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: 10308675
• 负责人: Monica Smith Pearl
• 金额: $ 20.74万
• 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/10308675
• 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.

项目总结