Dynamic Magnetic Targeting of Activated Brain Macrophages for Glioma Therapy

激活脑巨噬细胞的动态磁靶向用于神经胶质瘤治疗

基本信息

批准号：
8638705
负责人：
Behnam Badie
金额：
$ 26.99万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638705
关键词：
Antibodies Blood - brain barrier anatomy Brain Brain Neoplasms Brain Pathology Carbon Nanotubes Carbon nanoparticle Cells Combined Modality Therapy Data Degenerative Disorder Disease Distant Dose Encephalitis Environment Fluorescence Glioma Goals Human Immune Immune response Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Implant In Vitro Injection of therapeutic agent Label Life Literature Magnetic Resonance Imaging Magnetism Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Methodology Methods Microglia Microscopy Modeling Movement Mus Myelogenous Myeloid Cells Pathology Patients Penetration Process Property Proteins Reporting Route Site Stroke Surface Techniques Testing Time Tissues Toxic effect Translating Translations Transplantation Trauma Treatment Efficacy Treatment Failure Tumor Immunity base cell motility cytotoxic fluorescence microscope in vivo innovation iron oxide macrophage magnetic field nanoparticle nerve stem cell novel novel strategies particle prevent programs public health relevance repaired research study response trafficking tumor tumor microenvironment uptake

项目摘要

PROJECT SUMMARY Even when treated with aggressive current therapies, most patients with primary malignant brain tumors survive less than two years. Our goal is to develop novel immunotherapies against malignant glioma that are based on activating and targeting tumor-associated macrophages (TAMs) to the glioma. Although immunotherapy is being studied as a potential treatment, the blood-brain barrier and local tumor immunosuppressive milieu often prevent penetration of cytotoxic antibodies or immune cells into the brain. The local delivery of immunostimulatory molecules such as CpG can overcome this suppressive environment, However, high CpG doses could cause toxic brain inflammation. Therefore, there is a pressing need for a safer, more effective, targeted strategy that will enhance the CNS immune response to malignant brain tumors. We recently took advantage of the inherent phagocytic properties of TAMs to enhance CpG uptake by the cells using carbon nanoparticles and demonstrated a 60% cure rate in treated mice bearing gliomas. In these experiments however, the activated TAMs cleared from the tumor environment within seven days of the first nanoparticle injection, which might have contributed to the treatment failure in some mice that were not cured of their tumors. We hypothesize that methods which prolong the presence of activated TAMs within brain tumors should enhance the anti-tumor efficacy of this nanoparticle-based therapy. The objective of this proposal is to test a dynamically programmable, low-intensity magnetic field (DPMF) for its ability to selectively route and traffic brain microglia and macrophages that have been treated with CpG conjugated to iron oxide nanoparticles (IONP-CpG). Unlike current methods of generating magnetic fields, our grid-generated DPMF allow us a broad range of control over the spatial and temporal profile of the magnetic field, which should potentially enhance TAM routing to gliomas. We will first define conditions for DPMF-mediated motility of IONP-treated microglia cells in vitro. After optimizing the DPMF programming and functionalization of IONP, we will then develop our technique to modulate the trafficking and retention of microglia and macrophage in normal mouse brains. Finally, we will determine the in vivo efficacy of DPMF-IONP therapy in mice with intracranial gliomas. We expect DPMF to retain and traffic the activated macrophage and microglia to the tumors, thereby enhancing the therapeutic efficacy of this novel therapy. The results from these studies will not only significantly impact the treatment of gliomas, but should also impact treatment of other CNS pathologies such as stroke or trauma, in which microglia and macrophages are known to participate in the disease process and/or CNS repair. Finally, combined use of IONP and DPMF has the potential to modulate and direct neural stem cell trafficking following CNS transplantation.

项目概要即使采用目前积极的治疗方法，大多数原发性恶性脑肿瘤患者存活不到两年。我们的目标是开发针对恶性胶质瘤的新型免疫疗法基于激活肿瘤相关巨噬细胞（TAM）并将其靶向神经胶质瘤。虽然免疫疗法作为一种潜在的治疗方法正在研究中，血脑屏障和局部肿瘤免疫抑制环境通常会阻止细胞毒性抗体或免疫细胞渗透到大脑中。这免疫刺激分子（例如 CpG）的局部递送可以克服这种抑制环境，然而，高剂量的 CpG 可能会导致中毒性脑部炎症。因此，迫切需要一个更安全、更有效、更有针对性的策略将增强中枢神经系统对恶性脑肿瘤的免疫反应。我们最近利用 TAM 固有的吞噬特性来增强细胞对 CpG 的摄取使用碳纳米粒子，并在治疗的患有神经胶质瘤的小鼠中证明了 60% 的治愈率。在这些然而，在实验中，激活的 TAM 在首次激活后 7 天内从肿瘤环境中清除。纳米颗粒注射，这可能导致一些未治愈的小鼠治疗失败他们的肿瘤。我们假设可以延长大脑中激活的 TAM 存在的方法肿瘤应该增强这种基于纳米颗粒的疗法的抗肿瘤功效。此举的目的建议测试动态可编程低强度磁场 (DPMF) 的选择性能力路线和运输已用 CpG 与氧化铁结合处理的大脑小胶质细胞和巨噬细胞纳米颗粒（IONP-CpG）。与当前生成磁场的方法不同，我们的网格生成 DPMF 使我们能够对磁场的空间和时间分布进行广泛的控制，这应该潜在地增强 TAM 向神经胶质瘤的路由。我们首先定义 DPMF 介导的运动的条件体外 IONP 处理的小胶质细胞。优化DPMF编程和IONP功能化后，然后，我们将开发我们的技术来调节小胶质细胞和巨噬细胞的运输和保留正常小鼠的大脑。最后，我们将确定 DPMF-IONP 疗法在小鼠中的体内疗效颅内神经胶质瘤。我们期望 DPMF 保留活化的巨噬细胞和小胶质细胞并将其运输至肿瘤，从而增强这种新疗法的治疗效果。这些研究的结果不会不仅会显着影响神经胶质瘤的治疗，而且还会影响其他中枢神经系统疾病的治疗例如中风或创伤，已知小胶质细胞和巨噬细胞参与疾病过程和/或中枢神经系统修复。最后，IONP 和 DPMF 的联合使用有可能调节和指导神经中枢神经系统移植后的干细胞贩运。