Maximizing Local Access to Therapeutic Deliveries in Glioblastoma

最大限度地提高胶质母细胞瘤的本地治疗交付机会

基本信息

批准号：
10220880
负责人：
Waldemar Debinski
金额：
$ 182.74万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220880
关键词：
Address Affect Animal Model Area Biotechnology Blood - brain barrier anatomy Blood Circulation Brain Diseases Brain Neoplasms Bypass Canis familiaris Catheters Cell Differentiation process Cells Cellularity Clinical Complex Convection Cytotoxic agent Diffuse Drug Delivery Systems Drug Design Drug Targeting Drug Transport Effectiveness Electroporation Excision Feedback Focused Ultrasound Therapy Frequencies Future Glioblastoma Glioma Heat-Shock Proteins 70 Human Hypoxia IgG1 Immune Implant Induced Hyperthermia Infiltration Knowledge Light Magnetic Resonance Imaging Malignant Glioma Malignant neoplasm of brain Medical Medical Device Mesenchymal Stem Cells Modeling Necrosis Needles Operative Surgical Procedures Patients Peptides Perfusion Pharmaceutical Preparations Physiological Positioning Attribute Primary Brain Neoplasms Production Prognosis Property Protocols documentation Rattus Recurrence Research Personnel Site System TNF gene Testing Therapeutic Therapeutic Effect Time Translating Translations Tumor Biology Work base blood-brain barrier disruption blood-brain barrier permeabilization blood-brain tumor barrier brain parenchyma brain tissue chemotherapy combinatorial cytokine cytotoxic design drug candidate drug distribution drug efficacy engineered stem cells improved innovation macrophage molecular drug target neoplastic cell neovascularization neovasculature next generation novel novel strategies novel therapeutic intervention novel therapeutics prevent programs promoter remote control scaffold stem cells stem-like cell targeted delivery therapy resistant tool treatment planning tumor tumor heterogeneity tumor progression virtual

项目摘要

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.

胶质母细胞瘤 (GBM) 是一种原发性脑肿瘤，其医疗需求仍然未得到满足，这是 GBM 的主要障碍。治疗是GBM肿瘤通过自然生理和病理生物学对药物的可及性分别是血脑屏障（BBB）和血脑肿瘤屏障（BBTB）等屏障此外，GBM 的病理学也很复杂，包括局部侵袭和侵袭。瘤内异质性是产生有效的抗 GBM 药物的主要挑战。我们 PPG 的主题是利用局部通路获取 GBM 等脑肿瘤，以实现并最大化这种局部通路可以通过直接局部区域递送来实现。例如，可以通过破坏 BBB/BBTB 来递送药物。通过对流增强递送 (CED) 进行本地递送该 PPG 的总体假设是我们可以递送。下一代分子靶向药物候选物可以通过显着重新有效地治疗 GBM 设计的 CED 和/或通过精确的 BBB/BBTB 破坏来解决这一假设，我们正在开发。基于新型树状导管的对流增强热化疗导管系统（CETCS）。此外，BBB 破坏将以两种创新方式进行测试：(i) 高频不可逆电穿孔 (H-FIRE)，或 (ii) 表达肿瘤坏死因子-α (TNFα) 的干细胞的组合方法，一种细胞因子，在热响应启动子的作用下，有可能显着增强 BBB 通透性可以使用高强度聚焦超声波（HIFU）远程激活我们将利用一种独特的动物。狗的自发性神经胶质瘤模型，适合测试医疗设备/手术程序，以及因此，这是解决 PPG 统一主题的最有价值的工具之一，我们将探讨我们的假设。三个具体目标在目标 1 中，我们将生产更容易进入肿瘤的靶向细胞毒性药物。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。在 Aim2 中，我们将尝试通过开发 CED 来绕过 BBB/BBTB。我们将评估用于广泛分布输液的树枝状导管。以及脑组织中目标体积的准确饱和度，我们将评估靶向药物的分布和情况。 CETCS 在犬模型中治疗自发性 GBM 的疗效在目标 3 中，我们将绕过 BBB/BBTB。这将通过 H-FIRE 处理来实现，允许优先靶向渗透。我们将评估 H-FIRE 方案联合治疗患有以下疾病的狗的自发性神经胶质瘤：我们还将检查经过改造以表达 TNFα 的干细胞。该提案代表了一种新的治疗方法的综合合理方法，以改善药物的输送增强进入 GBM 肿瘤及其区室的独特候选药物非常适合该计划。在可预见的未来快速转化为临床环境。