用于阿尔茨海默症治疗的多功能多肽—聚合物纳米材料的制备及其性能研究

发布时间：2018-02-19 19:50

本文关键词： 阿尔茨海默症 Aβ 共组装自噬降解协同　出处：《东北师范大学》2017年硕士论文　论文类型：学位论文

【摘要】：阿尔茨海默症,是一种最典型的神经性退行性疾病。近年来,关于阿尔茨海默症治疗研究所面临的一个最大挑战是如何保持体内β淀粉样蛋白(Aβ)的平衡。纳米材料,由于其独有的特性,在众多疾病治疗领域中被广泛使用,包括常见的神经性疾病领域,具有重大的生物应用价值。其中,多肽-聚合物纳米材料作为一种新型的功能化材料,具有良好的生物相容性和安全性。将此聚合物材料有针对性地修饰上具有不同生物效应的多肽残基之后,可以有效地实现单一材料具备多种生物效应,从而提高药物疗效。所制备的纳米材料不仅可以提高抗阿尔茨海默症活性,也对阿尔茨海默症的治疗效果作出有效的评估,具有重要的研究意义和潜在的药物应用价值。我们首先合成了丙烯酰化的壳聚糖聚合物(Acryl-CS)和含有分子间多重氢键的多肽残基CFFVLKG-PEG368,并分别通过核磁共振(NMR)和飞行质谱对其进行了表征。接着,我们将CFFVLKG-PEG368与自噬激活肽Beclin-1(CTNVFNATFHIWHSGQFGT)按照1:1的比例,通过迈克尔加成反应方式与Acryl-CS进行反应,进而得到多肽-聚合物体系CS-K-B(M3),利用NMR对其结构进行了表征。该聚合物多肽M3在缓冲溶液中会自组装成纳米颗粒,通过透射电子显微镜(TEM)对其形貌进行表征,显示为直径为43.8±11.1 nm纳米颗粒。一方面,M3纳米材料中含有Aβ的同源序列KLVFF,可以识别Aβ并与其共组装,进而阻止Aβ的纤维化;另一方面,由于M3功能化修饰了自噬激活肽Beclin-1,可以上调细胞的自噬,因此,当M3与Aβ组成的共组装体进入细胞之后细胞的自噬功能被激活或上调,进而通过自噬降解Aβ。因此,两种相互协同的策略,能够实现阿尔茨海默症有效治疗。
[Abstract]:Alzheimer's disease is one of the most typical neurodegenerative diseases. In recent years, one of the biggest challenges facing the Alzheimer disease treatment institute has been how to maintain the balance of beta-amyloid A 尾 in the body. Because of its unique characteristics, it has been widely used in many fields of disease treatment, including common neurological diseases, and has great biological application value. Among them, polypeptide polymer nanomaterials as a new type of functional materials, It has good biocompatibility and safety. By modifying the polypeptide residues with different biological effects, we can realize that the single material has many biological effects. To improve the efficacy of the drug. The prepared nanomaterials not only improve the anti-Alzheimer 's activity, but also effectively evaluate the efficacy of the treatment of Alzheimer's disease. It has important research significance and potential drug application value. Firstly, we synthesized acryl-CSA, a chitosan polymer, and polypeptide residues containing intermolecular multiple hydrogen bonds, CFFVLKG-PEG368, which were synthesized by NMR and FMS, respectively. It was characterized. Then, We reacted CFFVLKG-PEG368 with the autophagy activating peptide Beclin-1 CTNVFNATFHIWHSGQFGT1 at 1: 1 by Michael's addition reaction with Acryl-CS. The structure of CS-K-BN M3N was characterized by NMR. The polypeptide M3 was self-assembled into nanoparticles in buffer solution and characterized by transmission electron microscopy (TEM). On the one hand, the homologous sequence KLVFFFF containing A 尾 in the M3 nanomaterials can recognize A 尾 and co-assemble with it, thereby preventing the fibrosis of A 尾. Since M3 functionalizes the autophagy activating peptide Beclin-1, it can up-regulate the autophagy of the cells. Therefore, the autophagy function of the cells is activated or upregulated when the co-assembly of M3 and A 尾 enters the cell, and the autophagy degrades A 尾 through autophagy. Two synergistic strategies can be used to effectively treat Alzheimer's disease.
【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.1;TB383.1

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