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，这严重限制了GBM的治疗。目前规避血脑屏障的策略（如Gliadel晶圆和对流增强输送）是侵入性的，只能适度改善生存。显然，为脑肿瘤提供持续和分散的药物递送的低侵入性策略是必要的。为了满足这一需求，我们提出了一种创新的图像引导给药方法，将磁共振（MR）靶向血脑屏障通过聚焦超声（FUS）和微泡（mb）与载药纳米粒子耦合在一起，这些纳米粒子被设计成极其致密的聚乙二醇（PEG）涂层，以快速穿透脑组织（即脑组织）。“穿透大脑的纳米颗粒”（BPNs）。我们假设这种方法将通过加强血脑屏障到fus靶向肿瘤的药物传递，提供肿瘤内部持续的药物传递，并最大限度地减少全身副作用，从而改善脑癌治疗。我们将用4个目标来检验这个假设。在Aim 1中，我们将优化脑肿瘤穿透和长循环时间的BPN尺寸和表面化学。示踪剂bpn将用于确定纳米颗粒的尺寸范围和表面化学性质，以在体外新获得的脑肿瘤中产生具有受控颗粒穿透深度的bpn。随后，生物可降解聚合物将产生具有这些最佳特性的bpn并进行测试。在与Aim 1并行的Aim 2中，我们将确定9L大鼠颅内肿瘤中安全可逆的mr引导血脑屏障向钆开放的FUS压力阈值作为MB直径的函数。然后，FUS压力阈值将作为确定最佳FUS和MB参数的基础，以便从Aim 1向脑肿瘤提供最有希望的BPN配方。这些FUS和MB参数将被带入Aim 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。BPN在通过血脑屏障输送后进入大脑的分散将使用共聚焦显微镜进一步详细分析。脑组织炎症，可忽略不计或不存在，将进行组织学评估。在Aim 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肿瘤生长的减少和动物存活率的提高，来确定MR引导的FUS和MBs药物负载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照预期进行，我们就能很好地转化为临床。下一步，我们将使用弗吉尼亚大学的Insightec Exablate临床系统，在大型动物（猪）身上测试核磁共振引导下BPN输送方法的安全性，然后进行临床试验。

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.