The overall goal of this research proposal is to understand the exchange interactions between lipid bilayer membranes and physiologically and clinically important membrane-soluble molecules. In characterizing the molecular exchange, both the chemical composition of the exchanging molecule, and the physical state of the membrane (tested in bilayers with high and low compressibility) before and after the exchange will be considered. The proposal has four specific aims. SA1 is to characterize the exchange and effect on bilayer structure and mechanical properties for Polyethyleneglycol-lipids (PEG-lipids) as monomer and micelle. SA2 is to characterize binding, uptake, trans-bilayer transport, and effect on bilayer structure and mechanical properties for three drugs with low water solubility (doxorubicin, paclitaxel, and camptothecins), including drug loading and leakage. SA3 is to measure the uptake, cohesion and eventual disruption of membranes as a result of exchange with polymers (polyethylacrylic acid) and proteins (albumin) where the solubility of the macromolecule is dependent on pH. SA4 is to characterize the degradative reactions of lipid membrane components caused by enzymes (phospholipases) and chemical degradation (pH and light), or release at a lipid phase change. The main techniques that will be used to achieve these aims are micropipet manipulation and x-ray diffraction. Micropipet manipulation will be used in each SA to measure molecular exchange directly as vesicle area change coupled, in some cases, to bilayer fluorescence intensity; and any change in mechanical cohesion of the bilayers due to the presence (SA1, 2, 3) or absence (SA4) of the exchanging molecule. X-ray diffraction will be used to determine any changes in bilayer structure due to the presence of PEG-lipids (SA1) and the three drugs (SA2). The exchanging molecules display a range of interactions dependent on water solubility, pH, and chemical and biological degradation. Exchange can originate from molecules in solution (Sas, 1,2 and 3) involving surfactant lipids, drugs, and water-soluble polymers and proteins, where both uptake and desorption will be measured. Alternatively exchange out of the bilayer can a result from membrane-lipid degradation (SA 4), due to the action of enzymes, pH, light, and lipid phase change, producing molecules that re- partition into the aqueous phase. The lipid systems and the exchanging molecules under study have been chosen in part because they are important in clinical applications such as drug delivery, in particular to cancer detection and treatment. Of particular relevance here, in the last year we have created and tested a new drug delivery system that has shown 100 percent local control of tumors in an animal model.