Bevacizumab Delivery to Glioblastoma with MR-Guided Focused Ultrasound

通过 MR 引导聚焦超声将贝伐珠单抗递送至胶质母细胞瘤

• 批准号: 8628120
• 负责人: Richard J. Price
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628120
• 关键词: Address; Aftercare; Animal Model; Animals; Antibodies; Avastin; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Brain Neoplasms; Caliber; Cells; Clinical Trials; Confocal Microscopy; Contrast Media; Convection; Development; Diffusion; Drug Targeting; Endothelium; Equipment; Excision; FDA approved; Fluorescence; Focused Ultrasound Therapy; Gadolinium; Glioblastoma; Growth; Head; Heating; Histology; Housing; Human; Image; Imagery; Immunoglobulin G; Implant; Injury; Institution; Intravenous; Liquid substance; Location; Luciferases; Magnetic Resonance Imaging; Malignant neoplasm of brain; Measurement; Mechanics; Methods; Microbubbles; Microbubbles Ultrasound Contrast Medium; Molecular; Nude Rats; Outcome; Patients; Perfusion; Pharmaceutical Preparations; Physiologic pulse; Pilot Projects; Positioning Attribute; Primary Neoplasm; Procedures; Radial; Rattus; Reporter Genes; Research; Safety; Surface; Survival Rate; System; Testing; Time; Tissues; Tracer; Translations; Treatment Efficacy; Tumor Angiogenesis; Ultrasonography; Unresectable; Work; Xenograft procedure; antiangiogenesis therapy; base; bevacizumab; biodegradable polymer; bioluminescence imaging; brain tissue; cancer therapy; chemotherapy; gadolinium oxide; implantation; improved; innovation; intravenous administration; minimally invasive; nanoparticle; neoplastic cell; new technology; preclinical study; pressure; public health relevance; sonoporation; targeted delivery; tumor; tumor growth; tumor xenograft

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.

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是最常见的原发脑癌，5年生存率仅为12%。对于GBM患者来说，预后较差是司空见惯的，因为化疗药物由于血脑屏障(BBB)而以非常低的浓度到达大脑。可生物降解的聚合物植入物和对流增强的输送方法绕过了血脑屏障，但它们只导致了存活率的适度改善。幸运的是，最近使用抗血管生成药物贝伐单抗(人源化抗血管内皮生长因子抗体)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，免疫球蛋白分子(~150kD M.W.)不要轻易通过血脑屏障，这表明目前贝伐单抗的治疗远非最佳。在这项建议中，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对GBM的治疗，这种方法将允许BBB在明确的位置向Ig G分子开放。在静脉注射超声造影剂微泡(MBS)后，脉冲1 MHz聚焦超声(FUS)将被应用于MR靶向的GBM。我们的初步研究表明，用1 MHz FUS激活MBS可以导致BBB的声学修饰，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此方法。所有研究都将使用rNU/rnu裸鼠移植人Hs683人颅内肿瘤。在目标1中，对于给定的MB直径，我们将定义下FUS压力阈值和上FUS压力阈值，在该阈值下，血脑屏障向Gd开放，在该压力阈值下，热组织损伤和/或微血管损伤可能开始发生。这些FUS压力阈值将被用作确定最佳FUS和MB直径参数的指南，以通过BBB将荧光示踪剂IgG分子输送到Hs683肿瘤。在目标2中，这些最佳的FUS和MB参数将被用来确定与标准静脉给药相比，通过MR引导的FUS和MBS将贝伐单抗定向递送到颅内脑瘤是否显著抑制肿瘤生长。如果这些临床前研究成功，我们就可以很好地将其转化为临床试验。PI是UVA FUS中心的研究总监，该中心拥有InSightec ExAblate MR引导的头部和身体FUS系统。我们这个项目的下一步将是在一个大型动物模型中验证FUS和MB程序对BBB开放的安全性。随后将启动临床试验。涉及FUS应用于大脑的临床试验已被批准用于UVA的其他适应症，因此他的工作在我们机构的翻译有明显的先例。