Therapy of Murine Liver Metastases by Administration of MDP Encapsulated in Liposomes

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Abstract
In a reproducible murine model of liver metastases, it was demonstrated that liposomal muramyl dipeptide (MDP) as an adjuvant therapy reduces and prevents the development of metastases. C26 colon adenocarcinoma cells were injected into the spleen (5x104 cells per mouse) of syngeneic BALB/c mice. On day 3, the spleen was removed to prevent a large tumor burden in the spleen. On day 17, 100 % of the mice had developed tumor foci in the liver. Liposomal MDP treatment consisted of the i.v. or i.p. administration of 1 umol of liposomal lipid containing 5 ug of MDP per mouse for ten consecutive days. When therapy was initiated two days after tumor cell inoculation, the number of metastases that had developed on day 17 was strongly reduced compared to control mice. Approximately 20 % of the mice were free of liver metastases. Initiation of therapy two days prior to tumor cell inoculation enhanced the effect significantly: about 45% of the mice were free of metastases on day 17. The treatment protocol for survival studies was slightly different; liposomal MDP was administered on the first six consecutive days followed by administration twice weekly, through day 24. Control mice died between day 21 and 33 after tumor cell inoculation, whereas liposomal MDP treated mice died between day 26 and 46 with 1 out of 25 mice surviving for more than 120 days. The mortality of the liposomal MDP treated mice that were free of liver metastases was caused by a local tumor at the site of operation. The results show that liposomal MDP strongly reduced the number of hepatic metastases developing after intrasplenic inoculation of tumor cells, and significantly prolonged the survival time of these tumor bearing mice.