Brain Tumor-Penetrating Nanoparticle Delivery with MR-Guided Focused Ultrasound

描述（申请人提供）：多形性胶质母细胞瘤（GBM）是最常见的原发性脑癌，5年生存率<12%。由于血脑屏障（BBB），化疗药物以非常低的浓度到达大脑，这一事实严重限制了GBM治疗。目前规避BBB的策略（即Gliadel晶片和对流增强递送）是侵入性的，并且仅导致存活率的适度改善。显然，需要为脑肿瘤提供持续和良好分散的药物递送的微创策略。为了满足这一需求，我们提出了一种创新的图像引导药物递送方法，该方法通过聚焦超声（FUS）和微泡（MB）将磁共振（MR）靶向BBB开放与载药纳米颗粒相结合，载药纳米颗粒已被设计成具有极高密度的聚乙二醇（PEG）涂层，以快速穿透脑组织（即“脑穿透纳米颗粒”或BPN）。我们假设这种方法将通过增强药物穿过BBB递送到FUS靶向肿瘤，在肿瘤深处提供持续的药物递送，并最大限度地减少全身副作用来改善脑癌治疗。 我们将用四个目标来检验这个假设。在目标1中，我们将优化BPN尺寸和表面化学，以实现脑肿瘤渗透和长循环时间。示踪剂BPN将用于确定在离体新鲜获得的脑肿瘤中产生具有受控颗粒穿透深度的BPN所需的纳米颗粒尺寸范围和表面化学。随后，具有这些最佳特性的BPN将由可生物降解的聚合物产生并进行测试。在目标2中，与目标1平行运行，我们将确定颅内9L大鼠脑肿瘤中安全和可逆MR引导BBB开放至钆的FUS压力阈值，作为MB直径的函数。然后，FUS压力阈值将用作确定最佳FUS和MB参数的基础，用于将Aim 1中最有前途的BPN制剂输送至脑肿瘤。这些FUS和MB参数将用于目标3，其中我们将通过荧光分子断层扫描（FMT）评估可生物降解BPN的全身和脑生物分布。将使用共聚焦显微镜进一步详细分析BPN穿过BBB输送后进入大脑的分散情况。将对预期可忽略不计或不存在的脑组织炎症进行组织学评估。在目标4中，我们将首先确定紫杉醇负载BPN的最大耐受剂量（MTD），然后评估药物药代动力学（PK）。最后，我们将通过测量治疗后减少的肿瘤生长和提高的动物存活率来确定使用MR引导的FUS和MB的载药BPN递送对侵袭性脑肿瘤的总体疗效。如果这些临床前研究按预期进行，我们就有能力将其转化为临床研究。我们的下一步将是使用弗吉尼亚大学的临床Insightec Exablate系统在大型动物（猪）中测试MR引导BPN输送方法的安全性，然后启动临床试验。 公共卫生相关性：化疗在治疗脑肿瘤时通常是无效的，因为血流和大脑之间的界面，即所谓的血脑屏障，对血流中的药物是不可渗透的。我们正在测试一项新技术的能力，该技术使用MR成像和专门的超声设备打开脑肿瘤周围的血脑屏障，以允许提供专门设计的载药纳米颗粒，以改善脑癌治疗。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common primary brain cancer, has a 5-year survival rate of <12%. GBM treatment is severely limited by the fact that chemotherapeutic drugs reach the brain in very low concentrations due to the blood brain barrier (BBB). Current strategies to circumvent the BBB (i.e. Gliadel wafers and convection enhanced delivery) are invasive and lead to only moderate improvements in survival. Clearly, less-invasive strategies that provide sustained and well-dispersed drug delivery to brain tumors are needed. To address this need, we propose an innovative image guided drug-delivery approach that couples magnetic resonance (MR)-targeted BBB opening via focused ultrasound (FUS) and microbubbles (MBs) with drug-loaded nanoparticles that have been engineered with extremely dense polyethylene glycol (PEG) coatings to rapidly penetrate brain tissue (i.e. "brain penetrating nanoparticles" or BPNs). We hypothesize that this approach will improve brain cancer treatment by enhancing drug delivery across the BBB to FUS-targeted tumors, providing sustained drug delivery deep within tumors, and minimizing systemic side effects. We will test this hypothesis with 4 aims. In Aim 1, we will optimize BPN size and surface chemistry for brain tumor penetration and long circulation time. Tracer BPNs will be used to determine the nanoparticle size range and surface chemistry required to produce BPNs with controlled particle penetration depths in freshly obtained brain tumors ex vivo. Subsequently, BPNs with these optimal characteristics will be generated from biodegradable polymers and tested. In Aim 2, running in parallel with Aim 1, we will determine FUS pressure thresholds for safe and reversible MR-guided BBB opening to gadolinium in intracranial 9L rat brain tumors as a function of MB diameter. Then, FUS pressure thresholds will be used as a basis for determining optimal FUS and MB parameters for delivering the most promising BPN formulation from Aim 1 to brain tumors. These FUS and MB parameters will be carried to Aim 3, wherein we will evaluate whole-body and brain biodistributions of biodegradable BPNs via Fluorescence Molecular Tomography (FMT). BPN dispersion into the brain after delivery across the BBB will be further analyzed in detail using confocal microscopy. Brain tissue inflammation, which is expected to be negligible or absent, will be assessed histologically. In Aim 4, we will first determine the maximum tolerated dose (MTD) of paclitaxel-loaded BPNs, followed by an evaluation of drug pharmacokinetics (PK). Finally, we will determine the overall efficacy of drug-loaded BPN delivery with MR- guided FUS and MBs to invasive brain tumors by measuring reduced tumor growth and enhanced animal survival after treatment. If these pre-clinical studies proceed as expected, we are well-positioned for translation to the clinic. Our next step would be to test the safety of the MR-guided BPN delivery approach in large animals (pig) using the University of Virginia's clinical Insightec Exablate system, followed by the initiation of a clinical trial. PUBLIC HEALTH RELEVANCE: Chemotherapy is often ineffective when treating brain tumors because the interface between the bloodstream and the brain, which is called the blood-brain barrier, is not permeable to drugs in the bloodstream. We are testing the ability of a new technology, which uses MR imaging and specialized ultrasound equipment to open the blood-brain barrier around brain tumors, to permit the delivery of specially designed drug-carrying nanoparticles for improved brain cancer treatment.