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， 选择为了检验这些假设，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。

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.