UIC-2004-062 – Serum Albumin Docking Sequence in Myeloperoxidase

The transport of fatty acids, steroids, thyroxine, and amino acids across the endothelial barrier is regulated by the plasma protein albumin. Albumin binds to albumin-binding proteins localized in caveolae and the caveole transport albumin across the endothelial barrier. Caveole are essential for albumin transport and are a key determinant of transcellular endothelial permeability. Myeloperoxidase (MPO) is expressed in polymorphonuclear neutrophils (PMNs) and monocytes. MPO plays an important role in innate immunity and regulation of nitric oxide-derived oxidants and is essential for protein tyrosine nitration during vascular inflammation. For MPO to induce protein tyrosine nitration, it needs to be transported across the endothelial barrier into the subendothelium. When activated, PMNs release MPO into the blood that is then transported across the endothelial barrier by transcytosis after binding to the negatively charged endothelial surface. However, the precise mechanism of MPO transendothelial transport has not been defined. UIC inventors have discovered that MPO is an albumin-binding protein and that the MPO-albumin interaction is essential for MPO transcytosis by caveolae. Furthermore, they have identified a MPO-derived high affinity albumin docking sequence (ADS) that can bind albumin and be transported across the endothelial barrier by caveolae. ADS is charge-dependent (cationic ADS interacts with anionic albumin) and does not affect albumin binding to the endothelial surface or albumin transport across the endothelial barrier. Therefore, ADS conjugated with therapeutic agents, such as drugs, proteins, or nucleic acids, presents a novel approach for drug delivery into the subendothelial space and may be particularly useful for preventing and/or treating cardiovascular diseases. The potential of this drug delivery system has been confirmed in vivo by delivery of ADS-conjugated antibodies across the vascular endothelial barrier. Veronica Haywood vhaywo2@uic.otm.edu 312-996-4865