Translational use of focused ultrasound to increase blood-tumor barrier permeability as a mechanism to increase drug accumulation into brain metastases of breast cancer

转化使用聚焦超声来增加血液肿瘤屏障通透性，作为增加乳腺癌脑转移药物积累的机制

• 批准号: 10305088
• 负责人: Tasneem Arsiwala
• 金额: $ 4.3万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305088
• 关键词: ABCG2 gene; Acute; Alzheimer' s disease model; Animals; Bioluminescence; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Neoplasms; Breast; Breast cancer metastasis; Cells; Cerebrum; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Distribution; Clinical Trials; Consensus; Cytotoxic agent; Data; Diagnosis; Disease; Dose; Drug Approval Processes; Drug Kinetics; Endothelial Cells; Excision; Focused Ultrasound; Focused Ultrasound Therapy; Genus Hippocampus; Glioma; Goals; Hospitals; Hour; Human; Human Pathology; Intervention; Investigation; Lesion; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mechanics; Mediating; Metalloproteases; Metastatic malignant neoplasm to brain; Mitochondria; Modeling; Mus; Neoplasm Metastasis; Neurologic Symptoms; Operative Surgical Procedures; Outcome; Paclitaxel; Pathology; Patients; Permeability; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Property; Proteins; Publishing; Radiation; Radiation therapy; Research; Signal Transduction; Skin; Sonication; Stroke; Technology; Therapeutic; Tight Junctions; Time; Transducers; Translating; Translations; Trastuzumab; Trauma; Ultrasonic wave; Vascular Endothelial Cell; Vascular Permeabilities; Western Blotting; Woman; Work; blood-brain barrier permeabilization; blood-brain tumor barrier; burden of illness; chemotherapy; clinical effect; clinically relevant; cytotoxic; cytotoxicity; genetic regulatory protein; improved; insight; malignant breast neoplasm; nervous system disorder; novel therapeutic intervention; palliative; pre-clinical; protein expression; response; standard of care; success; traditional therapy; transcriptome; transcriptome sequencing; treatment response; tumor; tumor progression

Project Summary: Once a cancer has disseminated approximately 20% of the time it will go to brain. The most common brain metastases originate from lung, breast and or skin. Brain metastases often are often not diagnosed until neurological symptoms are pronounced, which usually indicates a significant disease burden. Traditional therapy including surgical resection and radiation therapy have a low degree of efficacy as evidenced by a low two-year survival of 8.1%. The blood-tumor barrier (BTB) while disrupted compared to the blood-brain barrier, remains a physicochemical barrier limiting effective drug accumulation in 90% of lesions. Our long-term goal is to temporarily disrupt the BTB and enhance drug accumulation within metastatic brain lesions. We hypothesize that disruption of the BTB will allow drugs to accumulate at cytotoxic concentrations within the lesions, increasing chemotherapeutic efficacy and prolonging overall survival. Transcranial low intensity focused ultrasound (LiFUS) has been previously used in neurological disorders to non-invasively increase drug accumulation within the brain using increased paracellular transport between endothelial cells. In this study, we propose the investigation of LiFUS exposure on BTB permeability of standard chemotherapies in order to increase tumor cytotoxicity and survival in mice. To do this, we first need to control LiFUS mediated BTB disruption. The first specific aim will elucidate key LiFUS parameters including cavitation dose, power and duration on BTB permeability as well as brain/lesion accumulation of chemotherapeutics. Survival and tumor progression will also be measured using this model, with weekly treatments being completed. The second specific aim will elucidate potential long-term vascular changes induced by the ultrasound waves. Specifically, we will evaluate five proteins that are integral to the BTB, over five time points (24h – 7d), with two doses cavitation doses in naive and treated animals. Two efflux transporters (P-gp, BCRP) will be evaluated for expression and the ability to efflux substrates. Three tight junction proteins will be evaluated for expression and localization. Together, these two phases will potentially provide a novel therapeutic strategy for treating metastatic CNS lesions and understanding the effect of LiFUS on the underlying vascular mechanisms.

项目摘要：一旦癌症分散了大约20％的时间 脑。最常见的脑转移来自肺，乳房和或皮肤。脑 在神经系统症状发音之前，通常不会被诊断出来，这 通常表明伯恩患有重大疾病。传统疗法包括手术切除 辐射疗法的效率程度较低，这是由低两年的生存率的 8.1％。与血脑屏障相比，血液肿瘤屏障（BTB）被干扰， 仍然是限制90％病变中有效药物积累的物理障碍。我们的 长期目标是暂时破坏BTB并增强药物积累 转移性脑病变。我们假设BTB的破坏将允许药物 在病变内以细胞毒性浓度积聚，提高了化学治疗效率 并延长总体生存。经颅低强度聚焦超声（LIFUS）已是 以前用于神经系统疾病，可无创地增加药物的积累 大脑使用内皮细胞之间的细胞细胞转运增加。在这项研究中，我们 提案对标准化学疗法的BTB渗透性的LIFUS暴露投资投资 为了增加小鼠的肿瘤细胞毒性和存活。为此，我们首先需要控制 Lifus介导的BTB破坏。第一个特定目的将阐明关键Lifus参数 包括空化剂量，BTB通透性的功率和持续时间以及大脑/病变 化学治疗药的积累。还将测量生存和肿瘤进展 使用此模型，每周治疗完成。第二个特定目标将 阐明超声波引起的潜在长期血管变化。具体来说， 我们将评估五种与BTB不可或缺的蛋白质，超过五个时间点（24h - 7d） 幼稚和治疗的动物中的两剂气量剂量。两个外排转运蛋白（P-GP，BCRP） 将评估表达和排出底物的能力。三个紧密连接蛋白 将评估表达和本地化。一起，这两个阶段将有可能 提供了一种新型的热策略来治疗转移性中枢神经系统病变并了解 生物对潜在血管机制的影响。