Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model

Abstract

We have examined the anti-tumour activity of liposome-entrapped Adriamycin in a murine metastatic tumour model produced by i.v. inoculation of J-6456 lymphoma cells and affecting predominantly the liver. Sonicated liposomes containing phosphatidylcholine, a negatively-charged phospholipid and cholesterol were used in these experiments. Liposome-entrapped Adriamycin was more effective than free Adriamycin at equivalent doses of the drug. The superior therapeutic effect of the liposome-associated drug was manifest, either with a single i.v. treatment using a dose bordering the toxicity threshold of free Adriamycin or with a multi-injection schedule using smaller doses. Based on the growth kinetics data of the J-6456 lymphoma, our results indicate that tumour cell killing was enhanced by a factor of approximately 100 using the liposome associated form of Adriamycin. Histopathologic studies in mice bearing well-established metastases of the J-6456 lymphoma in liver and spleen indicated that the extent and duration of pathologic remission were significantly improved in mice receiving the liposome-entrapped drug as compared to mice receiving free drug. No significant differences in the anti-tumour effect of liposome entrapped Adriamycin were observed replacing phosphatidylserine by phosphatidylglycerol and reducing the cholesterol:phospholipid molar ratio from 100% to 25%. In contrast to the metastatic tumour model, liposome-entrapped Adriamycin was significantly less effective than free Adriamycin on the local i.m. growth of the J-6456 tumour. Altogether the survival and histopathological data presented suggest that, with regard to a group of neoplastic conditions with a predominant pattern of liver dissemination, a substantial increase in the therapeutic index of Adriamycin can be achieved in a selective manner with the use of liposomes.