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针对血管细胞的基因治疗代表了一种有望用于预防和治疗内膜增生、血管支架狭窄和血管成形术后狭窄等病理状态的方法.聚合物非病毒载体的基因传递系统可以安全替代病毒载体,但是为了提高临床效果,它们的治疗效率及细胞相容性还需要进一步改善.本文合成了一系列24种被疏水基团修饰的分枝状聚乙酰亚胺衍生物(bPEI),并进行了表征及在体外原发性血管细胞内的测试,旨在筛选出具有优异的转染效率和低细胞毒性的传递剂.低分子量的聚乙酰亚胺(0.6,1.2 and 2 kDa)以不同取代程度接枝上了不同饱和度的长(C18)和短(C3)的不饱和脂肪链.丙酰取代衍生物(PEI2-PrA1,C3:0)在血管平滑肌细胞和内皮细胞转染中是最有效的,与著名的黄金标准25 kDa bPEI相比,具有更优异、更持久的基因表达,且毒性更低.此外,亚油酰基取代衍生物(PEI1.2-LA6,C18:2)由于在血管平滑肌细胞转染过程中效率高,而在内皮细胞中相对无效,且其具有可容忍的细胞毒性,可作为特定靶向于血管平滑肌细胞的载体.
Gene therapy targeting vascular cells represents a promising approach for the prevention and treatment of pathologies such as intimal hyperplasia, stenosis of the stents and stenosis after angioplasty, etc. Gene delivery systems for non-viral vectors can safely replace viral vectors, However, in order to improve the clinical efficacy, their therapeutic efficiency and cell compatibility still need further improvement.In this paper, a series of 24 kinds of hydrophobic group-modified branched polyethyleneimine derivatives (bPEI) were synthesized and characterized And in vitro primary vascular cells in order to screen out a transfection agent with excellent transfection efficiency and low cytotoxicity.Low molecular weight polyimides (0.6, 1.2 and 2 kDa) with varying degrees of substitution (C18) and short (C3) unsaturated fatty chains with different degrees of saturation.The propionyl substituted derivatives (PEI2-PrA1, C3: 0) were most effective in the transfection of vascular smooth muscle cells and endothelial cells , Which has superior and longer lasting gene expression and lower toxicity compared with the well-known gold standard 25 kDa bPEI.In addition, linoleoyl-substituted derivatives (PEI1.2-LA6, C18: 2) During cell transfection It is highly efficient but relatively ineffective in endothelial cells and has tolerable cytotoxicity as a carrier that is specifically targeted to vascular smooth muscle cells.