Anti-tumor effects of polybutylcyanoacrylate nanoparticles of diallyl trisulfide on orthotopic transplantation tumor model of hepatocellular carcinoma in BALB/c nude mice

摘要

＜正＞ Background Hepatocellular carcinoma（HCC）ranked the second among the causes of cancer mortality in China sincethe 1990s.Up to now,medication still plays an important role in the treatment of HCC.The therapies based on the allicinas a potential chemopreventive analog although is in its infancy at the present time,may have a significant role in thefuture management of HCC.Diallyl trisulfide（DATS）is a natural compound derived from garlic.In this study,weinvestigated the inhibitory effects of hepatic targeted polybutylcyanoacrylate nanoparticles of diallyl trisulfide（DATS-PBCA-NP）on orthotopic transplanted HepG2 hepatocellular carcinoma in nude mice.Methods DATS-PBCA-NP were detected by transmission electron microscope（TEM）and high-performance liquidchromatography（HPLC）.The orthotopic transplantation HCC models were established by implanting HCC HepG2xenograft bits under the envelope of the mice liver.Successful models（n=29）were divided into 4 groups:normal saline（NS）,empty nanoparticles（EN）,DATS and DATS-PBCA-NP were intravenously administered to the mice respectively for2 weeks.In vivo antitumor efficacy was evaluated by the measurement of tumor volume.Terminal deoxynucleotidyltransferase mediated dUTP nick end labeling（TUNEL）assay and protein levels of apoptosis and cell proliferationproteins by immunoblotting in tumor tissues were performed to elucidate the possible mechanism.Results DATS-PBCA-NP possessed smooth and round appearance,dispersed well,and released in vitro in accordwith double phase kinetics model.DATS-PBCA-NP changed the tissue/organ distribution of DATS in vivo.The successfulrate of tumor implantation was 100%.Intravenous administration of DATS-PBCA-NP significantly retarded the growth oforthotopically transplanted hepatoma in BALB/c nude mice（compared with the other three groups,all P＜0.05）withoutcausing weight loss（P＞0.05）.TUNEL staining showed that the tumors from DATS-PBCA-NP treated mice exhibited amarkedly higher apoptotic index compared with control tumors.Western blot analysis of tumor tissue revealed that thedown-regulated expression of proliferation cell nuclear antigen（PCNA）and Bcl-2 proteins in DATS-PBCA-NP group,andthere were no significant differences in the expression of Fas,FasL and Bax proteins among the four groups（P＞0.05）.Conclusions DATS-PBCA-NP has good prolonged release effect in vivo and hepatic-targeted activity,and significantanti-tumor effect on the orthotopic transplantation HCC model in mice in association with the suppression of proliferationand the induction of apoptosis of tumor cells.These advantages are probably due to their liver targeting characteristicsand consequently bring a higher anti-tumor activity.