Tumor Cell Binding and Induction of Endothelial Cell Tumoricidal Activity In Vitro by Muramyl Dipeptide Is Enhanced by Liposomal Encapsulation

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Abstract
We investigated the ability of phosphatidylcholine (PC):phosphatidylserine (PS) liposomes containing muramyl dipeptide (MDP) to enhance tumor cell binding and induction of vascular endothelial cell tumoricidal activity in vitro against syngeneic B16-BL6 melanoma tumor cells. Endothelial cell-liposome interaction was influenced by the proportion of PS in the liposome and the length of fatty acid chain of PC. Optimum phagocytosis occurred with multilamellar liposomes (mean diameter 0.8 microns) composed of distearoylphosphatidylcholine (DSPC):PS, 1:1 molar ratio. Hydrosoluble MDP stimulated endothelial cell binding of tumor cells in the dose range 10-100 micrograms/ml. Liposome-incorporated MDP or liposomes containing the lipophilic MDP prodrug MDP-glyceroyl dipalmitate (GDP) significantly enhanced tumor cell binding in the dose range 0.01-1 micrograms/ml. MDP, MDP-containing liposomes, or liposomal MDP-GDP induced endothelial cell tumoricidal activity against B16-BL6 tumor cells with relative potencies of 1.0, 10, and 500, respectively. MDP or liposomal MDP did not induce or enhance endothelial cell nitric oxide (NO) synthase activity (as determined by NO2- production) in the absence or presence of interferon-tau (IFN-tau) or tumor necrosis factor-alpha (TNF-alpha), respectively, indicating the induction of an NO-independent cytotoxic mechanism.

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