Immune-modifying nanoparticles for the treatment of traumatic brain injury

创伤性脑损伤是一个重大的健康问题。原发损伤后，有实质性的继发性损伤。 可归因于免疫细胞的渗透、细胞因子的释放、活性氧物种、兴奋性毒性等 机械装置。尽管许多临床前和临床试验旨在限制这种继发性损害，但没有一项成功 治疗方法应运而生。然而，我们发现免疫修饰纳米粒(IMP)是一种强大的 临床可翻译的急性药物干预治疗脑外伤的候选者。小鬼是高度负面的 带电的、直径500 nm的颗粒，由FDA批准的可生物降解的生物聚合物组成，羧化 聚乳酸-羟基乙酸(PLGA-COOH)。静脉给药后，IMP与巨噬细胞结合 单核细胞上具有胶原性结构的受体(MARCO)。与IMP结合的单核细胞不再前往部位 炎症，而是隔离在脾里。因为IMP专门针对Marco子集 对于单核细胞，它与其他非特异性针对所有单核/巨噬细胞的方法有明显的不同 包括小胶质细胞在内的谱系细胞。在两种不同的颅脑损伤模型中，静脉注射IMP显著降低了 免疫细胞的数量渗入大脑，减轻渗入细胞的炎症状态，以及 一系列细胞因子和趋化因子水平降低。更重要的是，IMP治疗导致了 水肿，保存脑组织，并显著保存生理视觉和运动功能。 拟议的研究将检验IMP介导的改变炎症状态的基因表达的变化。 减少浸润性细胞，限制胶质增生，减少水肿，促进神经元存活。他们还将检查以下因素的影响 在其他细胞类型上的IMP，包括小胶质细胞、祖细胞和其他免疫细胞。值得注意的是，IMP由 FDA批准的材料，在室温下稳定，可以很容易地在脑损伤后立即静脉注射 在现场由急救人员或在急诊室。从机械上讲，拟议的研究将有助于理解 更清楚的是，脑外伤后血源性单核细胞来源的巨噬细胞的渗入作用。值得注意的是， 他们还将有助于开发一种潜在有效和实用的治疗人类脑外伤的方法。

Traumatic Brain Injury (TBI) is a major health issue. After the primary injury, there is substantial secondary injury attributable to infiltrating immune cells, cytokine release, reactive oxygen species, excitotoxicity, and other mechanisms. Despite many preclinical and clinical trials designed to limit such secondary damage, no successful therapies have emerged. However, we have found that Immune-modifying nanoParticles (IMP) are a strong candidate for a clinically translatable acute pharmacologic intervention for TBI. IMP are highly negatively charged, 500 nm-diameter particles composed of the FDA-approved biodegradable biopolymer, carboxylated poly(lactic-co-glycolic) acid (PLGA-COOH). After intravenous (IV) administration, IMP bind to the macrophage receptor with collagenous structure (MARCO) on monocytes. Monocytes bound to IMP no longer travel to sites of inflammation, but instead are sequestered in the spleen. Because IMP specifically target the MARCO+ subset of monocytes, it is distinctly different from other approaches that non-specifically target all monocyte/macrophage lineage cells including microglia. IV treatment with IMP in two different TBI models profoundly reduced the number of immune cells infiltrating into the brain, mitigated the inflammatory status of the infiltrating cells, and reduced levels of an array of cytokines and chemokines. More importantly, IMP treatment resulted in attenuated edema, preservation of brain tissue, and significant preservation of both physiologic visual and motor function. The proposed studies will examine IMP-mediated changes in gene expression that alter the inflammatory status of infiltrating cells, limit gliosis, reduce edema, and promote neuronal survival. They also will examine effects of IMP on other cell types including microglia, progenitor cells, and other immune cells. Notably, IMP are made of an FDA-approved material that is stable at room temperature and could easily be given immediately IV after TBI in the field by EMTs or in the emergency room. Mechanistically the proposed studies will help to understand more clearly the effects of infiltrating hematogenous monocyte-derived macrophages after TBI. Significantly, they also will help to develop a potentially effective and practical therapy for human TBI.