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Novel Image-guided, remote-controlled opening of the blood-brain barrier for systemic brain tumor therapy

新型图像引导远程控制血脑屏障打开系统脑肿瘤治疗

基本信息

批准号：
10220884
负责人：
Akiva Mintz
金额：
$ 28.19万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220884
关键词：
Antitumor Response Area Biological Biological Products Blood - brain barrier anatomy Brain Brain Neoplasms Cells Cessation of life Cyclophosphamide Data Disease Feedback Focused Ultrasound Therapy Frequencies Glioblastoma Goals Heat-Shock Proteins 70 Heating Ideal 1 Immunocompetent Infiltration Infusion procedures Invaded Location Luciferases Malignant - descriptor Malignant Glioma Malignant neoplasm of brain Maximum Tolerated Dose Mediating Methodology Methods Microbubbles Modeling Molecular Target Molecular Weight Normal tissue morphology PET/CT scan Patients Peptides Permeability Pharmaceutical Preparations Primary Brain Neoplasms Primary Neoplasm Production Prognosis Proteins Radiolabeled Rattus Recurrence Reporter Rodent Safety Site Systemic Therapy TNF gene Techniques Temperature Testing Therapeutic Therapeutic Agents Therapeutic Effect Thermometry Time Toxic effect Tropism Ultrasonography United States X-Ray Computed Tomography base blood-brain barrier disruption blood-brain barrier permeabilization blood-brain tumor barrier brain parenchyma brain tissue chemotherapy clinically relevant cytokine drug candidate drug distribution engineered stem cells image guided improved in vivo innovation molecular targeted therapies nanoparticle neoplastic cell novel novel therapeutics prevent promoter real time monitoring remote control selective expression stem cells targeted agent targeted treatment tumor

项目摘要

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a dismal prognosis. The poor prognosis is a direct result of the fact that potentially efficacious therapeutics cannot access all primary tumor and infiltrating GBM cells due to the blood-brain barrier (BBB) or blood-brain tumor barrier (BBTB). Our central hypothesis is that we can use novel high-frequency ultrasound (HIFU)-based techniques to remotely permeabilize the BBB and systemically delivery conventional chemotherapy and novel molecular targeted therapeutics to GBM, especially infiltrating cells that reside in predominantly normal brain. In addition to conventional HIFU techniques, we will use an innovative remote-controllable stem cell-based platform to allow us to non-invasively activate engineered stem cells to produce specific cytokines at the time and site of our choosing. To test these hypotheses, 2 specific aims will be performed: (Specific Aim 1) To demonstrate the feasibility of using image-guided HIFU remote activation to artificially induce TNFα and permeabilize the BBB and thereby allowing systemically administered therapeutics to access invasive GBM cells; (Specific Aim 2) To demonstrate anti-GBM efficacy of novel molecular targeted therapeutics after systemic infusion and HIFU- mediated BBB/BBTB focal permeability. Delivery of therapeutic agents through the BBB specifically to tumor cells but not to the surrounding normal brain tissue offers hope against GBM, an invariably fatal disease. Thus, this proposal has strong translational relevance.

胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性脑肿瘤，预后不良。的预后差是潜在有效的治疗剂不能进入所有原发性肿瘤的直接结果。由于血脑屏障（BBB）或血脑肿瘤屏障（BBTB），肿瘤和浸润性GBM细胞。我们中心假设是，我们可以使用新的高频超声（HIFU）为基础的技术，透化血脑屏障并全身递送常规化疗和新的分子靶向 GBM的治疗剂，特别是主要存在于正常脑中的浸润细胞。除了传统的HIFU技术，我们将使用一种创新的基于干细胞的远程可控平台，我们非侵入性地激活工程干细胞，在我们的时间和地点产生特定的细胞因子。选择为了测试这些假设，将执行2个具体目标：（具体目标1）为了证明利用图像引导的HIFU远程激活来人工诱导TNFα和透化血脑屏障的可行性从而允许全身施用的治疗剂接近侵袭性GBM细胞;（具体目的2）证明了新型分子靶向治疗剂在全身输注和HIFU后的抗GBM功效- 介导的BBB/BBTB局灶通透性。治疗剂通过血脑屏障特异性递送至肿瘤而不是周围的正常脑组织提供了对抗GBM的希望，GBM是一种致命的疾病。因此，在本发明中，这一建议具有很强的翻译相关性。