Histidinylated poly-L-lysine-based vectors for cancer-specific gene expression via enhancing the endosomal escape.
In this work, we synthesized a series of poly-L-lysine (PLL)-based polymers for gene delivery, by modifying the PLL with both cationic peptide and histidine. The peptide moieties serve as cationic centers for polyplex formation, and also as substrates for protein kinase Cα (PKCα), which is specifically activated in many types of cancer cells, to achieve cancer-specific gene expression. The histidine groups serve as buffering moieties to increase the ability of the plasmid DNA (pDNA)-polymer complex (polyplex) to escape the endosome and thus to promote expression of the pDNA in the transfected cells. The facile synthesis of the polymers proceeded by modifying the PLL with side-group-protected peptide and protected histidine, followed by deprotection of the functional groups. The synthesized polymers showed significant buffering capacity over the neutral to acidic pH range and showed less cytotoxicity in vitro compared with histidine-unmodified polymers. The polyplexes successfully showed PKCα-responsive gene expression immediately after their introduction into cancer cells and the gene expression continued for at least 24 h. These PLL-based carriers thus show promise for cancer-targeted gene therapy.
a Graduate School of Systems Life Sciences , Kyushu University , 744 Motooka, Nishi-ku, Fukuoka 819-0395 , Japan.
Guo Xi
GX
Zhao
Hiroyuki
H
Tanaka
Chan Woo
CW
Kim
Kai
K
Li
Daiki
D
Funamoto
Takanobu
T
Nobori
Yuta
Y
Nakamura
Takuro
T
Niidome
Akihiro
A
Kishimura
Takeshi
T
Mori
Yoshiki
Y
Katayama
D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D011992:Endosomes / Q000378:metabolism*; D015870:Gene Expression; D015316:Genetic Therapy; D006639:Histidine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics; D011107:Polylysine / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection
D011107:Polylysine; D006639:Histidine; D004247:DNA