This proposal incorporates several projects all in the general area of lipid bio-organic chemistry: ( l ) Multi-step synthesis of new phospholipids will be carried out with the expectation that these materials will form biomembranes containing semi-polar cavities that can adsorb ions, drugs, and other guests within them. The relationship of adsorption and transport processes to lipid structure will be examined. ( 2 ) An enzyme-induced drug release mechanism from membrane-bound drugs will be explored using compounds that possess (in sequence) a lipid tail, a peptide, and an anti-cancer drug, ara-C. The drug and peptide are attached by an enzyme-labile linkage. The length and polarity of the peptide will control the release of the drug from the membrane surface. 3 ) Synthetic organic methodology, acquired in the synthesis of several lipid systems, will be applied to the preparation of """"""""drug-drug prodrugs"""""""". The idea is to attach, via labile linkages, two different anti- metabolites onto the same molecule. The hope is to create double-prodrugs that minimize the ability of pathological cells to acquire drug resistance. ( 4 ) Light microscopy will be applied to giant vesicles composed of both phospholipids and synthetic lipids in an effort to understand important cellular processes including membrane fusion, fission, budding and endocytosis. Since it is possible to visualize directly membrane bilayer structures, it is also planned to examine membrane-healing and L the factors that affect this important biological phenomenon ( e.g. the cholesterol content of the membrane ). A considerable amount of preliminary work demonstrates the feasibility of the giant vesicle project as well as the other ones.
