Organ distribution and antitumor activity of free and liposomal doxorubicin injected into the hepatic artery.

The plasma levels, organ distribution, and in vivo antitumor activity of free and liposomal doxorubicin injected into the hepatic artery of rats bearing W256 liver tumors were studied. The administration of liposomal doxorubicin resulted in liver-tumor and liver-parenchyma doxorubicin areas under the curve (AUCs) that were 4.7- and 3.8-fold, respectively, those obtained after the administration of free doxorubicin. Spleen and plasma AUCs were also increased by 2.8 and 2.5 times, respectively, following administration of the liposomal form. In contrast, liposomal doxorubicin did not affect heart AUCs; peak doxorubicin levels in heart tissue were three times lower in animals treated with liposomal doxorubicin. Following treatment with the liposomal form, the cumulative urinary excretion of doxorubicin at 8 h was 38 times lower. In good correlation with these findings, liposomal doxorubicin (2.35 mg/kg on day 7) was more effective than free doxorubicin against liver W256 tumors as measured by tumor-growth inhibition at 5 days after treatment (16% for liposomal doxorubicin versus -53.7% for free doxorubicin, P < 0.05) and increased life span (ILS; 108% for liposomal doxorubicin versus 27% for free doxorubicin, P < 0.05). These results demonstrate that as compared with free doxorubicin, the administration of liposomal doxorubicin into the hepatic artery results in higher drug levels in the liver tumor and enhanced antitumor activity while maintaining the cardioprotective effect of the liposome carrier as suggested by the decreased peak drug levels measured in the heart tissue.