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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040149-02
Application #
3179705
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Nayar, R; Tilcock, C P; Hope, M J et al. (1988) N-succinyldioleoylphosphatidylethanolamine: structural preferences in pure and mixed model membranes. Biochim Biophys Acta 937:31-41
Connor, J; Schroit, A J (1988) Transbilayer movement of phosphatidylserine in erythrocytes: inhibition of transport and preferential labeling of a 31,000-dalton protein by sulfhydryl reactive reagents. Biochemistry 27:848-51
Fidler, I J; Schroit, A J (1988) Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self. Biochim Biophys Acta 948:151-73
Schroit, A J; Madsen, J; Ruoho, A E (1987) Radioiodinated, photoactivatable phosphatidylcholine and phosphatidylserine: transfer properties and differential photoreactive interaction with human erythrocyte membrane proteins. Biochemistry 26:1812-9
Connor, J; Schroit, A J (1987) Determination of lipid asymmetry in human red cells by resonance energy transfer. Biochemistry 26:5099-105
Tanaka, Y; Schroit, A J (1986) Calcium/phosphate-induced immobilization of fluorescent phosphatidylserine in synthetic bilayer membranes: inhibition of lipid transfer between vesicles. Biochemistry 25:2141-8
Denkins, Y M; Schroit, A J (1986) Phosphatidylserine decarboxylase: generation of asymmetric vesicles and determination of the transbilayer distribution of fluorescent phosphatidylserine in model membrane systems. Biochim Biophys Acta 862:343-51
Schroit, A J; Madsen, J; Nayar, R (1986) Liposome-cell interactions: in vitro discrimination of uptake mechanism and in vivo targeting strategies to mononuclear phagocytes. Chem Phys Lipids 40:373-93