Delivery of Macrophage Activating Factors by Means of Liposomes

Successful treatment of patients with cancer is often hampered by the development of metastases (Fidler, 1985). Especially the biological heterogeneity of metastatic tumor cells with respect to growth rate, ability to metastasize, sensitivity to various cytotoxic drugs etc. is a tremendous obstacle to complete eradication of tumor cells. Therefore, alternative methods for the treatment of metastases are highly desirable. Activation of the host mononuclear phagocyte system appears to be a promising approach towards that purpose (Fidler, 1985). In vitro exposure of monocytes and alveolar or peritoneal macrophages to a variety of macrophage activating factors such as lymphokines (Kleinerman et al., 1983), γ-interferon (Varesio et al., 1984) and muramyl dipeptide (MDP) (Lopez-Berestein et al., 1984; Fidler et al., 1982) has been shown to render these cells tumoricidal. After in vivo administration of free MDP, however, no enhancement of macrophage-mediated cytotoxicity is achieved since the drug is rapidly excreted from the body (Parant et al., 1979; Fogler et al., 1985). This circumstance calls for the design of an efficient drug delivery system for these agents. Studies on the use of liposomes as drug carriers have shown that these phospholipid vesicles are predominantly taken up by cells of the mononuclear phagocyte system (Roerdink et al., 1977; Ellens et al., 1981; Poste et al., 1982). Encapsulation of the MDP within liposomes indeed greatly enhances the ability of the drug to render mouse peritoneal and alveolar macrophages tumoricidal in vivo (Poste et al., 1982). Fidler et al. (1984), for example, achieved significant reduction of experimental lung metastases by the systemic administration of MDP-containing liposomes into mice inoculated with syngeneic B16 melanoma cells. Similar results were reported by Thombre and Deodhar (1984) on the inhibition of liver metastases from murine colon adenocarcinoma by liposome-encapsulated C-reactive protein or crude lymphokines