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）是最常见的原发性脑癌，其 5 年生存率仅为 12%。 GBM 患者的不良预后很常见，因为由于血脑屏障 (BBB)，化疗药物到达大脑的浓度非常低。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，但它们仅导致了生存率的适度改善。幸运的是，最近使用抗血管生成药物贝伐单抗（人源化抗 VEGF IgG）治疗 GBM 的临床试验显示出良好的前景，FDA 批准其用于 GBM 治疗。然而，众所周知，IgG 分子（~150 kD M.W.）不容易通过 BBB，这表明目前的贝伐单抗治疗远非最佳。在这项提案中，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珠单抗对 GBM 的治疗，该方法将允许 BBB 在明确的位置向 IgG 分子开放。静脉注射超声造影剂微泡 (MB) 后，脉冲 1 MHz 聚焦超声 (FUS) 将应用于 MR 靶向 GBM。我们的初步研究表明，使用 1 MHz FUS 激活 MB 会导致 BBB 发生声孔作用，而不会造成机械或热损伤。我们将使用 2 个具体目标来开发这种方法。所有研究都将使用带有颅内人类 Hs683 肿瘤异种移植物的 rnu/rnu 裸鼠。在目标 1 中，对于给定的 MB 直径，我们将定义 BBB 对钆打开的 FUS 压力下限和可能开始发生热组织损伤和/或微血管损伤的 FUS 压力上限。然后，这些 FUS 压力阈值将用作确定最佳 FUS 和 MB 直径参数的指南，以将荧光示踪剂 IgG 分子穿过 BBB 传递到 Hs683 肿瘤。在目标 2 中，这些最佳 FUS 和 MB 参数将用于确定与标准静脉注射药物相比，通过 MR 引导的 FUS 和 MB 将贝伐单抗靶向递送至颅内脑肿瘤是否显着抑制肿瘤生长。如果这些临床前研究成功，我们就可以很好地转化为临床试验。该 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。我们该项目的下一步是验证 FUS 和 MB 程序在大型动物模型中打开 BBB 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在 UVa 获得批准用于其他适应症，因此我们机构有一个明确的先例来翻译他的工作。