title: In vivo targeted gene delivery by cationic nanoparticles for treatment of hepatocellular carcinoma.
abstract: BACKGROUND
  Transgene expression in vivo for therapeutic purposes will require methods that allow for efficient gene transfer into cells. Although current vector technologies are being improved, the development of novel vector systems with improved targeting specificity, higher transduction efficiencies and improved safety is necessary.
  
  
  METHODS
  Asialoglycoprotein receptor-targeted cationic nanoparticles for interleukin (IL)-12 encapsulation (NP1) or adsorption (NP2) have been formulated by blending poly(D,L-lactic-co-glycolic) acid (PLGA) (50 : 50) with the cationic lipid 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP) and the ligand asialofetuin (AF), by using a modified solvent evaporation process.
  
  
  RESULTS
  We present a novel targeted lipopolymeric vector, which improves significantly the levels of luciferase gene expression in the liver upon i.v. administration. Targeted-NP2 particles showed a five- and 12-fold higher transfection activity in the liver compared to non-targeted (plain) complexes or naked pCMV DNA, respectively. On the other hand, BNL tumor-bearing animals treated with AF-NP1 containing the therapeutic gene IL-12, showed tumor growth inhibition, leading to a complete tumor regression in 75% of the treated mice, without signs of recurrence. High levels of IL-12 and interferon-gamma were detected in the sera of treated animals. Mice survival also improved considerably. Tumor treatment with AF-NP2 formulations lead only to a retardation in the tumor growth.
  
  
  CONCLUSIONS
  In the present study, we have developed an efficient targeted non-viral vector for IL-12 gene transfer in hepatocellular carcinoma in vivo, by employing non-toxic cationic PLGA/DOTAP/AF nanoparticles. These results demonstrate for the first time that this cationic system could be used successfully and safely for delivery of therapeutic genes with antitumor activity into liver tumors with targeting specificity.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Díez
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.forename: Conchita Tros
authors.initials: CT
authors.lastname: de ILarduya
mesh_terms: D000818:Animals; D001212:Asialoglycoproteins / Q000008:administration & dosage / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D060748:Fetuins; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000235:genetics*; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000737:chemistry; D019076:Transgenes; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D001212:Asialoglycoproteins; D005229:Fatty Acids, Monounsaturated; D060748:Fetuins; D000644:Quaternary Ammonium Compounds; D000509:alpha-Fetoproteins; C017029:asialofetuin; D018664:Interleukin-12; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane