Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas

胶质瘤是人类最常见的恶性脑肿瘤。即使在接受手术治疗的时候， 放疗和化疗，患者最常被诊断为胶质瘤，IV级胶质母细胞瘤 (GB)，预期寿命只有14个月。治疗银屑病的主要挑战是其高度侵袭性， 由于浸润性癌细胞受到保护，不会受到全身化疗的影响， 血脑屏障(BBB)。在这里，我们建议开发一种针对GB夫妇的治疗方法 MRI引导聚焦通过激活血管内微泡(MBS)无创开放血脑屏障 超声(FUS)和可生物降解的[聚天冬氨酸-聚乙二醇(PAA-PEG)]，顺铂(CDDP)- 装满的“脑穿透纳米颗粒”。我们之前已经证明了“第一代”的功效。 CDDP-BPN代理，FUS能够精确地将BPN通过BBB传递到MR图像- 大脑中的选定靶点，以及CDDP-BPN对胶质瘤的传递。 在此，我们提出了四个具体目标，旨在显著提高 接近并将其推进到临床试验。在目标1中，我们将为以下目标设计下一代CDDP-BPN 专门用于系统性给药和FUS靶向递送的配方。同时，目标2和目标3将 通过对FUS的新的、临床可操作的改进显著增加BPN对侵袭性胶质瘤的输送 应用程序协议。这些措施将包括根据MRI指导扩大治疗量，测试 BBB开启期间“现场选择性”声发射反馈的概念，以及对新识别的评估 FUS“预调节”脉冲序列以提高BPN穿透的能力。值得注意的是，一种创新的新 在AIMS 2和AIMS 3中，将使用MR图像引导的肿瘤间质流动和扩散分析 直接确定FUS如何调节肿瘤微环境以促进CDDP-BPN通过 治疗体积。然后，目标4将通过建立CDDP-BPN的最大耐受剂量(MTD)和 使用优化的FUS方案评估CDDP-BPN给药后脑胶质瘤的顺铂水平。接下来，我们将测试 将下一代CDDP-BPN与用于增强BPN交付的新型FUS协议相结合是否将 控制肿瘤生长，阻断侵袭，提高存活率。重要的是，我们即将在 UVA，其中MR图像引导的FUS(InSightec ExAblate Neuro System)将与MBS一起使用以打开BBB 并在接受手术切除后每周向GB患者提供化疗 辐射。此外，MPI Hanes在推进药物控释制剂方面拥有丰富的经验 交付给临床试验。因此，翻译开了一个明确的先例。鉴于我们的基础设施和 凭借专业知识，我们非常有能力将成功的研究成果转化为临床应用。

Gliomas are the most common malignant human brain tumors. Even when treated with surgery, radiotherapy, and chemotherapy, patients with the most commonly diagnosed glioma, grade IV glioblastoma (GB), have a life expectancy of only 14 months. The primary challenge to treating GB is its highly invasive nature, as infiltrating cancer cells are “protected” from exposure to systemically administered chemotherapies by the blood brain barrier (BBB). Here, we propose the development of a therapeutic approach for GB that couples non-invasive BBB opening via the activation of intravascular microbubbles (MBs) with MRI-guided focused ultrasound (FUS) and biodegradable [polyaspartic acid-polyethyleneglycol (PAA-PEG)], cisplatin (CDDP)- loaded, “brain-penetrating nanoparticles”. We have previously demonstrated the efficacy of “first-generation” CDDP-BPN agents, the ability of FUS to precisely target the delivery of BPN across the BBB to MR image- selected targets in the brain, and the delivery of CDDP-BPN to gliomas. Here, we propose four specific aims designed to markedly improve the therapeutic efficacy of the approach and advance it to clinical trials. In Aim 1, we will engineer a “next-generation” CDDP-BPN for formulation specifically for systemic administration and FUS-targeted delivery. In parallel, Aims 2 and 3 will be to markedly augment BPN delivery to invasive gliomas via novel, clinically-operable, modifications to FUS application protocols. These will include extending treatment volumes based on MRI guidance, testing the concept of “site-selective” acoustic emissions feedback during BBB opening, and evaluating newly identified FUS “pre-conditioning” pulse sequences for their ability to increase BPN penetration. Of note, an innovative new MR image-guided transport analysis of tumor interstitial flow and diffusion will be employed in Aims 2 and 3 to directly ascertain how FUS modulates the tumor microenvironment to facilitate CDDP-BPN spread though the treatment volume. Aim 4 will then start by establishing the maximum tolerated dose (MTD) of CDDP-BPN and assessing cisplatin levels in gliomas after CDDP-BPN delivery using optimized FUS protocols. Next, we will test whether combining next-generation CDDP-BPN with novel FUS protocols for augmented BPN delivery will control tumor growth, block infiltration, and improve survival. Importantly, we are about to open a clinical trial at UVA wherein MR image-guided FUS (Insightec Exablate Neuro System) will be used with MBs to open the BBB and deliver chemotherapy on a weekly basis to GB patients after they have undergone surgical resection and radiation. Moreover, MPI Hanes has deep experience with advancing controlled-release formulations for drug delivery to clinical trials. Thus, a clear precedent has been set for translation. Given our infrastructure and expertise, we are exceptionally well-positioned to translate successful findings to the clinic.