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影响，因此通过血液供应将大分子药物递送到中枢神经系统（CNS）中通常是不可能的。决定物质从血液渗透到CNS的因素是脂溶性、分子大小和电荷。BBB防止分子量大于180道尔顿的离子化水溶性物质渗透。因此，大多数潜在的分子成像剂不能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。实验室实验表明，聚焦超声波束可用于无创地打开大脑深处高度局部化组织体积中的BBB。虽然已经在动物中进行了关于超声与CNS相互作用的广泛研究，但是超声在脑中的临床应用受到普遍接受的观点的严重限制，该观点认为必须去除一块颅骨以使超声束传播到脑中。 这种额外的程序使得大脑的超声治疗更加复杂，危险和昂贵。因此，超声波对大脑的影响尚未在临床试验中得到广泛研究。我们已经证明，高度聚焦的超声波束可以准确地通过一个完整的人类颅骨无创地与多个换能器的相控阵列，从而消除了最重要的障碍，在大脑中使用聚焦超声。本研究的总体目标是将我们通过完整颅骨提供聚焦超声的能力与允许我们使用超声打开BBB的方法相结合，并开发一种可用于打开BBB的分子成像剂的装置。该器械将与MRI兼容，以便其可用于靶向大脑中的特定解剖位置。在BBB开放后，可以注射分子成像剂，并且可以使用任何成像方法进行成像。要求系统精确聚焦和超声束是非常复杂的。虽然这种复杂性以及剃光头的需要对于靶向治疗是可接受的，但它使得当前系统对于常规诊断成像是不现实的。申请人的假设是，可以用简单得多的系统进行BBB打开。同样，我们估计，人类头发的影响很可能会减少我们提出的方法。目前尚无使用拟定超声暴露打开血脑屏障的日期。我们建议使用组合的R21/R33机制，首先建立可行性，然后开发一种相对简单的装置来选择性地打开BBB用于分子成像的方法。 该方法的成功实施将使许多新的脑分子成像方法成为可能。 即使是一种常规临床使用的成像方法的开发也会对患者护理产生重大影响。

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.