Serum albumin, the most abundant plasma protein, serves as a carrier for a wide variety of physiologic ligand and drugs. These substances are delivered to target cells in an albumin-mediated process of unknown mechanism. The long term goal of this work is to identify structural and binding properties of albumin-ligand complexes that facilitate delivery of ligand to cells.
The aims of the current proposal are to identify the role of surface-bound albumin in the delivery of ligand to cells and to determine whether the same mechanism that effects delivery of albumin- transported ligand to normal tissue functions for tumor cells. Surface-bound albumin will be compared with dissolved albumin for ability to bind fatty acids and bilirubin, for ability to bind to the surface of isolated hepatocytes, and for the ability to transfer fatty acids and bilirubin to hepatocytes. Albumin immobilized on agarose beads and albumin entrapped in polyacrylamide microspheres will be compared with albumin in solution to test whether direct interaction of albumin with cells is a requirement for ligand delivery. Hepatoma cells will be compared to hepatocytes to determine whether the increased avidity of hepatomas for albumin and the avid uptake of fatty acids by hepatoma cells is a reflection of an enhanced surface-albumin interaction or a receptor-mediated uptake process. These studies, using thermodynamic and kinetic data from binding of iodinated proteins and uptake of radiolabeled ligand, are designed to evaluate the role of albumin and its conformational changes at the interface between vascular circulation and cells and organs and to determine whether the albumin-receptor affect is really an albumin-surface interaction that induces a conformational change in albumin to facilitate ligand delivery. These studies will provide general information about albumin-membrane recognition processes that may be important for the uptake of fatty acids by rapidly growing tumor cells, the entry of hepatitis B virus into hepatocytes, the clearance of lipoprotein particles from the circulation and platelet recognition of albumin-coated prosthetic devices.
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