Ultrasound-induced blood-brain/tumor barrier disruption in brain metastases

脑转移中超声诱导的血脑/肿瘤屏障破坏

• 批准号: 8506197
• 负责人: Ferenc A Jolesz
• 金额: $ 39.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-05 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506197
• 关键词: Ablation; Animals; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain Neoplasms; Breast Cancer Cell; Caring; Central Nervous System Diseases; Clinical; Clinical Trials; Contrast Media; Cranial Irradiation; Data; Devices; Dose; Drug Delivery Systems; ERBB2 gene; Effectiveness; FDA approved; Focused Ultrasound Therapy; Goals; Grant; Growth; Hour; Image; Instruction; Lead; Life; Magnetic Resonance Imaging; Metastatic malignant neoplasm to brain; Methods; Microbubbles; Modeling; Monoclonal Antibodies; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Outcome; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Radiation; Radiation therapy; Rattus; Relapse; Relative (related person); Research; Roche brand of trastuzumab; Safety; Site; System; Techniques; Technology; Testing; Tissues; Tracer; Trastuzumab; Tyrosine Kinase Inhibitor; Ultrasonography; Work; base; chemotherapy; clinical efficacy; comparative efficacy; cranium; efficacy testing; erbB-2 Receptor; expectation; improved; lapatinib; malignant breast neoplasm; nonhuman primate; outcome forecast; patient population; receptor; safety testing; small molecule; sound; tumor

When ultrasound bursts are combined with a circulating microbubble agent, a temporary disruption in the blood-brain barrier (BBB) is induced that lasts for several hours. This procedure, when combined with ultra- sound devices that can accurately and safely focus an ultrasound beam through the intact skull, has a great potential as a completely noninvasive and targeted method to deliver drugs to the brain. Numerous animal studies have shown that this method does not produce any significant damage to the brain and can also in- crease the permeability of tumor blood vessels. While this technology has potential for a wide range of brain disorders, we think it is likely that initial tests of the method will be in brain tumors. Brain metastases, for which there may already exist drugs that are effective outside the brain, may be a good target to test clinical efficacy. This project aims to perform studies that are needed before we can start a clinical trial to test the efficacy of BBB and blood-tumor barrier disruption for targeted drug delivery in brain tumors. We are aiming to be ready to test the efficacy of this technique in breast cancer brain metastases patients, and we have tai- lored the research around that application. We will perform three studies that evaluate safety and effective- ness of focused ultrasound induced BBB disruption under scenarios we will encounter in a clinical trial. First, we will evaluate the relative efficacy of the two currently-approved agents for treating HER2-positive breast cancer, trastuzumab (Herceptin(R)) and lapatinib (Tykerb(R)). Next, we will evaluate the safety and effectiveness of inducing BBB disruption in the brain and in brain tumors after radiation therapy, a scenario that we expect to encounter in patients. Finally, we will test the safety of repeatedly disrupting extensive volumes in the brain in nonhuman primates using a clinical MRI-guided transcranial focused ultrasound system. These is- sues all need to be resolved before initiating clinical trials. At the end of the grant, we expect to have the data necessary to begin clinical trials on the efficacy of this promising image-guided targeted drug delivery method. RELEVANCE (See instructions); Ineffective drug delivery caused by the blood-brain barrier, limited permeability of tumor blood vessels, and other factors are thought to lead to the poor outcomes of patients with breast cancer metastases in the brain. Focused ultrasound, when combined with a microbubble agent, offers a noninvasive method to get around these barriers and deliver effective doses of drugs to the brain and to brain tumors. Here we will perform the work needed before we can begin clinical trials evaluating the efficacy of this method.

当超声脉冲与循环微泡剂相结合时， 血脑屏障(BBB)被诱导，持续几个小时。这一过程，当与超 音响设备可以准确和安全地聚焦超声束穿过完整的头骨，具有很好的 有可能成为一种完全非侵入性的、有针对性地将药物输送到大脑的方法。数量众多的动物 研究表明，这种方法不会对大脑造成任何重大损害，而且还可以- 增加肿瘤血管的通透性。虽然这项技术具有广泛的大脑潜力 我们认为，这种方法的初步测试很可能会在脑瘤中进行。脑转移瘤，对于 可能已经存在的在脑外有效的药物，可能是一个很好的临床测试目标 功效。这个项目的目的是在我们可以开始临床试验之前进行必要的研究，以测试 血脑屏障和血-肿瘤屏障破坏对脑肿瘤靶向给药的疗效。我们正在瞄准 准备在乳腺癌脑转移患者中测试这项技术的疗效，我们已经有了TAI- 失去了围绕这一应用程序的研究。我们将进行三项评估安全性和有效性的研究- 在我们将在临床试验中遇到的情况下，聚焦超声的NESS导致了血脑屏障的破坏。第一, 我们将评估目前批准的两种药物治疗HER2阳性乳房的相对疗效。 癌症、曲妥珠单抗(Herceptin(R))和拉帕替尼(Tykerb(R))。接下来，我们将对其安全性和有效性进行评估。 在放射治疗后导致大脑和脑瘤中血脑屏障中断的可能性，这是我们预期的情况 在病人身上遇到。最后，我们将测试重复中断大量卷的安全性 临床核磁共振引导经颅聚焦超声系统在非人灵长类动物大脑中的应用。这些是- 在启动临床试验之前，所有诉讼都需要得到解决。在拨款结束时，我们预计会有数据 有必要开始对这种前景看好的图像导向靶向药物输送的有效性进行临床试验 方法。 相关性(见说明)； 血脑屏障、肿瘤血管通透性有限导致的药物传递无效，以及 其他因素被认为是导致乳腺癌脑转移患者预后较差的原因。 当聚焦超声与微泡剂相结合时，提供了一种非侵入性的走动方法。 这些障碍并将有效剂量的药物输送到大脑和脑瘤。在这里，我们将表演 在我们可以开始临床试验评估这种方法的有效性之前，还需要做一些工作。