The process of membrane fusion occurs in various cellular activities such as endocytosis, exocytosis and fertilization. The transport of drugs and other substances into cells may be enhanced by incorporating them in phospholipid vesicles, and fusing the vesicles with the cells. The objectives of this project are: (1) Analysis and prediction of the combined effect of various factors affecting the fusion of pure or mixed phospholipid vesicles. The factors to be considered include composition and size of vesicles, concentration, temperature, ionic strength and specific ions such as Ca2 ion and Mg2 ion. (2) Analysis and prediction of the fusion of phospholipid vesicles with cells, and of the optimal conditions for transferring drugs and other substances to cells by preloading vesicles with these substances and fusing them with target cells. (3) Analysis of the thermodynamics of vesicle population with an emphasis on the question of aggregation of vesicles and micelles, optimal vesicle size, and effect of various ions. The study will concentrate on interdisciplinary theoretical analysis, but small scale experimental tests of the theory will also be performed, including optical density, electron microscopy, electrophoretic mobility, and scanning calorimetry measurements. The study is guided by the view that the requirements for membrane fusion include: (a) close approach of particles, (b) a state of instability of the combined system of closely apposed and non fused particles, and (c) a state of lower free energy in the final fused form. The analysis of (a) will be based on calculations with the DLVO and Lifshitz theories. In the attempt to explain the repulsion between charged and neutral membranes at distances of separation around 20 A, the interaction between relatively fixed dipoles, and possible involvement of structured water will be considered. The analysis of parts (b) and (c) will include phenomenological approaches and application of theories of intermolecular interactions such as the reaction field theory and consideration of solvent effects.
NIH ExPorter
NIH ExPorter