Bevacizumab Delivery to Glioblastoma with MR-Guided Focused Ultrasound

描述（申请人提供）：多形性胶质母细胞瘤（GBM）是最常见的原发性脑癌，5年生存率仅为12%。由于血脑屏障（BBB），化疗药物到达大脑的浓度非常低，因此GBM患者预后不佳是很常见的。可生物降解聚合物植入物和对流增强输送方法绕过血脑屏障，但它们只导致生存的适度改善。幸运的是，最近用抗血管生成药物贝伐单抗（人源抗vegf IgG）治疗GBM的临床试验显示出了希望，导致其被FDA批准用于GBM治疗。然而，众所周知，IgG分子（~ 150kd M.W.）不容易通过血脑屏障，这表明目前的贝伐单抗治疗远非最佳。在本提案中，我们的目标是通过开发一种创新的图像引导方法来改善贝伐单抗治疗GBM，该方法将允许血脑屏障在明确的位置向IgG分子开放。脉冲1 MHz聚焦超声（FUS）将应用于静脉注射超声造影剂微泡（mb）后的mr靶向GBMs。我们的初步研究表明，用1mhz的FUS激活BBB会导致BBB的声穿孔，而不会造成机械或热损伤。我们将使用两个具体目标来开发这种方法。所有的研究都将使用rnu/rnu裸鼠颅内人类Hs683肿瘤异种移植。在目的1中，对于给定的MB直径，我们将定义低FUS压力阈值，当此阈值时血脑屏障向钆开放，而在高FUS压力阈值时，热组织损伤和/或微血管损伤可能开始发生。这些FUS压力阈值将用作确定最佳FUS和MB直径参数的指南，以便将荧光示踪剂IgG分子通过血脑屏障传递到Hs683肿瘤。在Aim 2中，这些最佳的FUS和MB参数将用于确定与标准静脉给药相比，mr引导的FUS和MB靶向递送贝伐单抗到颅内脑肿瘤中是否能显著抑制肿瘤生长。如果这些临床前研究成功，我们将很好地将其转化为临床试验。PI是UVa FUS中心的研究主任，该中心拥有insighttec exabelate mr制导头部和身体FUS系统。我们的下一步计划是在大型动物模型上验证FUS和MB治疗血脑屏障打开的安全性。随后将启动临床试验。在弗吉尼亚大学，涉及FUS应用于大脑的临床试验已被批准用于其他适应症，因此在我们机构翻译他的工作有一个明确的先例。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common primary brain cancer, has a 5-year survival rate of only 12%. Poor outcomes are commonplace for GBM patients because chemotherapeutic drugs reach the brain in very low concentrations due to the blood brain barrier (BBB). Biodegradable polymer implants and convection-enhanced delivery approaches circumvent the BBB, but they have only led to moderate improvements in survival. Fortunately, recent clinical trials for GBM with the anti-angiogenesis drug bevacizumab (humanized anti-VEGF IgG) have shown promise, leading to its approval by the FDA for GBM treatment. However, it is also well known that IgG molecules (~150 kD M.W.) do not easily pass through the BBB, suggesting that current bevacizumab treatment is far from optimal. In this proposal, we aim to improve GBM treatment with bevacizumab through the development of an innovative image guided approach that will permit BBB opening to IgG molecules in well-defined locations. Pulsed 1 MHz focused ultrasound (FUS) will be applied to MR-targeted GBMs following the intravenous administration of ultrasound contrast agent microbubbles (MBs). Our pilot studies indicate that the activation of MBs with 1 MHz FUS leads to sonoporation of the BBB without mechanical or thermal damage. We will use 2 specific aims to develop this approach. All studies will use rnu/rnu nude rats with intracranial human Hs683 tumor xenografts. In Aim 1, for given MB diameters, we will define lower FUS pressure thresholds at which the BBB opens to gadolinium and upper FUS pressure thresholds at which thermal tissue injury and/or microvessel damage may begin to occur. These FUS pressure thresholds will then be used as guides for determining optimal FUS and MB diameter parameters for delivering fluorescent tracer IgG molecules across the BBB to Hs683 tumors. In Aim 2, these optimal FUS and MB parameters will be used to determine whether the targeted delivery of bevacizumab to intracranial brain tumors with MR-guided FUS and MBs significantly inhibits tumor growth when compared to standard intravenous administration of the drug. If these pre-clinical studies are successful, we are well positioned for translation to clinical trials. The PI is the Research Director of the UVa FUS Center, which houses InSightec Exablate MR-Guided head and body FUS systems. Our next step for this project would be to verify the safety of the FUS and MB procedures for BBB opening in a large animal model. This would be followed by the initiation of a clinical trial. Clinical trials involving FUS application to the brain have been approved for othr indications at UVa, so there is a clear precedent for translation of his work at our institution.