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.

当超声波爆发与循环微泡剂结合时，会暂时破坏