组织体积中的血脑屏障。虽然超声与中枢神经系统的相互作用已经在动物身上进行了广泛的研究，但超声波在大脑中的临床应用受到了普遍接受的观点的严重限制，即必须切除一块颅骨才能使超声束传播到大脑。这一额外的程序使大脑的超声波治疗变得更加复杂、危险和昂贵。因此，在临床试验中，超声波对大脑的影响还没有得到广泛的探索。我们已经证明，利用多个换能器的相控阵，高聚焦超声束可以无创地准确地通过完整的人类头骨，从而消除了在大脑中使用聚焦超声的最大障碍。这项研究的总体目标是将我们通过完整头骨传递聚焦超声波的能力与允许我们使用超声波打开血脑屏障的方法结合起来，并开发一种可用于打开血脑屏障的设备，用于分子成像试剂。该设备将与MRI兼容，这样它就可以用来定位大脑中的特定解剖位置。在BBB打开后，可以注射分子显像剂，并且可以使用任何成像方法进行成像。精确聚焦和超声波束的系统要求非常复杂。虽然这种复杂性，以及剃头的需要，对于靶向治疗是可以接受的，但这使得目前的系统对于常规诊断成像是不现实的。申请者的假设是，BBB的开放可以用一个简单得多的系统来进行。同样，我们估计，通过我们提出的方法，人类头发的影响很可能会降低。目前还没有使用建议的BBB开放超声暴露的日期。我们建议使用R21/R33的组合机制首先确定可行性，然后开发一种相对简单的设备选择性打开BBB进行分子成像的方法。这种方法的成功实施将使许多新的脑分子成像方法成为可能。即使是开发一种常规临床使用的成像方法，也会对患者的护理产生重大影响。

DESCRIPTION (provided by applicant): The delivery of large molecular agents into the central nervous system (CNS) via the blood supply is often impossible as the blood brain barrier (BBB) protects the brain tissue from foreign molecules. The factors that determine penetration of substances from the blood to the CNS are lipid solubility, molecular size, and charge. The BBB prevents penetration of ionized water-soluble materials with molecular weight greater than 180 daltons. Thus most of the potential molecular imaging agents cannot reach the brain tissue via the blood supply. A technique that allows these agents to reach the brain tissue will open the door to new possibilities for the diagnosis and monitoring of brain disorders that currently cannot be performed. Laboratory experiments have shown that focused ultrasound beams can be used to noninvasively open the BBB in a highly localized tissue volume deep in the brain. While extensive research on the interaction with ultrasound and the CNS has been performed in animals, the clinical utilization of ultrasound in the brain has been seriously limited by the commonly accepted view that a piece of the skull bone must be removed for the ultra-sound beam to propagate into the brain. This additional procedure makes ultrasound treatments of the brain more complex, hazardous, and expensive. As a result, the effects of ultrasound in the brain have not been widely explored in clinical trials. We have demonstrated that highly focused ultrasound beams can be accurately delivered through an intact human skull noninvasively with a phased array of multiple transducers, thus eliminating the most significant barrier for using focused ultrasound in brain. The overall objective of this research is to combine our ability to deliver focused ultrasound through the intact skull and the method that allows us to use the ultrasound to open the BBB and to develop a device that can be used to open the BBB for molecular imaging agents. The device will be made MRI compatible so that it can be used to target specified anatomic locations in the brain. After the BBB is open, the molecular imaging agent can be injected, and the imaging can be performed using any imaging method. The system required to accurately focus and ultrasound beam is very complicated. While this complexity, as well as the need to shave the head, is acceptable for the targeted treatments, it makes the current system unrealistic for routine diagnostic imaging. The applicants' hypothesis is that the BBB opening can be performed with a much simpler system. Similarly, we estimate that the effect of human hair will most likely be reduced with our proposed approach. There is currently no date using the proposed ultrasound exposures for BBB opening. We propose to use the combined R21/R33 mechanisms to first establish the feasibility and then to develop a method for a relatively simple device to selectively open the BBB for molecular imaging. A successful implementation of this method will make many new molecular imaging approaches possible in brain. The development of even one such imaging method for routine clinical use would have a major impact on patient care.