Noninvasive monitoring of brain tumor development with focused ultrasound andextracellular vesicles

项目摘要 多形性胶质母细胞瘤是最常见的原发脑肿瘤，也是人类最致命的癌症之一。 早期诊断和灵敏的治疗监测仍然是该病治疗中的主要挑战。 监测肿瘤的发展和治疗干预在很大程度上依赖于临床评估和MRI。 然而，临床检查和MRI都是对疾病状态不敏感的指标。例如，核磁共振 分辨率被限制在毫米量级，这意味着在肿瘤可以被检查之前有一个显著的延迟 检测到。虽然活组织检查很有价值，但它们是侵入性的，可能会导致严重的发病率。侵入性较小 迫切需要用于早期诊断和治疗监测的平台。在过去的二十年里， 细胞外小泡在不同的生物过程中已成为重要的调节因子。 包括脑癌在内的各种病症。这些囊泡是一类被膜包裹的纳米颗粒。 具有多种生物学功能、诊断潜力和治疗应用。这些小泡通常是 &lt；1000 nm大小，在癌症患者的血液中浓度高达1000个小泡/毫升。他们 已被证明含有肿瘤特异的核酸、蛋白质和脂类物质，并且看起来高度集中。 富含癌症特异的miRNA。胞外囊泡作为循环的生物标志物是最重要的促进剂之一。 癌症研究中的新诊断和治疗范例。胞外小泡包括两个主要的裂口-- 根据大小、货物和功能作用的不同而不同的部分(外体和微粒)。这两个分数都可以用作 潜在的用于诊断、分期和监测治疗干预措施的生物标志物。的一个主要限制 利用细胞外小泡进行脑肿瘤的诊断和监测，在脑肿瘤的诊断和监测中所占比例较低。 MOR特异的胞外小泡，在血浆样本中，特别是大尺寸胞外小泡部分(mi-1)。 由于血-脑屏障(BBB)和血-肿瘤屏障(BTB)的存在而导致的疾病。要解决这个问题 挑战，我们将使用超声脉冲和循环微泡来暂时破坏这些 分析包括较大尺寸在内的所有细胞外小泡组分的障碍和独特方法 血浆中的微粒分数。这一过程可以使用超声设备进行，该设备可以- 精确而安全地聚焦超声束穿过人类头骨，作为一种无创的 和有针对性的方法来扰乱BBB/BTB的药物输送。这里将改为使用它来增加 细胞外小泡是患者血浆中较大尺寸的小泡。结合对肿瘤特异性的分析 在血浆样本中发现胞外小泡，这项技术可能成为诊断和诊断 脑肿瘤的治疗--非侵入性活组织检查。为了实现这一目标，我们将在慕尼黑进行广泛的研究。 RINE胶质瘤模型，以优化手术过程，并在不同的肿瘤阶段进行评估。如果提议的前男友- 如果试验成功，我们将拥有令人信服的证据，可能导致人体试验。

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.