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首页> 外文期刊>Chemistry: A European journal >Polycationic Amphiphilic Cyclodextrins for Gene Delivery: Synthesis and Effect of Structural Modifications on Plasmid DNA Complex Stability, Cytotoxicity, and Gene Expression
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Polycationic Amphiphilic Cyclodextrins for Gene Delivery: Synthesis and Effect of Structural Modifications on Plasmid DNA Complex Stability, Cytotoxicity, and Gene Expression

机译：聚阳离子两亲环糊精用于基因传递：合成和结构修饰对质粒DNA复合物稳定性，细胞毒性和基因表达的影响。

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摘要

A molecular-diversity-oriented approach for the preparation of well-defined polycationic amphiphilic cyclodextrins (paCDs) as gene-delivery systems is reported. The synthetic strategy takes advantage of the differential reactivity of primary versus secondary hydroxyl groups on the CD torus to regio-selectively decorate each rim with cationic elements and lipophilic tails, respectively. Both the charge density and the hydrophobic-hydrophilic balance can be finely tuned in a highly symmetrical architecture that is reminiscent of both cationic lipids and cationic polymers, the two most prominent types of nonviral gene vectors. The monodisperse nature of paCDs and the modularity of the synthetic scheme are particularly well suited for structure-activity relationship studies. Gel electrophoresis revealed that paCDs self-assemble in the presence of plasmid DNA (pDNA) to provide homogeneous, stable nanoparticles (CDplexes) of 70-150 nm that fully protect pDNA from the environment. The transfection efficiency of the resulting CDplexes has been investigated in vitro on BNL-CL2 and COS-7 cell lines in the absence and presence of serum and found to be intimately dependent on architectural features. Facial amphiphilicity and the presence of a cluster of cationic and hydrogen-bonding centers for cooperative and reversible complexation of the polyanionic DNA chain is crucial to attain high transgene expression levels with very low toxicity profiles. Further enhancement of gene expression, eventually overcoming that of polyplexes from commercial polyethyleneimine (PEI) polymers (22 kDa), is achieved by building up space-oriented dendritic polycationic constructs.
机译：报道了一种以分子多样性为导向的方法，用于制备定义明确的聚阳离子两亲环糊精（paCD）作为基因传递系统。合成策略利用了CD圆环上伯羟基和仲羟基的不同反应性，分别在区域选择性地用阳离子元素和亲脂性尾巴修饰了每个边缘。电荷密度和疏水-亲水平衡都可以在高度对称的结构中进行微调，这种结构让人联想到两种最突出类型的非病毒基因载体阳离子脂质和阳离子聚合物。 paCD的单分散性质和合成方案的模块性特别适用于结构活性关系研究。凝胶电泳显示，在质粒DNA（pDNA）存在的情况下，paCD会自组装，以提供70-150 nm的均匀，稳定的纳米颗粒（CDplex），从而完全保护pDNA免受环境污染。在没有血清和存在血清的情况下，已在BNL-CL2和COS-7细胞系上体外研究了所得CDplex的转染效率，发现其与体系结构特征密切相关。面部两亲性以及聚阴离子DNA链协同和可逆络合的阳离子和氢键中心簇的存在对于获得高转基因表达水平和极低毒性谱至关重要。通过构建面向空间的树枝状聚阳离子构建体，可以实现基因表达的进一步增强，最终克服商业聚乙烯亚胺（PEI）聚合物（22 kDa）的多链体的表达。

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