可视化联合给药体系促进神经干细胞可控分化用于阿尔茨海默治疗的研究

发布时间：2019-07-07 21:20

【摘要】：阿尔茨海默病(AD)是与年龄相关的一类神经退行性疾病,近年来随着人口老龄化的加剧,在全球范围内患者数量攀升。研究结果显示,该病是由于患者脑内胶质细胞过多而神经元严重缺乏,从而引起学习认知障碍。目前的治疗方法使用乙酰胆碱酯酶抑制剂来加强脑内乙酰胆碱的功能,但是,这类药物难以透过血脑屏障且对病患部位的靶向性差,从而导致治疗效果差。因此,寻找有效地治疗方法迫在眉睫。神经干细胞具有低免疫源性,可以分化为阿尔茨海默疾病(AD)所需要的神经元,并且通过脑内定点注射避免血脑屏障迁移到达病患部位。但是有两方面原因限制了神经干细胞的应用,首先,神经干细胞在自然状态下分化成神经元的数量并不足以弥补AD病人脑内神经元的缺失,其次,难以对移植的神经干细胞进行实时监测。因此,神经干细胞用于治疗阿尔茨海默不仅要实现神经干细胞可控分化为神经元,还要实现移植神经干细胞的实时监测。为了解决上述两个问题,我们联合维甲酸(RA)和小干扰RNA(si SOX9)共同促进神经干细胞向神经元分化,利用SPIONs具有较高的弛豫性能通过小动物核磁成像仪来实时检测神经干细胞的注射位点以及注射后的迁移路径。为了增强药物的联合作用以及实现成像功能,我们构建了聚羧基甜菜碱甲基丙烯酸酯(PCB)修饰的PHEMA50-RA-PCB20-CPP/SPIONs/si SOX9 NPs(AB20C/SPIONs/si RNA NPs)载药体系用于AD的治疗。本课题设计的载体可以实现两种药物的程序释放,即由于在内涵体中PCB的质子化作用发生内涵体逃逸,si SOX9先释放到细胞质发挥作用切断神经干细胞向胶质细胞分化的途径,然后维甲酸在酸性和酯酶的作用下缓慢释放进入细胞核发挥作用促进神经干细胞的分化。实验结果表明本课题设计并合成的纳米药物载体AB20C/SPIONs/si SOX9NPs可以显著促进神经干细胞向神经元的分化,增加AD模型鼠海马区神经元的数量,提高AD模型鼠的行为认知能力,并且通过小动物核磁成像仪可以实现实时成像,检测神经干细胞的注射位点以及在脑内的迁移路径。因此,我们相信本课题所构建的纳米药物载体为AD的治疗提供了一种有效的新方法。
文内图片：
图片说明：全球痴呆患者人数阿尔茨海默是一种中枢神经系统变性病，主要表现为渐进性记忆能力衰退，
[Abstract]:Alzheimer's disease (AD) is an age-related neurodegenerative disease. In recent years, with the aging of the population, the number of patients has increased around the world. The results showed that the disease was caused by excessive glial cells and severe lack of neurons in the brain, resulting in learning and cognition impairment. At present, acetylcholinesterase inhibitors are used to enhance the function of acetylcholine in the brain, but these drugs are difficult to penetrate the blood-brain barrier and have poor targeting to the patient site, which leads to poor therapeutic effect. Therefore, it is urgent to find an effective treatment. Neural stem cells (NSCs) have low immunity and can differentiate into neurons needed for Alzheimer's disease (AD), and avoid the migration of blood-brain barrier (BBB) to the patient by fixed-point injection into the brain. However, there are two reasons that limit the application of neural stem cells. First, the number of neural stem cells differentiated into neurons in natural state is not enough to make up for the loss of neurons in the brain of patients with AD. Secondly, it is difficult to monitor the transplanted neural stem cells in real time. Therefore, the use of neural stem cells in the treatment of Alzheimer's disease not only realizes the controllable differentiation of neural stem cells into neurons, but also realizes the real-time monitoring of transplanted neural stem cells. In order to solve the above two problems, we combined (RA) and RNA (si SOX9) to promote the differentiation of neural stem cells into neurons. SPIONs had high relaxation performance and detected the injection site and migration path of neural stem cells in real time by small animal nuclear magnetic imager. In order to enhance the combined effect of drugs and realize the imaging function, we constructed polycarboxy betaine methacrylate (PCB) modified PHEMA50-RA-PCB20-CPP/SPIONs/si SOX9 NPs (AB20C/SPIONs/si RNA NPs) drug delivery system) for the treatment of AD. The vector designed in this paper can realize the programmed release of two kinds of drugs, that is, because of the protonation of PCB in the endosome, si SOX9 is first released into the cytoplasm to cut off the differentiation of neural stem cells into glial cells, and then the slow release of retinic acid into the nucleus under the action of acid and esterase plays a role in promoting the differentiation of neural stem cells. The experimental results show that the nano-drug carrier AB20C/SPIONs/si SOX9NPs designed and synthesized in this paper can significantly promote the differentiation of neural stem cells into neurons, increase the number of neurons in the hippocampus of AD model mice, improve the behavioral cognitive ability of AD model mice, and can realize real-time imaging through small animal nuclear magnetic imager, detect the injection site of neural stem cells and the migration path in the brain. Therefore, we believe that the nano-drug vector constructed in this paper provides an effective new method for the treatment of AD.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R749.16


本文编号：2511449