Enhanced intra-arterial drug delivery to the brain after blood brain barrier opening: comparison between osmotic and MRI-guided focused ultrasound opening techniques

血脑屏障开放后增强动脉内药物向大脑的输送：渗透和 MRI 引导聚焦超声开放技术之间的比较

• 批准号: 10040794
• 负责人: Monica Smith Pearl
• 金额: $ 24.93万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040794
• 关键词: Address; Adoption; Adult Glioblastoma; Animals; Area; Autopsy; Biodistribution; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Brain Stem Neoplasms; Catheters; Central Nervous System Neoplasms; Childhood; Clinical Protocols; Complex; Control Animal; Control Groups; Deposition; Diffuse intrinsic pontine glioma; Drug Delivery Systems; Drug Targeting; Firefly Luciferases; Fluoroscopy; Focused Ultrasound; Gadolinium; Glioma; Half-Life; Hour; Image; Immunocompetent; Infiltrative Growth; MRI Scans; Magnetic Resonance Imaging; Malignant neoplasm of brain; Mannitol; Measures; Mediating; Methods; Modeling; Monoclonal Antibodies; Mus; Natural History; Oncology; Operative Surgical Procedures; Outcome; Pattern; Perfusion; Pharmaceutical Preparations; Positron-Emission Tomography; Radiation therapy; Radioisotopes; Radiolabeled; Reporting; Reproducibility; Retinoblastoma; Roentgen Rays; Route; Safety; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Tumor Volume; X-Ray Computed Tomography; base; bevacizumab; cancer therapy; cellular engineering; chemotherapeutic agent; chemotherapy; drug distribution; effective therapy; experimental group; follow-up; head-to-head comparison; human model; image guided; imaging platform; improved; innovation; macromolecule; mouse model; multimodality; new technology; novel; primary outcome; response; targeted treatment; treatment response; treatment strategy; tumor; tumor growth

Project Summary Intra-arterial chemotherapy (IAC) converts systemic chemotherapy into a targeted therapeutic strategy that has revolutionized retinoblastoma treatment. For decades, the IAC approach has attempted to similarly transform brain cancer treatment; however, despite high hopes and many recognized advantages, IAC outcomes proved highly variable, if not outright discouraging. Over the last decade, our group has focused on identifying and addressing the impediments to effective IAC for brain tumors. Spatial image-guided control of chemotherapeutic perfusion throughout the entire tumor and manipulation of the blood brain barrier (BBB) with high spatial and temporal precision are fundamental challenges that we will to continue to address in this proposal. Our approach with IAC is particularly relevant to brainstem tumors and other highly aggressive, unresponsive brain tumors, for which surgery, radiotherapy, stereotactic drug delivery, and systemic chemotherapy, have failed to show an overall survival benefit. Most tumors have regions of BBB integrity and, in some gliomas, such as diffuse intrinsic pontine glioma (DIPG), the BBB is predominantly intact. The BBB, which effectively blocks nearly all therapeutic agents to brain tumors, represents a formidable challenge, and in order to fully exploit the potential of IAC, it must be performed in conjunction with BBB opening (BBBO). Several methods of BBBO have been developed and two dominant techniques represent compelling adjuncts for enhancing IAC efficacy. Osmotic BBB opening (OBBBO) via intra-arterial (IA) mannitol is used in clinical protocols that have remained essentially unchanged since the late 1970s. Inconsistent results and imprecise BBBO have hindered the widespread adoption of this method, which was performed solely under x- ray guidance. We have previously demonstrated that OBBBO and IA drug delivery under MRI guidance is essential, as it allows one to predict, adjust, and visualize BBBO in real-time. Precise control of the OBBBO territory, however, may be challenging, reflecting the brain’s complex and dynamic angioarchitecture. MRI-guided focused ultrasound (MRgFUS) has emerged as a new technology capable of BBBO in a highly spatially precise manner, yet the utility of and its full therapeutic potential when used with IAC remains uninvestigated. We hypothesize that IAC after MRgFUS BBBO is a safe and efficacious technique with more consistent and effective drug delivery to the targeted brain area vs. IAC after mannitol mediated OBBBO. The absence of effective treatment options for brainstem tumors and other highly aggressive, unresponsive CNS tumors promotes the use of novel multimodality methods to enhance drug delivery to the brain. We will address in a head-to-head comparison of MRgFUS vs. osmotic BBBO whether MRgFUS is comparable or superior to the established osmotic technique in regards to safety, tolerability, and efficacy of IAC after BBBO.

项目摘要 动脉内化疗（IAC）将全身化疗转化为靶向治疗策略 这彻底改变了视网膜母细胞瘤的治疗方法。几十年来，IAC的方法一直试图类似地 改变脑癌治疗;然而，尽管寄予厚望和许多公认的优势，IAC 事实证明，结果即使不是完全令人沮丧，也是大相径庭。在过去的十年里，我们的团队专注于 识别和解决对脑肿瘤有效的IAC的障碍。空间图像制导控制 在整个肿瘤中进行化疗灌注并操纵血脑屏障（BBB） 高空间和时间精度是我们在这方面将继续应对的基本挑战， 提议我们对IAC的治疗方法与脑干肿瘤和其他高度侵袭性， 无反应的脑肿瘤，手术，放疗，立体定向药物输送，和全身 化疗未能显示出总体生存益处。大多数肿瘤具有BBB完整性的区域， 在一些神经胶质瘤如弥漫性内在脑桥神经胶质瘤（DIPG）中，BBB主要是完整的。BBB， 其有效地阻断几乎所有脑肿瘤的治疗剂，代表了一个巨大的挑战， 为了充分发挥IAC的潜力，它必须与BBB开放（BBBO）结合进行。 已经开发了几种BBBO方法，其中两种主要技术代表了引人注目的 增强IAC功效的药物。通过动脉内（IA）甘露醇的渗透性BBB开放（OBBBO）用于 自20世纪70年代末以来基本保持不变的临床方案。不一致的结果和 不精确的BBBO阻碍了该方法的广泛采用，该方法仅在x- 射线制导我们之前已经证明，在MRI引导下的OBBBO和IA药物递送是有效的。 这是必不可少的，因为它允许人们实时预测，调整和可视化BBBO。OBBBO的精确控制 然而，这一领域可能具有挑战性，反映了大脑复杂而动态的血管结构。 MRI引导的聚焦超声（MRgFUS）已经成为一种能够在一个特定的时间段内进行BBBO的新技术。 高度空间精确的方式，但当与IAC一起使用时，其效用及其全部治疗潜力仍然存在 未经调查我们假设MRgFUS BBBO后的IAC是一种安全有效的技术， 甘露醇介导的OBBBO后，与IAC相比，向靶向脑区域的药物递送一致且有效。 脑干肿瘤和其他高度侵袭性， 无反应的CNS肿瘤促进了新的多模态方法的使用，以增强药物递送到 个脑袋我们将在MRgFUS与渗透性BBBO的头对头比较中解决MRgFUS是否是 在安全性、耐受性和有效性方面与已确立的渗透技术相当或上级 BBBO之后的IAC。