title: Combination of PEI-Mn0.5Zn0.5Fe2O4 nanoparticles and pHsp 70-HSV-TK/GCV with magnet-induced heating for treatment of hepatoma.
abstract: BACKGROUND
  To explore a new combination of thermal treatment and gene therapy for hepatoma, a heat-inducible herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy system was developed in which thermal energy generated by Mn0.5Zn0.5Fe2O4 nanoparticles (MZF-NPs) under an alternating magnetic field was used to activate gene expression.
  
  
  METHODS
  First, a recombinant eukaryotic plasmid, pHsp 70-HSV-TK, was constructed as a target gene for therapy. This recombinant plasmid was used to transfect SMMC-7721 hepatoma cells and the gene expression was evaluated. Magnet-induced heating was then applied to cells to assess the antihepatoma effects of the polyethylenimine (PEI)-MZF-NPs/pHsp 70-HSV-TK/GCV complex, in vitro and in vivo.
  
  
  RESULTS
  The results showed that cells were successfully transfected with pHsp 70-HSV-TK and that expression levels of HSV-TK remained stable. Both in vitro and in vivo results indicated that the combination of gene therapy and heat treatment resulted in better therapeutic effects than heating-alone group. The rates of apoptosis and necrosis in the combined treatment group were 49.0% and 7.21%, respectively. The rate of inhibition of cell proliferation in the combined treatment group was significantly higher (87.5%) than that in the heating-alone group (65.8%; P<0.01). The tumor volume and mass inhibition rates of the combined treatment group were 91.3% and 87.91%, respectively, and were significantly higher than the corresponding rates of the heating-alone group (70.41% and 57.14%; P<0.01). The expression levels of Stat3 and Bcl-xL messenger RNA and p-Stat3 and Bcl-xL protein in the combined treatment group were significantly lower than those in the other groups (P<0.01). The expression levels of Bax messenger RNA and protein in the recombinant plasmid group were significantly higher than those in the other groups (P<0.01).
  
  
  CONCLUSIONS
  It can therefore be concluded that the combined application of heat treatment and gene therapy has a synergistic and complementary effect and that PEI-MZF-NPs can simultaneously act both as a nonviral gene vector and a magnet-induced source of heat, thereby representing a viable approach for the treatment of cancer.
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Qiusha
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Genetic Laboratory, Wuxi Hospital for Maternal and Child Health Care, the Affiliated Hospital of Nanjing Medical University, Wuxi, People's Republic of China.
authors.forename: Mudan
authors.initials: M
authors.lastname: Lu
authors.affiliation: Genetic Laboratory, Wuxi Hospital for Maternal and Child Health Care, the Affiliated Hospital of Nanjing Medical University, Wuxi, People's Republic of China.
authors.forename: Daozhen
authors.initials: D
authors.lastname: Chen
authors.affiliation: School of Medicine, Southeast University, Nanjing, People's Republic of China.
authors.forename: Peidang
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D006801:Humans; D006979:Hyperthermia, Induced; D008113:Liver Neoplasms / Q000628:therapy*; D059346:Magnets; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011094:Polyethyleneimine / Q000494:pharmacology; D015183:Restriction Mapping; D017422:Sequence Analysis, DNA; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D011094:Polyethyleneimine; D013937:Thymidine Kinase; D015774:Ganciclovir
keywords: HSV-TK/GCV; Mn0.5Zn0.5Fe2O4 nanoparticles; SMMC-7721 hepatoma cells; gene therapy; heat-inducible gene expression; hyperthermia