Efficacy of liposomal as compared with free ampicillin in treatment of infection due to Listeria monocytogenes was studied in normal and congenitally athymic (nude) mice. After intravenous injection the multilamellar vesicles used were taken up mainly by liver and spleen, the target organs of L. monocytogenes. Injection of empty liposomes in two doses of 2 mumol of vesicle lipid each, administered at 40 and 112 hr after bacterial inoculation, did not influence the course of listerial infection in normal and nude mice. In normal mice liposomal entrapment of ampicillin resulted in significant improvement in the antibiotic's therapeutic index. The use of liposomal ampicillin at a total dose of 0.54 mg (two doses of 0.27 mg each) resulted in a therapeutic effect similar to that resulting from a total dose of 48 mg of free ampicillin (eight doses of 6 mg each). However, neither ampicillin treatment schedules cured infections in nude mice.

We investigated the intracellular metabolic fate of choline-labeled phosphatidylcholines and sphingomyelin taken up by rat Kupffer cells in maintenance culture during interaction with large unilamellar liposomes composed of cholesterol, labeled choline-phospholipid and phosphatidylserine (molar ration 5 : 4 : 1).With both labeled compounds only small proportions of water-soluble radioactivity were found to accumulate in the cells and in the culture medium, suggesting limited phospholipid degradation. However, after a lag period of 30 min progressively increasing proportions of cell-associated liposomal phospholipid were found to be converted to cellular phospholipid, nearly all of which was phosphatidylcholine. This conversion as well as the limited release of watersoluble label from the cells was inhibited by the lysosomotropic agents ammonium chloride and chloroquine.With [Me-'4C]choline-labeled lysophosphatidylcholine, label was found to become cell-associated far in excess of an encapsulated liposomal label, [3H]inulin. Without a lag period virtually all of this was rapidly converted to phosphatidylcholine, a process which was not inhibited by the lysosomotropic agents..It is concluded that Kupffer cells, after endocytosis of liposomes, degrade the liposomal phospholipids effectively but reutilize the choline moiety for de novo synthesis of cellular phosphatidylcholine.

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While investigating the effects of 5-fluorouracil (5FU) on the tumoricidal state of rat liver macrophages activated in vitro by means of liposome-encapsulated muramyl dipeptide (MDP), we observed that 5FU in combination with macrophages produced substantially higher extents of cytolytic activity on tumor cells than 5FU alone. 5FU was able to enhance the cytolytic activity of macrophages activated by liposome-encapsulated MDP. This finding indicates that, rather than inhibiting the activation of macrophages by liposomal MDP, 5FU can act as a stimulator of macrophage activation by itself. This is further supported by the observation that a second treatment of macrophages with the drug, 24 h after the first, fails to produce increased macrophage cytotoxicity. Our results also show that 5FU does not unfavorably influence the induction of cytotoxic activity of the macrophages. Rather, combinations of 5FU and liposomal MDP may result in an additive or synergistic tumoricidal effect. The therapeutic effect of a combination of liposomal MDP and 5FU was studied in a murine tumor model of hepatic metastases of the tumor cell line C26, a colon adenocarcinoma. Liposomal MDP and a low, non-toxic, dose of 5FU were mixed and administered during six consecutive days once daily. Treatment was initiated four days after intrasplenic tumor cell injection. The combination of liposomal MDP and 5FU significantly reduced the number of liver metastases and the total tumor load in the liver. The liver weights of 27 Copyright 0 1994 by Marcel Dekker, Inc. Journal of Liposome Research Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/02/14 For personal use only. 28 DAEMEN ET AL.tumor bearing mice treated with the combination were significantly lower than the liverweights of control mice and of mice treated with 5FU alone or liposomal MDP alone. Liposomal MDP and 5FU when given as single treatment modalities had no significant effect on the number of metastases and liverweight. These results show that liposomal MDP can enhance the therapeutic effect of 5FU for the treatment of liver metastases.