title: E-selectin binding peptide-polymer-drug conjugates and their selective cytotoxicity against vascular endothelial cells.
abstract: The hypothesis that E-selectin on activated endothelial cells could be exploited to selectively target drug delivery systems to tumor vasculature was investigated. HPMA copolymer-doxorubicin (DOX) conjugates displaying the high affinity E-selectin binding peptide (Esbp, primary sequence DITWDQLWDLMK) as targeting ligand were synthesized and tested for their cytotoxicity and intracellular fate in human immortalized vascular endothelial cells (IVECs). The targeted copolymers displaying multiple copies of Esbp are bound to surface-associated E-selectin with affinity at the low nano-molar range, three orders of magnitude stronger than the free Esbp. In addition, the binding affinity of the HPMA-Esbp copolymers to E-selectin expressing IVECs was found to be 10-fold superior relative to non-targeted copolymers. Once bound, E-selectin facilitated rapid internalization and lysosomal trafficking of the copolymers. This lysosomotropism of HPMA-Esbp-bound DOX copolymers was then correlated with a 150-fold higher cytotoxicity relative to non-targeted HPMA-DOX conjugates. These findings strongly support the emerging role of E-selectin as a viable target for controlled drug delivery in cancer therapy.
authors.affiliation: Department of Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, 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: D000178:Acrylamides / Q000008:administration & dosage* / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D019040:E-Selectin / Q000737:chemistry* / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology*; D005688:Galactosamine / Q000008:administration & dosage* / Q000737:chemistry*; D018922:HL-60 Cells; D006801:Humans; D008422:Materials Testing
chemical_list: D000178:Acrylamides; D004337:Drug Carriers; D019040:E-Selectin; C438845:HPMA coploymer-doxorubicin-galactosamine; D005688:Galactosamine; D004317:Doxorubicin