Amphiphilic block copolymers enhance cellular uptake and nuclear entry of polyplex-delivered DNA.
Amphiphilic block copolymers enhance cellular uptake and nuclear entry of polyplex-delivered DNA.
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DOI：
10.1021/bc800144a
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发表时间：
2008-10
影响因子：
4.7
通讯作者：
Kabanov, Alexander V.
中科院分区：
文献类型：
--
作者：
Yang, Zhihui;Sahay, Gaurav;Sriadibhatla, Srikanth;Kabanov, Alexander V.
这项工作首次证明了合成聚合物通过激活细胞运输机制来增强质粒DNA （pDNA）的摄取和核输入。聚（环氧乙烷）和聚（环氧丙烷）的非离子嵌段共聚物Pluronics作为赋形剂广泛应用于制药行业。我们之前证明Pluronics增加了i - κ b的磷酸化和随后的NFκB核定位，以及上调许多NFκB相关基因。在这项研究中，我们表明Pluronics以一种依赖启动子的方式通过pDNA/多阳离子复合物（“多聚体”）增强基因转移。Pluronic P123或P85添加到聚乙烯亚胺基多聚体中对多聚体粒径影响不大，但显著提高了几种细胞系pDNA的细胞摄取、核易位和基因表达。将Pluronics添加到转染后的多体转染细胞中，Pluronics增强了含有nfκ b结合位点的pDNA的细胞核输入，但对不含这些位点的pDNA的输入没有影响。综上所述，我们的研究表明Pluronics能快速激活NFκB，它能结合胞质中含有NFκB结合位点的启动子的pDNA，从而通过NFκB核易位增加pDNA的核输入。
This work for the first time demonstrates that synthetic polymers enhance uptake and nuclear import of plasmid DNA (pDNA) through the activation of cellular trafficking machinery. Nonionic block copolymers of poly(ethylene oxide) and poly(propylene oxide), Pluronics, are widely used as excipients in pharmaceutics. We previously demonstrated that Pluronics increase the phosphorylation of IκB and subsequent NFκB nuclear localization as well as upregulate numerous NFκB-related genes. In this study, we show that Pluronics enhance gene transfer by pDNA/polycation complexes (“polyplexes”) in a promoter-dependent fashion. Addition of Pluronic P123 or P85 to polyethyleneimine-based polyplexes had little effect on polyplex particle size but significantly enhanced pDNA cellular uptake, nuclear translocation and gene expression in several cell lines. When added to polyplex-transfected cells after transfection, Pluronics enhanced nuclear import of pDNA containing NFκB–binding sites, but have no effect on import of pDNA without these sites. All together, our studies suggest that Pluronics rapidly activate NFκB, which binds cytosolic pDNA that possesses promoters containing NFκB binding sites and consequently increases nuclear import of pDNA through NFκB nuclear translocation.
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