title: VCAM-1 directed target-sensitive liposomes carrying CCR2 antagonists bind to activated endothelium and reduce adhesion and transmigration of monocytes.
abstract: Chemokines are critically involved in the development of chronic inflammatory-associated diseases such as atherosclerosis. We hypothesized that targeted delivery of compounds to the surface of activated endothelial cells (EC) interferes with chemokine/receptor interaction and thereby efficiently blocks inflammation. We developed PEGylated target-sensitive liposomes (TSL) encapsulating a CCR2 antagonist (Teijin compound 1) coupled with a specific peptide recognized by endothelial VCAM-1 (Vp-TSL-Tj). TSL were characterized for size (by dynamic light scattering), the amount of peptide coupled at the liposomal surface and Teijin release (by HPLC). We report that Vp-TSL-Tj binds specifically to activated EC in vitro and in situ, release the entrapped Teijin and prevent the transmigration of monocytes through activated EC. This is the first evidence that nanocarriers which transport and release chemokine inhibitors at specific pathological sites can reduce chemokine-dependent inflammatory processes.
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania. Electronic address: manuela.calin@icbp.ro.
authors.forename: Manuela
authors.initials: M
authors.lastname: Calin
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stan
authors.affiliation: Department of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlesinger
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Viorel
authors.initials: V
authors.lastname: Simion
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Mariana
authors.initials: M
authors.lastname: Deleanu
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Cristina Ana
authors.initials: CA
authors.lastname: Constantinescu
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Gan
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Monica Madalina
authors.initials: MM
authors.lastname: Pirvulescu
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Elena
authors.initials: E
authors.lastname: Butoi
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Ileana
authors.initials: I
authors.lastname: Manduteanu
authors.affiliation: Center for Surface Science and Nanotechnology, University "Politehnica" of Bucharest, Bucharest, Romania.
authors.forename: Marian
authors.initials: M
authors.lastname: Bota
authors.affiliation: Center for Surface Science and Nanotechnology, University "Politehnica" of Bucharest, Bucharest, Romania.
authors.forename: Marius
authors.initials: M
authors.lastname: Enachescu
authors.affiliation: Institute of Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
authors.affiliation: Department of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bendas
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors; D004337:Drug Carriers / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008081:Liposomes / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage; D011759:Pyrrolidines / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D001549:Benzamides; C515334:CCR2 protein, human; D018925:Chemokines; D004337:Drug Carriers; D008081:Liposomes; C541285:N-(carbamoylmethyl)-3-trifluoromethyl benzamido-4-chlorobenzyl 3-aminopyrrolidine; D011759:Pyrrolidines; D054390:Receptors, CCR2; D019010:Vascular Cell Adhesion Molecule-1
keywords: CCR2 antagonist; Endothelium; Monocyte; Target-sensitive liposomes; Targeted drug delivery; VCAM-1