title: Therapeutic efficacy of improved α-fetoprotein promoter-mediated tBid delivered by folate-PEI600-cyclodextrin nanopolymer vector in hepatocellular carcinoma.
abstract: SNPs in human AFP promoter are associated with serum AFP levels in hepatocellular carcinoma (HCC), suggesting that AFP promoter variants may generate better transcriptional activities while retaining high specificity to AFP-producing cells. We sequenced human AFP promoters, cloned 15 different genotype promoters and tested their reporter activities in AFP-producing and non-producing cells. Among various AFP variant fragments tested, EA4D exhibited the highest reporter activity and thus was selected for the further study. EA4D was fused with tBid and coupled with nano-particle vector (H1) to form pGL3-EA4D-tBid/H1. pGL3-EA4D-tBid/H1 could express a high level of tBid while retain the specificity to AFP-producing cells. In a HCC tumor model, application of pGL3-EA4D-tBid/H1 significantly inhibited the growth of AFP-producing-implanted tumors with minimal side-effects, but had no effect on non-AFP-producing tumors. Furthermore, pGL3-EA4D-tBid/H1 could significantly sensitize HCC cells to sorafenib, an approved anti-HCC agent. Collectively, pGL3-EA4D-tBid/H1, a construct with the AFP promoter EA4D and the novel H1 delivery system, can specifically target and effectively suppress the AFP-producing HCC. This new therapeutic tool shows little toxicity in vitro and in vivo and it should thus be safe for further clinical tests.
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; Department of Gastrointestinal Surgery, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.
authors.forename: Bao-guang
authors.initials: BG
authors.lastname: Hu
authors.affiliation: Department of Hepatobiliary and Pancreas Department of Hepatobiliary Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People׳s Hospital), Shenzhen, Guangdong Province, China.
authors.forename: Li-ping
authors.initials: LP
authors.lastname: Liu
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China. Electronic address: gchen@cuhk.edu.hk.
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Cai Guo
authors.initials: CG
authors.lastname: Ye
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Kevin K C
authors.initials: KK
authors.lastname: Leung
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Rocky L K
authors.initials: RL
authors.lastname: Ho
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
mesh_terms: D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D002482:Cellulose / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry; D005492:Folic Acid / Q000737:chemistry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D053758:Nanoparticles / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000235:genetics*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D003505:Cyclodextrins; D000509:alpha-Fetoproteins; C041953:cyclodextrin polymer; D011094:Polyethyleneimine; D002482:Cellulose; D005492:Folic Acid
keywords: AFP promoter; Folate grafted PEI600-CyD; HCC; tBid