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

脑胶质瘤是最常见的恶性脑肿瘤。即使是手术治疗， 放疗和化疗，最常诊断为胶质瘤的患者，IV级胶质母细胞瘤 (GB)，预期寿命只有14个月。治疗GB的主要挑战是其高度侵入性， 因为浸润癌细胞被“保护”免于暴露于全身施用的化疗， 血脑屏障（BBB）。在这里，我们建议开发一种治疗GB的方法， 通过激活血管内微泡（MB），使用MRI引导的聚焦 超声（FUS）和生物可降解[聚天冬氨酸-聚乙二醇（PAA-PEG）]，顺铂（CDDP）- 装载的“脑穿透纳米粒子”。我们之前已经证明了“第一代”的功效 CDDP-BPN试剂，FUS精确靶向将BPN输送穿过BBB至MR图像的能力- 脑中的选定靶点，以及CDDP-BPN向胶质瘤的递送。 在这里，我们提出了四个具体的目标，旨在显着提高治疗效果的 并将其推进临床试验。在目标1中，我们将设计“下一代”CDDP-BPN， 特别是用于全身给药和FUS靶向递送的制剂。与此同时，目标2和3将是 通过对FUS进行新的、临床可操作的改良，显著增加BPN向浸润性胶质瘤的输送 应用协议。这些将包括基于MRI引导扩展治疗体积，测试 在BBB开放期间的“位点选择性”声发射反馈的概念，并评估新发现的 FUS“预处理”脉冲序列，以提高BPN渗透能力。值得注意的是， 在目标2和3中，将采用肿瘤间质血流和扩散的MR图像引导传输分析， 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将从确定CDDP-BPN的最大耐受剂量（MTD）开始， 使用优化的FUS方案评估CDDP-BPN递送后胶质瘤中的顺铂水平。接下来，我们将测试 将下一代CDDP-BPN与新的FUS协议相结合以增强BPN输送是否将 控制肿瘤生长，阻断浸润，提高生存率。重要的是，我们即将在 UVA，其中MR图像引导FUS（Insightec Exablate Neuro System）将与MB一起用于打开BBB 并在接受手术切除后每周为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， 交付临床试验。因此，这为翻译树立了一个明确的先例。鉴于我们的基础设施和 凭借我们的专业知识，我们非常有能力将成功的发现转化为临床。

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.