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

• 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
• 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

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.

项目摘要 即使接受侵略性当前疗法治疗，大多数原发性恶性脑肿瘤的患者也 生存不到两年。我们的目标是开发针对恶性神经胶质瘤的新型免疫疗法 基于激活和靶向与肿瘤相关的巨噬细胞（TAM）的基础。虽然 正在研究免疫疗法作为潜在疗法，血脑屏障和局部肿瘤 免疫抑制环境通常可以防止细胞毒性抗体或免疫细胞渗透到大脑中。这 局部传递免疫刺激分子（例如CPG）可以克服这种抑制性环境， 但是，高CPG剂量可能引起有毒的脑部炎症。因此，迫切需要 更安全，更有效，有针对性的策略将增强CNS对恶性脑肿瘤的免疫反应。 我们最近利用TAM的固有吞噬特性来增强细胞的CpG摄取 使用碳纳米颗粒，并在带有神经胶质瘤的治疗小鼠中证明了60％的治愈率。在这些 但是，实验，激活的TA​​M从肿瘤环境中清除了，在第一次的七天内 纳米颗粒注射，这可能导致某些未固化的小鼠的治疗失败 他们的肿瘤。我们假设该方法延长了大脑内活化的TAM的存在 肿瘤应增强基于纳米颗粒的治疗的抗肿瘤功效。这个目的 建议是测试动态编程的低强度磁场（DPMF）的选择性的能力 路线和交通脑小胶质细胞和巨噬细胞已用氧化铁偶联的CpG处理的巨噬细胞 纳米颗粒（IONP-CPG）。与当前产生磁场的方法不同，我们的网格生成的DPMF 允许我们对磁场的空间和时间剖面进行广泛的控制，应 有可能增强与神经胶质瘤的TAM路由。我们将首先定义DPMF介导的运动的条件 IONP处理的小胶质细胞体外。优化了IONP的DPMF编程和功能化后， 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贩运和保留率 正常的小鼠大脑。最后，我们将确定DPMF-IOMP治疗在具有的小鼠中的体内功效 颅内神经胶质瘤。我们希望DPMF将激活的巨噬细胞和小胶质细胞保留和流动到 肿瘤，从而增强了这种新型疗法的治疗功效。这些研究的结果不会 仅显着影响神经胶质瘤的治疗，但也应影响其他CNS病理的治疗 例如中风或创伤，其中的小胶质细胞和巨噬细胞参与疾病过程 和/或CNS维修。最后，IONP和DPMF的联合使用具有调节和直接神经的潜力 中枢神经系统移植后干细胞运输。