Histone deacetylase inhibitor prodrugs in nanoparticle vector enhanced gene expression in human cancer cells.
Histone deacetylase inhibitor prodrugs in nanoparticle vector enhanced gene expression in human cancer cells.
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DOI：
10.1016/j.ejmech.2009.06.036
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发表时间：
2009-11
影响因子：
6.7
通讯作者：
Y. Ishii;Y. Hattori;Toshiharu Yamada;S. Uesato;Y. Maitani;Y. Nagaoka
中科院分区：
文献类型：
--
作者：
Y. Ishii;Y. Hattori;Toshiharu Yamada;S. Uesato;Y. Maitani;Y. Nagaoka
我们开发了组蛋白去乙酰化酶抑制剂（HDACI）前药，以增强阳离子纳米颗粒（NPs）转染到人类细胞中的外部基因的表达。我们合成了五种脂质连接的HDACI前药，其中正十二烷酸或胆固醇通过酯键或二硫碳酸酯连接基与有效的HDACI K-182连接。前药能够作为NP的组分混合，尽管完整的K-182未掺入NP中。即，制备由胆固醇基-3 β-羧酰胺基乙烯-N-羟乙胺和吐温80与10mol%K-182前药组成的NP作为DNA载体，以将质粒DNA转染到人前列腺癌细胞PC-3或人乳腺癌细胞Sk-Br-3中。含有K-182前药和正十二烷酸的NP表现出比原始NP高2至4倍的基因表达。基因表达的增强将是由于由整合到细胞中的载体中的前药降解的完整K-182引起的核心组蛋白的超乙酰化。
We developed histone deacetylase inhibitor (HDACI) prodrugs to enhance the expression of the external genes transfected into human cells with cationic nanoparticles (NPs). We synthesized five kinds of lipid-linked HDACI prodrugs in which n-dodecanoic acid or cholesterol is linked with a potent HDACI, K-182, by an ester bond or a disulfide carbonate linker. The prodrugs were able to admix as a component of NPs, although the intact K-182 was not incorporated into NPs. Namely, NPs composed of cholesteryl-3β-carboxyamidoethylene-N-hydroxyethylamine and Tween 80 with the 10mol% K-182 prodrug were prepared as a DNA vector to transfect plasmid DNAs into human prostate cancer cells, PC-3, or human breast cancer cells, Sk-Br-3. The NPs containing K-182 prodrugs with n-dodecanoic acid exhibited two to four times higher the gene expression than the original NPs. The enhancement of the gene expression will be due to the hyperacetylation of core histones caused by intact K-182 degraded from the prodrug in the vector incorporated into the cells.