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（由申请人提供）：最常见的原发性脑癌多形胶质母细胞瘤（GBM）的生存率仅为12％。对于GBM患者而言，不良预后是司空见惯的，因为由于血脑屏障（BBB），化学治疗药物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递送方法规避了BBB，但它们只会导致生存的适度改善。幸运的是，最近对GBM进行抗血管生成药物贝伐单抗（人源化抗VEGF IgG）的临床试验显示了有望，从而获得了FDA对GBM治疗的批准。但是，众所周知，IgG分子（〜150 kD M.W.）不容易通过BBB，这表明当前的贝伐单抗治疗远非最佳。在此提案中，我们旨在通过开发创新的图像指导方法来改善贝伐单抗的GBM治疗，该方法将允许在定义明确的位置向IgG分子开放BBB。静脉内施用超声对比剂微泡（MBS）后，脉冲1 MHz的浓缩超声（FUS）将应用于MR靶向的GBMS。我们的试点研究表明，具有1 MHz FUS的MBS激活导致BBB的超声处理而没有机械或热损伤。我们将使用2个特定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AIM 1中，对于给定的MB直径，我们将定义较低的FUS压力阈值，在该阈值中，BBB向Gadolinium和上FUS压力阈值打开，其中可能会发生热组织损伤和/或微血管损伤。然后，这些FUS压力阈值将用作确定最佳的FUS和MB直径参数的指南，用于在BBB上传递荧光示踪IgG分子至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内给药相比，用MR引导的FUS和MB的靶向递送是否具有MR引导的FUS和MB的颅内脑肿瘤是否会显着抑制肿瘤的生长。如果这些临床前研究是成功的，那么我们就可以很好地转化为临床试验。 PI是UVA FUS中心的研究主任，该中心设有Insightec，可提供MR引导的头部和身体FUS系统。该项目的下一步是验证大型动物模型中BBB开放的FUS和MB程序的安全性。随后将进行临床试验。在UVA的OTHR指示已批准涉及大脑的FUS应用的临床试验，因此在我们机构的工作中有明显的先例。