Maximizing Local Access to Therapeutic Deliveries in Glioblastoma

胶质母细胞瘤（GBM）是一种原发性脑肿瘤，仍然是一个未满足的医疗需求。GBM的主要障碍 GBM肿瘤的治疗是通过天然的生理和病理生物学的药物可及性 血脑屏障（BBB）和血脑肿瘤屏障（BBTB），以及 药物的适当性质。此外，GBM的复杂病理生物学，包括局部侵袭， 肿瘤内异质性是产生有效抗GBM药物的主要挑战。的统一 我们PPG的主题是利用局部进入脑肿瘤（如GBM）， 患者的治疗效果。这种本地访问可以通过直接本地区域交付 药物进入肿瘤块及其附近或通过破坏BBB/BBTB。例如，药物可以通过 局部通过对流增强输送（CED）。这个PPG的总体假设是，我们可以提供 下一代的分子靶向药物候选人GBM有效地通过显着重新- 设计的CED和/或通过精确的BBB/BBTB破坏。为了解决这一假设，我们正在开发 对流增强热化疗导管系统（CETCS）基于一种新型的树枝状导管。 此外，BBB破坏将以两种创新的方式进行测试，使用：（i）高频不可逆 电穿孔（H-FIRE），或（ii）表达肿瘤坏死因子-α（TNF α）的干细胞的组合方法， 一种在热响应启动子作用下具有显著增强BBB通透性潜力的细胞因子， 可以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 犬中自发性神经胶质瘤模型，适用于测试医疗器械/外科手术，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 三个具体目标。在目标1中，我们将产生靶向细胞毒性药物，增加对肿瘤的接触 和/或病理生理学上重要的肿瘤区室。我们将产生靶向药物缀合物， 血脑屏障穿透性化疗药物。在目标2中，我们将尝试通过开发CED来绕过BBB/BBTB 以满足临床的关键需求。我们将评估一个分支导管广泛分布的输液 以及脑组织中目标体积的精确饱和。我们将评估靶向药物的分布， CETCS治疗犬模型中自发性GBM的有效性。在目标3中，我们将绕过BBB/BBTB 通过诱导破坏。这将通过H-FIRE治疗实现，允许优先靶向浸润 肿瘤细胞我们将评估H-FIRE方案联合治疗狗的自发性胶质瘤， 靶向细胞毒性剂。我们还将检测表达TNFα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，以改善药物的递送。 独特的候选药物，增强了对GBM肿瘤及其区室的接近。这个项目非常适合 以便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.