Targeting liver tumors by administering liposomal doxorubicin into the hepatic artery

The plasma levels, organ distribution, and in vivo anti-tumor activity of liposomal doxorubicin administered i.v. or i.a. (hepatic) in rats bearing W256 liver tumors were studied. I.a. administration of liposomal doxorubicin resulted in 4-fold and 1.3-fold higher liver tumor and liver parenchyma doxorubicin levels, respectively, than i.v. administration, thus suggesting a more preferential distribution of liposomal doxorubicin into the liver tumor with i.a. administration. By contrast, the heart, spleen, and plasma AUCs were decreased 3.8-, 3.2-, and 16-fold, respectively, after i.a. administration. Cumulative urinary excretion at 8 hr was also 14 times lower in animals that received liposomal doxorubicin i.a. In good correlation with these findings, i.a. administration markedly enhanced the anti-tumor effect of liposomal doxorubicin against liver W256 tumors as measured by tumor growth inhibition 5 days after treatment (-16% for i.a. administration vs. +89% for i.v. administration, p less than or equal to 0.05) and prolongation of survival (ILS: 108% for i.a. administration vs. 26% for i.v. administration, p less than or equal to 0.05). Our results show that i.a. administration of liposomal doxorubicin results in preferential distribution of the anti-tumor agent into the tumor tissue and increased anti-tumor activity, while increasing the cardioprotective effect of the liposome carrier by decreasing the plasma peak and heart-tissue levels of the drug.