title: Codelivery of antitumor drug and gene by a pH-sensitive charge-conversion system.
abstract: In the present study, a gene and drug codelivery system was developed by electrostatic binding of polyethylenimine-poly(l-lysine)-poly(l-glutamic acid) (PELG), polyethylenimine (PEI), cis-aconityl-doxorubicin (CAD), and DNA. Zeta potential and drug release analysis confirmed the pH-responsive charge conversion and acid-sensitive drug release functional properties of the PELG/PEI/(DNA+CAD) system. Gel retardation assay and transfection experiment showed the codelivery system had effective DNA binding ability and good transfection efficiency on HepG2 cells. The therapeutic gene p53 was further employed to study its combinational effects with CAD. Cytotoxicity assay showed the half inhibitory concentration (IC50) of the PELG/PEI/(p53+CAD) codelivery system was lower than that of the gene or the drug delivery system. Confocal laser scanning microscopy (CLSM) showed that the drug and gene could be delivered into the cells simultaneously. A significant increase of p53 gene expression was achieved after HepG2 cells treated by PELG/PEI/(p53+CAD) codelivery system. The apoptosis experiment indicated clearly that the codelivery system could lead an effective apoptosis on tumor cells, which was beneficial for the treatment of cancer. The biodistribution and tumor accumulation of the codelivery system was explored via in vivo imaging in subcutaneous xenograft and in situ tumor models. The tumor and some major organs were excised and imaged, and the results showed that the codelivery system can accumulate efficiently in tumor for both tumor models. It can be suggested from the above results that the PELG/PEI/(DNA+CAD) codelivery system will have great potential applications in cancer therapy.
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, P. R. China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Guan
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.forename: Zixue
authors.initials: Z
authors.lastname: Jiao
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Zhaopei
authors.initials: Z
authors.lastname: Guo
authors.forename: Huayu
authors.initials: H
authors.lastname: Tian
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004338:Drug Combinations; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011108:Polymers / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D011108:Polymers; D004317:Doxorubicin; D004247:DNA
keywords: cancer therapy; charge conversion; codelivery; doxorubicin; p53; pH-sensitive