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: 8726502
• 负责人: Behnam Badie
• 金额: $ 19.51万
• 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/8726502
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：即使采用当前积极的疗法治疗，大多数原发性恶性脑肿瘤患者的生存时间也不到两年。 我们的目标是开发基于激活和靶向肿瘤相关巨噬细胞（TAMs）的恶性胶质瘤免疫治疗新方法。 尽管免疫疗法正在被研究作为一种潜在的治疗方法，但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。 免疫刺激分子如CpG的局部递送可以克服这种抑制环境，然而，高剂量的CpG可能导致毒性脑炎症。 因此，迫切需要一种更安全，更有效，有针对性的策略，将提高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，使用碳纳米颗粒增强细胞对CpG的摄取，并在治疗的胶质瘤小鼠中显示出60%的治愈率。 然而，在这些实验中，活化的TAM在第一次纳米颗粒注射后的七天内从肿瘤环境中清除，这可能导致一些未治愈肿瘤的小鼠的治疗失败。 我们假设，延长脑肿瘤内活化TAM存在的方法应该增强这种基于纳米颗粒的治疗的抗肿瘤功效。 本提案的目的是测试动态可编程的低强度磁场（DPMF）选择性路由和交通脑小胶质细胞和巨噬细胞的能力，这些细胞已经用CpG与氧化铁纳米颗粒（IONP-CpG）结合处理。 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，这可能会增强TAM向胶质瘤的路由。 我们将首先定义体外IONP处理的小胶质细胞的DPMF介导的运动的条件。 在优化DPMF编程和IONP的功能化之后，我们将开发我们的技术来调节正常小鼠脑中小胶质细胞和巨噬细胞的运输和保留。 最后，我们将确定DPMF-IONP疗法在患有颅内胶质瘤的小鼠中的体内功效。 我们期望DPMF能够将活化的巨噬细胞和小胶质细胞保留并运输到肿瘤中，从而增强这种新疗法的治疗效果。 这些研究的结果不仅将显著影响神经胶质瘤的治疗，而且还将影响其他CNS病理的治疗，例如中风或创伤，其中已知小胶质细胞和巨噬细胞参与疾病过程和/或CNS修复。 最后，IONP和DPMF的联合使用具有调节和指导CNS移植后神经干细胞运输的潜力。