Development of a nonviral gene delivery vehicle for systemic application
Development of a nonviral gene delivery vehicle for systemic application
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DOI：
10.1021/bc0155768
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发表时间：
2002-05-01
影响因子：
4.7
通讯作者：
Davis, ME
中科院分区：
文献类型：
--
作者：
Pun, SH;Davis, ME
用于体外基因递送的聚阳离子载体需要改变以在体内成功应用。通过直接接枝附加组分，例如，在DNA复合之前或之后，聚（乙二醇）（PEG）往往会干扰聚合物/DNA结合相互作用;这对于短聚阳离子如线性含β-环糊精的聚阳离子（β-CDP）是一个特别的问题。在这里，提出了一种新的方法betaCDP复合物（聚阳离子/DNA复合结构）的修改，利用环糊精和金刚烷之间形成包合物的能力。表面-PEG化的betaCDP复合物通过复合物与金刚烷-PEG缀合物的自组装形成。虽然未修饰的复合物在盐溶液中快速聚集和沉淀，但PEG化的betaCDP复合物在生理盐浓度的条件下是稳定的。向金刚烷-PEG缀合物中添加靶向配体允许受体介导的递送;基于半乳糖基化β CDP的颗粒显示通过脱唾液酸糖蛋白受体选择性靶向肝细胞。半乳糖基化颗粒转染肝癌细胞的效率比葡萄糖基化颗粒（对照）高10倍，但在缺乏脱唾液酸糖蛋白受体的细胞系中没有显示出优先转染。因此，通过使用环糊精/金刚烷主体/客体相互作用对基于betaCDC的聚合复合物进行表面修饰，赋予颗粒适合系统应用的性质。
Polycation vehicles used for in vitro gene delivery require alteration for successful application in vivo. Modification of polycations by direct grafting of additional components, e.g., poly(ethylene glycol) (PEG), either before or after DNA complexation, tend to interfere with polymer/DNA binding interactions; this is a particular problem for short polycations such as linear, beta-cyclodextrin-containing polycations (betaCDPs). Here, a new method of betaCDP polyplex (polycation/DNA composite structures) modification is presented that exploits the ability to form inclusion complexes between cyclodextrins and adamantane. Surface-PEGylated betaCDP polyplexes are formed by self-assembly of the polyplexes with adamantane-PEG conjugates. While unmodified polyplexes rapidly aggregate and precipitate in salt solutions, the PEGylated betaCDP polyplexes are stable at conditions of physiological salt concentration. Addition of targeting ligands to the adamantane-PEG conjugates allows for receptor-mediated delivery; galactosylated betaCDP-based particles reveal selective targeting to hepatocytes via the asialoglycoprotein receptor. Galactosylated particles transfect hepatoma cells with 10-fold higher efficiency than glucosylated particles (control), but show no preferential transfection in a cell line lacking the asialoglycoprotein receptor. Thus, surface modification of betaCDP-based polyplexes through the use of cyclodextrin/adamantane host/guest interactions endows the particles with properties appropriate for systemic application.