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

胶质母细胞瘤(GBM)是最常见和最具侵袭性的原发脑肿瘤，预后不良。这个 预后不良的直接原因是，潜在有效的治疗方法不能获得所有初级 肿瘤和由于血脑屏障(BBB)或血脑肿瘤屏障(BBTB)而浸润性的GBM细胞。我们的 中心假设是，我们可以使用基于高频超声(HIFU)的新技术来远程 渗透血脑屏障和全身给药的常规化疗和新型靶向分子 对基底膜的治疗，尤其是主要存在于正常大脑中的浸润性细胞。除了……之外 传统的HIFU技术，我们将使用创新的远程可控干细胞平台，以允许 美国将在我们的时间和地点以非侵入性方式激活工程干细胞以产生特定的细胞因子 选择。为了验证这些假设，将执行两个具体目标：(具体目标1)论证 图像引导高强度聚焦超声远程激活人工诱导肿瘤坏死因子α通透血脑屏障的可行性 从而允许系统管理的治疗方法获得侵袭性的GBM细胞；(具体目标2) 证明新型分子靶向治疗药物在全身输注和HIFU治疗后的抗GBM效果 介导的BBB/BBTB局灶性通透性。通过血脑屏障向肿瘤特异性输送治疗剂 细胞，而不是周围的正常脑组织，提供了对抗GBM的希望，GBM是一种总是致命的疾病。因此， 这项提议具有很强的翻译相关性。

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.