甜菜碱衍生物在基因载体材料中的应用

发布时间：2018-06-12 01:18

本文选题：基因载体 + 甜菜碱衍生物　；参考：《浙江大学》2011年硕士论文

【摘要】：基因治疗作为一种全新的疾病治疗方法,可用于癌症、心血管疾病和病毒性疾病等的治疗。如何找到一种高效、安全的基因载体已成为了基因治疗的关键。本课题旨在研究以叔胺型聚羧酸甜菜碱酯(polycarboxybetaine ester, pCB-ester)在基因载体材料上的应用。作为阳离子聚合物类的非病毒基因载体材料,pCB-ester具有毒性低、免疫原性低、结构灵活可控、便于基因携带、合成方便、便于修饰、费用低廉等特点；当其与DNA的复合物被胞内吞进入溶酶体时,可以发挥“质子海绵”的作用；并且具有良好的生物相容性,能够在生理条件下水解为呈电中性的具有抗蛋白质非特异性吸附(nonfouling)性的两性离子材料,从而降低对受体细胞的各种生理活动及细胞结构的影响和破坏,从而获得比聚乙烯亚胺(PEI)等常用阳离子聚合物类基因转染材料更低的细胞毒性。实验结果表明pCB-ester已能实现以下功能：1)通过凝胶阻滞实验证明在N/P=1/1时就能够有效包裹DNA；2)从pCB-ester细胞毒性试验、细胞凋亡实验验证实其具有其他常用载体材料,如PEI和聚甲基丙烯酸二甲氨基乙酯(pDMAEMA)所没有的良好的生物相容性。另外,针对pCB-ester所表现出来的低转染效率,通过跟踪载体的转运、改变载体的正电荷密度以及溶酶体逃脱过程等实验,推测pCB-ester DNA载体的低转染效率可能与聚合物疏水强有关。通过对pCB-ester聚合物进行亲水设计的改进,转染效率已获得一定的改善,但是实现聚合物高效转染仍需要进一步的研究。综上所述,pCB-ester是一种具有极大潜力的基因载体材料,通过一步提高转染效率,有望发展出一类新型安全的非病毒基因载体材料。
[Abstract]:Gene therapy is a new method for the treatment of cancer, cardiovascular and viral diseases. How to find an efficient and safe gene vector has become the key of gene therapy. The purpose of this paper is to study the application of tertiary amine polycarboxybetaine ester (pCB-ester) in gene vector materials. PCB-ester, as a cationic polymer, has the advantages of low toxicity, low immunogenicity, flexible and controllable structure, easy gene carrying, convenient synthesis, easy modification and low cost. When its complex with DNA is internalized into lysosomes, it acts as a "proton sponge" and has good biocompatibility. It can be hydrolyzed into electroneutral amphoteric material with nonspecific adsorption of nonfouling. which can reduce the influence and destruction of various physiological activities and cell structure of receptor cells. The results show that pCB-ester can perform the following function: 1: 1) through gel retardation experiments, it is proved that pCB-ester can effectively package at 1 / 1 of N / Pe / 1 / 1 cationic polymer gene transfection material with lower cytotoxicity than that of common cationic polymer gene transfection materials such as polyethylene imide (PEI). DNA 2) from pCB-ester cytotoxicity test, Cell apoptosis test confirmed that it had good biocompatibility compared with other commonly used carrier materials such as PEI and pDMAEMAA. In addition, in view of the low transfection efficiency of pCB-ester, it was suggested that the low transfection efficiency of pCB-ester DNA vector might be related to the hydrophobic strength of the polymer by tracking the transport of the vector, changing the positive charge density of the vector and the process of lysosome escape. By improving the hydrophilic design of pCB-ester polymer, the transfection efficiency has been improved to some extent, but further research is needed to realize the efficient transfection of pCB-ester polymer. In conclusion, pCB-ester is a kind of gene vector material with great potential. By improving the transfection efficiency, it is expected to develop a new class of safe non-viral gene vector materials.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R346

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