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

项目摘要 动脉内化疗(IAC)将全身化疗转变为靶向治疗策略 这使视网膜母细胞瘤的治疗发生了革命性的变化。几十年来，IAC方法一直试图以类似的方式 改变脑癌治疗；然而，尽管有很高的希望和许多公认的优势，IAC 事实证明，结果非常不稳定，如果不是完全令人沮丧的话。在过去的十年里，我们的团队专注于 识别和解决脑肿瘤有效的IAC的障碍。空间图像制导控制系统 整个肿瘤的化疗灌流和血脑屏障的操作 高空间和时间精度是我们将继续在这方面解决的根本挑战 求婚。我们对IAC的治疗方法特别适用于脑干肿瘤和其他高度侵袭性的肿瘤， 无反应的脑肿瘤，手术，放射治疗，立体定向药物输送，和全身 化疗，并没有显示出总体的生存益处。大多数肿瘤都有血脑屏障完整的区域， 在一些胶质瘤中，如弥漫性固有桥脑胶质瘤(DIPG)，血脑屏障基本完好。BBB， 它有效地阻止了几乎所有治疗脑瘤的药物，这是一个巨大的挑战，而且在 为了充分发挥IAC的潜力，它必须与BBB开放(BBBO)一起进行。 已经开发了几种BBBO方法，其中两种主要技术代表了令人信服的 增强IAC药效的辅助剂。经动脉内(IA)甘露醇渗透性血脑屏障开放(OBBBO)用于 自20世纪70年代末以来基本保持不变的临床方案。结果不一致，并且 不精确的BBBO阻碍了这种方法的广泛采用，这种方法只在x- 光线制导。我们先前已经证明，在MRI引导下的OBBBO和IA药物输送是 必不可少，因为它允许人们实时预测、调整和可视化BBBO。OBBBO的精准控制 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。 磁共振引导下的聚焦超声(MRgFUS)是一种能够治疗BBBO的新技术。 以高度空间精确的方式，然而当与IAC一起使用时，其效用和充分的治疗潜力仍然存在 未经调查。我们推测MRgFUS BBBO后IAC是一种安全有效的技术，具有更多的优点。 甘露醇介导的OBBBO后，持续有效的药物输送到靶脑区与IAC相比。 脑干肿瘤和其他高度侵袭性肿瘤缺乏有效的治疗选择， 无反应的中枢神经系统肿瘤促进使用新的多模式方法来增强药物对 大脑。我们将在MRgFUS和渗透性BBBO的正面比较中讨论MRgFUS是否 在安全性、耐受性和有效性方面可与已建立的渗透技术相媲美或优于现有的渗透技术 BBBO之后的IAC。

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.