title: Increase of doxorubicin sensitivity by doxorubicin-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is known to be chemoresistant to anticancer drugs due to the multidrug resistant (MDR) transporters expression. Here, we compared in vitro and in vivo the anti-tumor efficacy of doxorubicin-loaded polyisohexylcyanoacrylate nanoparticles (PIHCA-Dox) versus free doxorubicin (Dox). These nanoparticles are known to overcome the MDR phenotype.
  
  
  METHODS
  We first determined in vitro the 50% inhibition concentration (IC(50)) of these drugs on different human hepatoma cell lines. Secondly, the efficacy of the drugs in vivo was determined on the X/myc transgenic murine model of HCC by histological counting of apoptotic tumorous hepatocytes and by TUNEL labeling. We characterized by semi-quantitative RT-PCR the MDR-related gene (mdr1, mdr3, mrp1) expression pattern in this model.
  
  
  RESULTS
  In vitro, IC(50) was reduced with PIHCA-Dox versus Dox for Huh7 (1.7-fold reduction; P<0.001), HepaRG (4.5-fold reduction; P<0.01), HepG2 (1.5-fold reduction; P<0.001), and HepG2.2.15 (1.5-fold reduction; P=0.059). In vivo, HCC in transgenic mice overexpressed the mdr1 and mdr3 genes and the antitumor drugs efficacy was greatly enhanced after injection of PIHCA-Dox (9.0+/-5.0%; n=15) versus Dox (4.6+/-3.3%; n=13; P=0.01) for apoptotic bodies count.
  
  
  CONCLUSIONS
  These promising data showing a higher anti-tumor efficacy on HCC of PIHCA-Dox versus Dox, warrant further studies in both animals and humans.
authors.affiliation: INSERM Unit 271, 151 Cours Albert Thomas, 69424 Lyon Cedex 03, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Barraud
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.forename: Emilienne
authors.initials: E
authors.lastname: Soma
authors.forename: Lydie
authors.initials: L
authors.lastname: Lefrançois
authors.forename: Sylviane
authors.initials: S
authors.lastname: Guerret
authors.forename: Michèle
authors.initials: M
authors.lastname: Chevallier
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubernet
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
authors.forename: Christian
authors.initials: C
authors.lastname: Trépo
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vitvitski
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003487:Cyanoacrylates; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D003487:Cyanoacrylates; D004317:Doxorubicin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C057532:polyisohexylcyanoacrylate; C421109:multidrug resistance-associated protein 1