Increase cytotoxicity efficacy of doxorubicin-loaded nanoparticles agains hepatocellular carcinoma cells in vitro and in vivo.

L Barraud, PhDa,b P Merle, MDa E Soma, PhDbL Lefrancois a S Guerret, PhDc, M Chevallier, MDd, C Dubernet, PhDe, P Couvreur, PhDe, C Trepo, MDa, L Vitvitski, PhDa

a INSERM U271, Lyon, France, b Bioalliance pharma, Paris, France, c Novotec, Lyon, France, d Laboratoire Marcel Merieux, Lyon,France, e UMR 8612 Faculte de Pharmacie, Chatenay Malabry, France.

AIM: Unresectable human hepatocellular carcinoma (HCC) is associated with a poor prognosis due to its MultiDrug Resistance (MDR). The aims of our study were : i) to evaluate cytotoxic efficacy of doxorubicin-loaded nanoparticles (Transdrug-doxorubicin) against HCC cells lines; ii) evaluation of drug cytotoxicity in an HCC murin model, iii) to evaluate its impact on survival of this murin model. METHODS: i) Comparison of the use of IC50s of Transdrug-doxorubicin and doxorubicin in four HCC cell lines: HuH7, HepG2, HepG2.2.15 and HepaRG2, ii) VHB-X/myc bitransgenic mice(1) were used to study the cytotoxicity of drugs on HCC (9mg/kg, 1 iv injection) using the TUNEL technique and the histological quantification of necrotic bodies, iii) survival was followed on groups of 15 mice treated by drugs (3 iv injections at 3 weeks interval, 6mg/kg, started at 18 or 25 weeks). RESULTS: i) Transdrug-doxorubicin is always more cytotoxic than doxorubicin in the cell lines used except for HepG2.2.15. IC50s were decreased 1.2 to 4.3 fold. ii) in vivo, TUNEL analysis showed a two-fold higher efficacy of Transdrug-doxorubicin (p=0.009/controls) versus doxorubicin (p=0.05/controls). Histological examination determined that response to doxorubicin was partial and complete with Transdrug-doxorubicin. The two experiments undergone seem to confirm this in vivo increase in efficacy. iii) in advanced HCCs, an increase in survival is observed in the drug treated groups, without advantage in use of Transdrug-doxorubicin (after only three treatments). CONCLUSIONS : Transdrug-doxoribicin is more cytotoxic on HCC cells in vitro and in vivo than doxorubicin. The curative effect of this drug on HCC in vivo needs further investigation using new developed sonographic longitudinal follow up. (1) Terradillos, Oncogene 1997;14.

KEY WORDS: MDR resistance, doxorubicin-loaded nanoparticles.

For more information, contact

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.