【摘要】：阿爾茨海默病(AD)是與年齡相關(guān)的一類神經(jīng)退行性疾病,近年來隨著人口老齡化的加劇,在全球范圍內(nèi)患者數(shù)量攀升。研究結(jié)果顯示,該病是由于患者腦內(nèi)膠質(zhì)細(xì)胞過多而神經(jīng)元嚴(yán)重缺乏,從而引起學(xué)習(xí)認(rèn)知障礙。目前的治療方法使用乙酰膽堿酯酶抑制劑來加強腦內(nèi)乙酰膽堿的功能,但是,這類藥物難以透過血腦屏障且對病患部位的靶向性差,從而導(dǎo)致治療效果差。因此,尋找有效地治療方法迫在眉睫。神經(jīng)干細(xì)胞具有低免疫源性,可以分化為阿爾茨海默疾病(AD)所需要的神經(jīng)元,并且通過腦內(nèi)定點注射避免血腦屏障遷移到達(dá)病患部位。但是有兩方面原因限制了神經(jīng)干細(xì)胞的應(yīng)用,首先,神經(jīng)干細(xì)胞在自然狀態(tài)下分化成神經(jīng)元的數(shù)量并不足以彌補AD病人腦內(nèi)神經(jīng)元的缺失,其次,難以對移植的神經(jīng)干細(xì)胞進行實時監(jiān)測。因此,神經(jīng)干細(xì)胞用于治療阿爾茨海默不僅要實現(xiàn)神經(jīng)干細(xì)胞可控分化為神經(jīng)元,還要實現(xiàn)移植神經(jīng)干細(xì)胞的實時監(jiān)測。為了解決上述兩個問題,我們聯(lián)合維甲酸(RA)和小干擾RNA(si SOX9)共同促進神經(jīng)干細(xì)胞向神經(jīng)元分化,利用SPIONs具有較高的弛豫性能通過小動物核磁成像儀來實時檢測神經(jīng)干細(xì)胞的注射位點以及注射后的遷移路徑。為了增強藥物的聯(lián)合作用以及實現(xiàn)成像功能,我們構(gòu)建了聚羧基甜菜堿甲基丙烯酸酯(PCB)修飾的PHEMA50-RA-PCB20-CPP/SPIONs/si SOX9 NPs(AB20C/SPIONs/si RNA NPs)載藥體系用于AD的治療。本課題設(shè)計的載體可以實現(xiàn)兩種藥物的程序釋放,即由于在內(nèi)涵體中PCB的質(zhì)子化作用發(fā)生內(nèi)涵體逃逸,si SOX9先釋放到細(xì)胞質(zhì)發(fā)揮作用切斷神經(jīng)干細(xì)胞向膠質(zhì)細(xì)胞分化的途徑,然后維甲酸在酸性和酯酶的作用下緩慢釋放進入細(xì)胞核發(fā)揮作用促進神經(jīng)干細(xì)胞的分化。實驗結(jié)果表明本課題設(shè)計并合成的納米藥物載體AB20C/SPIONs/si SOX9NPs可以顯著促進神經(jīng)干細(xì)胞向神經(jīng)元的分化,增加AD模型鼠海馬區(qū)神經(jīng)元的數(shù)量,提高AD模型鼠的行為認(rèn)知能力,并且通過小動物核磁成像儀可以實現(xiàn)實時成像,檢測神經(jīng)干細(xì)胞的注射位點以及在腦內(nèi)的遷移路徑。因此,我們相信本課題所構(gòu)建的納米藥物載體為AD的治療提供了一種有效的新方法。
文內(nèi)圖片：
圖片說明：全球癡呆患者人數(shù)阿爾茨海默是一種中樞神經(jīng)系統(tǒng)變性病，主要表現(xiàn)為漸進性記憶能力衰退，
[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.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R749.16


本文編號：2511449