Histone deacetylase inhibitor prodrugs in nanoparticle vector enhanced gene expression in human cancer cells.
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-3beta-carboxyamidoethylene-N-hydroxyethylamine and Tween 80 with the 10 mol% 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.
Ishii
Yuta
Y
Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
Hattori
Yoshiyuki
Y
Yamada
Toshiharu
T
Uesato
Shinichi
S
Maitani
Yoshie
Y
Nagaoka
Yasuo
Y
D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011355:Prodrugs; D002784:Cholesterol