The p53 tumor suppressor gene is the most frequently mutated gene identified in marly tumors, including hepatocellular carcinoma (HCC). Gene therapy using the p53 gene has been Proposed and performed with inactivation of p53 function. However, there have been few reports of nonviral vector-mediated p53 gene delivery in HCC. In this study, the wild-type p53 (wt-p53) gene was transfected into human hepatocellular carcinoma cell line HepG(2) using the urocanic acid-modified chitosan (UAC) as a nonviral vector, and transfection efficiency was determined by FACS analysis. UAC-mediated p53 transfection in HepG(2) cells resulted in high expression levels of wt-p53 mRNA and protein and significant cellular growth inhibition. DAPI staining and Annexin V/PI double-staining assay revealed apoptosis occurrence in HepG(2) cells after treatment with UAC/pEGFP-p53 complexes. In in vivo studies, intratumoral injection of UAC/pEGFP-p53 complexes into BALB/c nude mice bearing HepG(2) cells clearly suppressed tumor growth, and significantly induced apoptosis. These results demonstrated that UAC-mediated efficient p53 gene transfer could induce apoptosis thereby significantly inhibiting the growth of HepG(2) cells in vitro and in vivo, and suggested that UAC-mediated p53 gene delivery might be a promising approach for HCC gene therapy. (C) 2008 Elsevier Inc. All rights reserved.