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.

项目总结 即使在目前积极的治疗方法下，大多数原发性恶性脑瘤患者 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 基于激活和靶向肿瘤相关巨噬细胞(TAMs)到胶质瘤。虽然 免疫疗法正在被研究作为一种潜在的治疗方法，包括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进入大脑。这个 局部递送免疫刺激分子如CpG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炎。因此，迫切需要一种 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瘤的免疫反应。 我们最近利用TAMs固有的吞噬特性来增强细胞对CpG的摄取 使用碳纳米颗粒，并在治疗后的胶质瘤小鼠中显示了60%的治愈率。在这些 然而，实验中，激活的TAMs在第一次实验的七天内就从肿瘤环境中清除了出来。 纳米颗粒注射，这可能是导致一些未治愈的小鼠治疗失败的原因 他们的肿瘤。我们假设，延长大脑中激活的TAMs存在的方法 肿瘤应该会增强这种基于纳米颗粒的治疗的抗肿瘤效果。这样做的目的是 建议测试一个动态可编程的低强度磁场(DPMF)，以了解其选择性 与氧化铁结合的CpG处理的小胶质细胞和巨噬细胞的路线和交通 纳米粒(IONP-CpG)。与目前产生磁场的方法不同，我们的网格产生的DPMF 允许我们对磁场的空间和时间分布进行广泛的控制，这应该 潜在地增强了向神经胶质瘤的转移。我们将首先定义DPMF介导的运动的条件 IONP处理小胶质细胞的体外实验。在对IONP的DPMF编程和功能化进行优化后， 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在体内的运输和保留 正常的小鼠大脑。最后，我们将确定DPMF-IONP治疗小鼠的体内疗效。 颅内胶质瘤。我们预计DPMF将保留激活的巨噬细胞和小胶质细胞并将其输送到 肿瘤，从而提高这种新疗法的治疗效果。这些研究的结果将不会 不仅对胶质瘤的治疗有显著影响，而且对其他中枢神经系统病变的治疗也有影响 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的联合使用具有调节和指导神经的潜力 中枢神经系统移植后的干细胞转移。