Enhancement of adriamycin delivery to liver metastatic cells with increased tumoricidal effect using liposomes as drug carriers.

We have investigated the tissue distribution of liposome-entrapped Adriamycin (ADM) in mice with metastatic spread to the liver and spleen after inoculation of J-6456 lymphoma cells. Sonicated phosphatidylserine:phosphatidylcholine:cholesterol liposomes were used as carriers of ADM, based on previous studies on the drug entrapment, stability, and tissue distribution of ADM-containing liposomes of various compositions (A. Gabizon, A. Dagan, D. Goren, Y. Barenholz, and Z. Fuks. Cancer Res., 42: 4734-4739, 1982). Increased hepatic and splenic levels of ADM were found in tumor-bearing mice when the drug was injected in the liposome-entrapped form. Concomitantly, decreased cardiac uptake of ADM was observed in tumor-bearing mice treated with liposome-entrapped ADM. In order to measure the concentration of ADM directly in metastatic cells, J-6456 lymphoma cells were isolated from the liver by Percoll density gradients. It was found that the ADM levels were significantly augmented in tumor cells from mice given injections of liposome-entrapped ADM as compared to those given injections of free ADM at all time intervals checked after drug injection. In addition, the in vitro and in vivo growth ability of these isolated metastatic cells was significantly more impaired when they were obtained from mice receiving liposome-entrapped ADM as compared to mice which received free ADM. The histopathological damage to the normal liver parenchyma of mice treated with liposome-entrapped ADM was mild and confined to discrete foci and was not significantly different from that observed in mice treated with free ADM. These results indicate that liposome delivery may provide an efficient means of improving the therapeutic efficiency of ADM in certain forms of metastatic liver disease, while diminishing the potential hazard of cardiotoxicity.