Maximizing Local Access to Therapeutic Deliveries in Glioblastoma

胶质母细胞瘤(GBM)是一种原发的脑肿瘤，仍然是一个未得到满足的医疗需求。GBM面临的主要障碍 治疗方法是通过自然、生理和病理生物学手段获得药物的可及性 屏障，如血脑屏障(BBB)和血脑肿瘤屏障(BBTB)，以及 药物的适当性质。此外，基底膜的复杂病理生物学，包括局部侵袭和 肿瘤内的异质性是产生有效的抗GBM药物的主要挑战。一元化 我们PPG的主题是利用局部获取像GBM这样的脑肿瘤来实现然后最大化 对患者的治疗效果。这种本地访问可以通过以下两种方式实现： 药物进入肿瘤肿块及其附近，或通过破坏BBB/BBTB。例如，药物可以运送到 在当地通过对流增强传递(CED)。这个PPG的总体假设是，我们可以交付 下一代分子靶向药物候选通过显著地重新定位于GBM 设计CED和/或通过精确的BBB/BBTB中断。为了解决这一假设，我们正在开发 基于新型树枝状导管的对流增强型热化疗导管系统。 此外，将以两种创新方式测试血脑屏障的干扰：(I)高频不可逆 电穿孔(H-FIRE)，或(Ii)表达肿瘤坏死因子-α(肿瘤坏死因子)的干细胞的组合方法， 一种有可能显著提高血脑屏障通透性的细胞因子，在热响应启动子的作用下 可使用高强度聚焦超声(HIFU)远程激活。我们将利用一种独特的动物 犬自发性胶质瘤模型，适用于测试医疗设备/手术程序，以及 因此，它是解决我们PPG统一主题的最有价值的工具之一。我们将探索我们的假设 有三个具体目标。在目标1中，我们将产生靶向细胞毒药物，增加肿瘤的获得性 和/或病理生理学上重要的肿瘤隔室。我们将产生靶向药物结合物 穿透血脑屏障的化疗药物。在AIM2中，我们将尝试通过开发CED来绕过BBB/BBTB 这解决了关键的临床需求。我们将评估树枝状导管对输液的广泛分布。 以及脑组织中目标体积的准确饱和。我们将评估有针对性的药物分配和 CETCS治疗犬自发性基底膜的疗效观察。在目标3中，我们将绕过BBB/BBTB 通过诱导破坏。这将通过允许优先定向渗透的H-Fire处理来实现 肿瘤细胞。我们将评估H-FIRE方案联合治疗犬自发性胶质瘤的疗效 靶向的细胞毒剂。我们还将检查经工程改造后可表达肿瘤坏死因子α的干细胞。因此，我们的PPG 该提案代表了一种新的治疗方法的组合合理方法，以改善 独特的候选药物，增强了对基底膜肿瘤及其间隔区的访问。这个节目很适合 用于在可预见的未来快速转化为临床环境。

Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. The major obstacles to GBM treatment are the accessibility of GBM tumors to drugs through natural physiological and pathobiological barriers like the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively, and the adequate properties of drugs. In addition, complex pathobiology of GBM, including local invasion and intratumoral heterogeneity represent major challenges to generating effective anti-GBM drugs. The unifying theme of our PPG is the exploitation of local access to brain tumors like GBM to achieve and then maximize therapeutic effect in patients. This local access can be accomplished either by direct loco-regional delivery of drugs into the tumor mass and its vicinity or by disrupting the BBB/BBTB. For example, drugs can be delivered locally through convection-enhanced delivery (CED). The overall hypothesis of this PPG is that we can deliver the next generation of molecularly targeted drug candidates to GBM effectively by either significantly re- designed CED and/or by precision BBB/BBTB disruption. To address this hypothesis, we are developing convection-enhanced thermo-chemotherapy catheter system (CETCS) based on a novel arborizing catheter. Furthermore, the BBB disruption will be tested in two innovative ways using: (i) high-frequency irreversible electroporation (H-FIRE), or (ii) a combined approach of stem cells expressing tumor necrosis factor-α (TNF), a cytokine with a potential to significantly enhance BBB permeability, under a heat responsive promoter that can be remotely activated using high intensity focused ultrasound (HIFU). We will exploit a unique animal model of spontaneous gliomas in dogs, which is amenable to testing medical devices/surgical procedures, and thus is one of the most valuable tools in addressing our PPG's unifying theme. We will explore our hypothesis in three Specific Aims. In Aim 1, we will generate targeted cytotoxic drugs with an increased access to tumors and/or pathophysiologically important tumor compartments. We will generate targeted drug conjugates with BBB-penetrating chemotherapeutics. In Aim2, we will attempt to bypass the BBB/BBTB by developing CED that addresses critical clinical needs. We will evaluate an arborizing catheter for broad distribution of infusates and accurate saturation of target volume in brain tissue. We will evaluate targeted drugs distribution and efficacy by CETCS for treating spontaneous GBM in a canine model. In Aim 3, we will bypass the BBB/BBTB by induced disruption. This will be achieved with H-FIRE treatment allowing for preferential targeting infiltrating tumor cells. We will assess H-FIRE protocols to combinatorially treat spontaneous gliomas in dogs with targeted cytotoxic agents. We will also examine stem cells engineered to express TNFα. Thus, our PPG proposal represents a combined rational approach of novel therapeutic approaches to improve delivery of unique drug candidates of enhanced access to GBM tumor and its compartments. This program is well suited for rapid translation to clinical settings in a foreseeable future.