Previous research has indicated that the successful approach to the treatment of metastasic disease will most likely be a treatment modality which circumvents the properties of tumor cell heterogeneity and phenotypic diversity. There is now an overwhelming body of data demonstrating that cells of the reticuloendothelial system (RES), e.g. macrophages, appropriately activated to the tumoricidal state can fulfill the demanding criteria necessary to obviate these problems. This project, therefore, is aimed at designing liposomes containing a known macrophage activator, muramyl dipeptide (MDP), which would selectively release and deliver the encapsulated compound to cells of the macrophage-monocyte lineage using mice as the model system. Previous work has indicated that monocytes and macrophages specifically phagocytose cells and liposomes that express phosphatidylserine (PS) in the outer leaflet of their membranes. However, the major problem in using negatively charged liposomes containing PS is that entrapped compounds readily leak from these particles both in vitro and in vivo. As a result, only a fraction of the encapsulated material reaches its primary destination, the macrophage. This proposal is therefore directed towards the development of a bifunctional liposome carrier system, using a pH sensitive PS analog which will 1) specifically home to cells of the RES, and 2) selectively release their entrapped contents following phagocytosis and acidification inside the macrophage lysosomal compartments. Once optimized, this drug-delivery system will be assessed for its ability to induce macrophage tumoricidal activity in in vitro system. Following identification of the optimal carrier system from these studies, in vivo studies will be performed encompassing in vivo macrophage activation with in vitro tumoricidal activity tests, and finally will be assayed for their efficacy in the treatment of metastatic disease using established mouse model systems.
