Increase of doxorubicin sensitivity by doxorubicin-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo

Background/Aims: 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 (IC50) 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 semiquantitative RT-PCR the MDR-related gene (mdr1, mdr3, mrp1) expression pattern in this model. Results: In vitro, IC50 was reduced with PHICA-Dox versus Dox for Huh7 (1.7-fold reduction; P < 0.001), HepaRG (4.5fold 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 PHICA-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 PHICA-Dox versus Dox, warrant further studies in both animals and humans. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.