title: Multivalent display of quinic acid based ligands for targeting E-selectin expressing cells.
abstract: The site-specific expression of molecular markers on endothelial cells of blood vessels during inflammatory response and angiogenesis provides an opportunity to target drugs and imaging molecules to the vascular endothelium of diseased tissues. This paper describes an innovative strategy for selective delivery of polymer conjugates to E- and P-selectin expressing cells using a series of quinic acid (Qa) based non-carbohydrate analogues of the natural ligand sialyl Lewis(x) (sLe(x)) as targeting moieties. We demonstrate that such analogues antagonize the adhesion of sLe(x) expressing HL-60 cells to both E- and P-selectin. Significantly, the apparent avidity of polymer conjugates carrying multiple Qa copies has increased by 3 orders of magnitude relative to their monomeric forms. Furthermore, we found that the major mechanism of copolymer entry and delivery into E-selectin expressing cells is endocytosis. These selectin-targetable copolymers provide the foundation to support controlled delivery of anticancer drugs and imaging agents to tumor vasculature for therapeutic and diagnostic applications.
authors.affiliation: Department of Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Yosi
authors.initials: Y
authors.lastname: Shamay
authors.forename: Denise
authors.initials: D
authors.lastname: Paulin
authors.forename: Gonen
authors.initials: G
authors.lastname: Ashkenasy
authors.forename: Ayelet
authors.initials: A
authors.lastname: David
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D002448:Cell Adhesion; D003952:Diagnostic Imaging / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D019040:E-Selectin / Q000378:metabolism*; D004705:Endocytosis; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D019007:P-Selectin / Q000378:metabolism; D011108:Polymers / Q000493:pharmacokinetics; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D019040:E-Selectin; D008024:Ligands; D019007:P-Selectin; D011108:Polymers; D011801:Quinic Acid