Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini
Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini
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DOI：
10.1073/pnas.031577698
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发表时间：
2001-01-30
影响因子：
11.1
通讯作者：
Langer, R
中科院分区：
文献类型：
--
作者：
Putnam, D;Gentry, CA;Langer, R
将质粒DNA递送到细胞核后的蛋白质表达取决于转录和翻译过程。细胞毒性基因传递系统可能会损害这些过程，并限制蛋白质表达。这种情况可能在目前的非病毒聚阳离子基因递送系统中最普遍，其中递送系统的聚阳离子性质可导致细胞毒性。为了解决产生无毒但有效的基因递送系统的问题，我们假设通过优化聚合物阳离子密度与内体逃逸部分之间的平衡，可以产生具有低细胞毒性的有效基因转移。作为模型系统，我们合成了一系列聚合物，其侧链末端根据阳离子中心和内体逃逸部分的平衡而变化。具体地，通过聚合物类似酰胺化，我们以不同的摩尔比（73.5摩尔%咪唑、82.5摩尔%咪唑和86.5摩尔%咪唑）将咪唑基团缀合至聚赖氨酸的α-胺。聚赖氨酸的伯α-胺末端用作阳离子中心的模型，而咪唑基团用作内体逃逸部分的模型。这些聚合物将质粒DNA凝聚成纳米结构
Protein expression after delivery of plasmid DNA to the cell nucleus depends on the processes of transcription and translation. Cytotoxic gene-delivery systems may compromise these processes and limit protein expression. This situation is perhaps most prevalent in current nonviral polycationic gene-delivery systems in which the polycationic nature of the delivery system can lead to cytotoxicity, To approach the problem of creating nontoxic but effective gene-delivery systems, we hypothesized that by optimizing the balance between polymer cationic density with endosomal escape moieties, effective gene transfer with low cytotoxicity could be created, As a model system, we synthesized a series of polymers whose side-chain termini varied with respect to the balance of cationic centers and endosomal escape moieties. Specifically, by polymer-analogous amidation we conjugated imidazole groups to the epsilon -amines of polylysine in varying mole ratios (73.5 mol % imidazole, 82.5 mol % imidazole, and 86.5 mol % imidazole), The primary epsilon -amine terminus of polylysine served as a model for the cationic centers, whereas the imidazole groups served as a model for the endosomal escape moieties. These polymers condensed plasmid DNA into nanostructures