Noninvasive monitoring of brain tumor development with focused ultrasound and extracellular vesicles

利用聚焦超声和细胞外囊泡无创监测脑肿瘤的发展

• 批准号: 10159901
• 负责人: Nathan J. McDannold
• 金额: $ 51.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159901
• 关键词: Address; Angiogenesis Inhibitors; Bilateral; Biological Process; Biopsy; Blood; Blood - brain barrier anatomy; Brain Neoplasms; Cancer Patient; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Disease; Drug Delivery Systems; Drug resistance; Ear; Early Diagnosis; Evaluation; Family; Flow Cytometry; Focused Ultrasound; Glioblastoma; Glioma; Goals; Growth; Human; Image; Image Cytometry; Implant; Intravenous; Label; Lead; Lipids; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Membrane; Methods; MicroRNAs; Microbubbles; Modeling; Monitor; Morbidity - disease rate; Mus; Nature; Nucleic Acids; Pathology; Patients; Peat; Permeability; Physiologic pulse; Plasma; Primary Brain Neoplasms; Procedures; Proteins; Rattus; Recurrence; Resolution; Role; Sampling; Staging; Stream; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Tumor Markers; Tumor stage; Ultrasonography; Vesicle; anticancer research; blood-brain tumor barrier; chemotherapy; circulating biomarkers; clinical examination; cranium; exosome; extracellular vesicles; implantation; improved; innovation; millimeter; nanoparticle; non-invasive monitor; novel diagnostics; novel therapeutics; potential biomarker; pressure; research clinical testing; response; temozolomide; tool; treatment response; tumor; tumor heterogeneity; zeta potential

Project Summary Glioblastoma multiforme is the most common primary brain tumor and one of the deadliest of human cancers. Early diagnosis and sensitive therapeutic monitoring remain major challenges in the treatment of this disease. Monitoring of tumor development and therapeutic interventions largely relies on clinical evaluation and MRI. However, both clinical examination and MRI are insensitive measures of disease status. For example, MRI resolution is limited to the order of millimeters, which translates to a significant delay before a tumor can be detected. While biopsies are valuable, they are invasive and can result in significant morbidity. Less invasive platforms for early diagnostic and therapeutic monitoring are desperately needed. Within the past two decades, extracellular vesicles have emerged as important regulators of a diverse range of biological processes in dif- ferent pathologies including brain cancer. These vesicles are a family of membrane-enveloped nanoparticles with diverse biological function, diagnostic potential, and therapeutic applications. These vesicles are typically <1000 nm in size and are present in blood at concentrations of up to 1000 vesicles/mL in cancer patients. They have been shown to contain tumor-specific nucleic acids, proteins, and lipid cargoes and appear highly en- riched with cancer-specific miRNA. Extracellular vesicles as circulating biomarkers are one of the most promis- ing new diagnostic and therapeutic paradigms in cancer research. Extracellular vesicles include two major frac- tions (exosomal and microparticles) differing by size, cargoes, and functional role. Both fractions can serve as potential biomarkers for diagnosis, staging, and monitoring of therapeutic interventions. A major limitation of using extracellular vesicles for diagnosis and monitoring of brain tumors is the relatively low proportion of tu- mor-specific extracellular vesicles, in plasma samples in particular large size extracellular vesicles fraction (mi- croparticles) due to the presence of blood-brain barrier (BBB) and blood-tumor barrier (BTB). To address this challenge, we will use ultrasound bursts combined with circulating microbubbles to temporarily disrupt these barriers and unique approach to analyze a presence of all extracellular vesicles fractions including larger size microparticle fraction in the plasma. This procedure, which can be performed using ultrasound devices that ac- curately and safely focus an ultrasound beam through the human skull, has a great potential as a noninvasive and targeted method to disrupt BBB/BTB for drug delivery. Here will instead use it to increase the presence of extracellular vesicles large-size fractions in the patient's plasma. Combined with analysis of the tumor-specific extracellular vesicles in plasma samples, this technology could be a powerful tool for both the diagnosis and treatment of brain tumors – a noninvasive biopsy. To reach this goal, we will perform extensive studies in mu- rine glioma models to optimize the procedure and evaluate it during different tumor stages. If the proposed ex- periments are successful, we will have compelling evidence that may lead to human trials.

项目摘要 多形胶质母细胞瘤是最常见的原发性脑肿瘤，也是最致命的人类癌症之一。 早期诊断和敏感的治疗监测仍然是治疗该疾病的主要挑战。 肿瘤发育和治疗干预措施的监测主要依赖于临床评估和MRI。 但是，临床检查和MRI都是对疾病状况的不敏感测量。例如，MRI 分辨率仅限于毫米的顺序，在肿瘤可能是明显的延迟之前 检测到。虽然活检是有价值的，但它们具有侵入性，可能导致明显的发病率。侵入性较小 迫切需要进行早期诊断和治疗监测的平台。在过去的二十年中， 细胞外蔬菜已成为潜水员生物过程的重要调节剂 包括脑癌在内的病理。这些蔬菜是膜开发的纳米颗粒家族 具有潜水员的生物学功能，诊断潜力和治疗应用。这些蔬菜通常是 在癌症患者中，大小<1000 nm的大小，以多达1000蔬菜/mL的浓度出现在血液中。他们 已显示包含肿瘤特异性核酸，蛋白质和脂质货物，并且看起来很高 富含癌症特异性miRNA。细胞外蔬菜作为循环生物标志物是最有希望的一种 - 在癌症研究中创造了新的诊断和治疗范例。细胞外蔬菜包括两个主要的冰冻 Tions（外泌体和微粒）因大小，货物和功能作用而有所不同。这两个分数都可以用作 用于诊断，分期和监测治疗干预措施的潜在生物标志物。一个主要限制 使用细胞外蔬菜诊断和监测脑肿瘤是Tu-相对低比例的 在血浆样品中，特定于特异性细胞外蔬菜，特别是大尺寸细胞外蔬菜部分（MI- 由于存在血脑屏障（BBB）和血肿瘤屏障（BTB），因此小片。解决这个问题 挑战，我们将使用超声爆发与循环微泡相结合来暂时破坏这些 障碍和独特的方法来分析所有细胞外蔬菜分数的存在，包括较大尺寸 血浆中的微粒分数。此过程，可以使用超声设备进行执行 巧妙，安全地将超声梁通过人颅骨聚焦，具有无创的巨大潜力 和破坏BBB/BTB进行药物输送的有针对性方法。相反，这里将使用它来增加 细胞外蔬菜在患者的血浆中大尺寸的分数。结合分析肿瘤特异性 血浆样品中的细胞外蔬菜，这项技术可能是诊断和 脑肿瘤的治疗 - 一种无创活检。为了实现这一目标，我们将在Mu-中进行广泛的研究 Rine Glioma模型以优化该过程并在不同的肿瘤阶段进行评估。如果提议的 内部是成功的，我们将有令人信服的证据，这些证据可能会导致人类试验。