新型改性聚乙烯亚胺脂质体载药系统用于传递寡核苷酸类药物的研究

发布时间：2018-06-25 00:34

本文选题：聚乙烯亚胺（PEI） + 寡核苷酸　；参考：《吉林大学》2015年博士论文

【摘要】：寡核苷酸是一类重要的特异性基因表达物质，包括小干扰RNA和反义寡核甘酸等，寡核苷酸作为治疗药物具有用量少，效果好，毒性低等优点，因此，在癌症、免疫治疗、肺部疾病和传染病等领域有着广阔的应用前景。寡核苷酸虽然效果较好，但存在以下问题：易被脱氧核糖核酸或核糖核酸酶降解、稳定性较差、具有较高的负电荷、难以跨膜等，因此治疗效果不理想。为了克服以上缺点，我们开发了新型的改性聚乙烯亚胺脂质体载药系统，传递寡核苷酸类药物，提高其稳定性和转染效果。本文自主合成了阳离子材料脂肪酸修饰的聚乙稀亚胺聚合物，并制备得到了脂质体载药系统；该载药系统毒性低，性质稳定，表面带有较强的正电荷，能够增强对细胞膜的亲和力，增强跨膜能力。采用脂质体载药系统传递寡核苷酸类药物，首先，，以反义寡核苷酸为例，制备纳米载药系统，得到了性质稳定的载药系统。结果显示该载药系统能够显著增加反义寡核苷酸的转染效果，增强其稳定性，在抗肿瘤实验中肿瘤细胞出现了凋亡现象。其次，为了进一步评价脂肪酸修饰的聚乙烯亚胺脂质体载药系统，我们又采用载药系统包裹小干扰核糖核酸（以下简称siRNA），使得siRNA的转染效果显著增强，具有明显的抗肿瘤效果。脂肪酸修饰的聚乙稀亚胺脂质体载药系统可以作为一种新型的寡核苷酸类药物载体，克服了聚乙稀亚胺较高的细胞毒性的缺点，能够与寡核苷酸形成比较稳定的体系，保护寡核苷酸不被降解，同时转染进入细胞，识别细胞活性位点，导致肿瘤细胞的凋亡。本文制备的脂肪酸修饰的聚乙烯亚胺阳离子脂质体与寡核苷酸形成的复合物传递系统，可以为今后进一步体内研究等工作打下坚实地基础，具有广阔的应用前景。
[Abstract]:Oligonucleotides are an important class of specific gene expression substances, including small interfering RNA and antisense oligonucleic acid. Oligonucleotides have the advantages of low dosage, good effect, low toxicity and so on. Pulmonary diseases and infectious diseases and other fields have a broad application prospects. Although the effect of oligonucleotides is good, there are some problems such as deoxyribonucleic acid or ribonuclease degradation, poor stability, high negative charge, difficult to transmembrane and so on, so the therapeutic effect is not ideal. In order to overcome these shortcomings, we developed a novel modified polyvinyleneimide liposome drug delivery system, delivery of oligonucleotide drugs, improve its stability and transfection effect. In this paper, polyethyleneimide polymer modified by cationic fatty acid was synthesized, and liposome drug loading system was prepared, which was characterized by low toxicity, stable properties and strong positive charge on the surface. Can enhance the affinity to the cell membrane, enhance the transmembrane ability. Oligonucleotides were transferred by liposome drug delivery system. Firstly, the antisense oligonucleotides were used as an example to prepare the nanometer drug carrier system, and a stable drug delivery system was obtained. The results showed that the drug carrier system could significantly increase the transfection effect of antisense oligodeoxynucleotides and enhance the stability of antisense oligodeoxynucleotides. Secondly, in order to further evaluate the fatty acid modified polyimide liposome drug delivery system, we also use drug carrier system to encapsulate small interfering ribonucleic acid (siRNA), so the transfection effect of siRNA is significantly enhanced, and has obvious anti-tumor effect. Fatty acid modified polyethylenimide liposome delivery system can be used as a new type of oligonucleotide drug carrier, overcome the shortcomings of high cytotoxicity of polyethyleneimide, and can form a more stable system with oligonucleotide. Protection of oligonucleotides from degradation, transfection into cells, recognition of cell active sites, leading to apoptosis of tumor cells. The fatty acid modified polyvinyleneimine cationic liposome and oligonucleotide complex transport system can lay a solid foundation for further research in vivo and have a broad application prospect.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R943

【共引文献】