Structural advantage of dendritic poly(L-lysine) for gene delivery into cells
Structural advantage of dendritic poly(L-lysine) for gene delivery into cells
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DOI：
10.1016/j.bmc.2006.09.033
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Niidome, Takuro
中科院分区：
文献类型：
--
作者：
Yamagata, Masato;Kawano, Takahito;Niidome, Takuro
本研究旨在研究基因载体分子的结构与其将基因递送至细胞的活性之间的关系。我们比较了两种类型的聚（L-赖氨酸）载体，即树枝状聚（L-赖氨酸）（KG6）和线性聚（L-赖氨酸）（PLL）。 KG6形成中性DNA复合物，其DNA压实水平弱于PLL。 PLL介导的DNA结合和摄取到细胞中的量比KG6高4倍。然而，KG6 介导的基因表达比 PLL 高 100 倍。由于即使少量 DNA 内化到细胞中，KG6 末端胺的 pK(a) 值也会降低，因此由于内体中的质子海绵效应，足够用于有效基因表达的 DNA 量逃逸到细胞质中。此外，用 KG6 弱压缩 DNA 有利于接触细胞核中的 RNA 聚合酶。另一方面，PLL在内体中没有表现出质子海绵效应，导致DNA强烈压缩。尽管大量 DNA 被内化到细胞中，但大多数 DNA 不会参与细胞核中的基因表达系统。静脉内注射KG6和PLL的DNA复合物后诱导的细胞因子产生量较低，与单独注射DNA时的情况相似。因此，KG6 和 PLL 之间对细胞因子产生的影响没有观察到显着差异。 (c) 2006 Elsevier Ltd. 保留所有权利。
This study aimed to investigate the relationships between structures of gene carrier molecules and their activities for gene delivery into cells. We compared 2 types of poly(L-lysine) as carriers, that is, dendritic poly(L-lysine) (KG6) and linear poly(L-lysine) (PLL). KG6 formed a neutral DNA complex, and its DNA compaction level was weaker than that of PLL. The amount of DNA binding and uptake into cells mediated by PLL was 4-fold higher than that with KG6. However, KG6-mediated gene expression was 100-fold higher than that by PLL. Since pK(a) values of terminal amines of KG6 were lowered even though small amounts of DNA were internalized into cells, sufficient DNA amounts for effective gene expression escaped to the cytosol due to the proton sponge effect in the endosome. In addition, weakly compacted DNA with KG6 was advantageous in accessing RNA polymerase in the cell nucleus. On the other hand, PLL did not show the proton sponge effect in the endosome and resulted in strong compaction of DNA. Even though large DNA amounts were internalized into cells, most of the DNA would not take part in gene expression systems in the nucleus. Amount of induced cytokine production after intravenous injection of DNA complexes with KG6 and PLL was low, and was similar to the case when DNA was injected alone. Therefore, no significant difference in effects on cytokine production was observed between KG6 and PLL. (c) 2006 Elsevier Ltd. All rights reserved.