Selectins ligand decorated drug carriers for activated endothelial cell targeting.
New active particulate polymeric vectors based on branched polyester copolymers of hydroxy-acid and allyl glycidyl ether were developed to target drugs to the inflammatory endothelial cell surface. The hydroxyl and carboxyl derivatives of these polymers allow grafting of ligand molecules on the polyester backbones at different densities. A known potent nonselective selectin ligand was selected and synthesized using a new scheme. This synthesis allowed the grafting of the ligand to the polyester polymers, preserving its binding activity as assessed by docking simulations. Selectin expression on human umbilical cord vascular endothelial cells (HUVEC) was induced with the pro-inflammatory bacterial lipopolysaccharide (LPS) or with the nonselective inhibitor of nitric oxide synthase L-NAME. Strong adhesion of the ligand decorated nanoparticles was evidenced in vitro on activated HUVEC. Binding of nanoparticles bearing ligand molecules could be efficiently inhibited by prior incubation of cells with free ligand, demonstrating that adhesion of the nanoparticles is mediated by specific interaction between the ligand and the selectin receptors. These nanoparticles could be used for specific drug delivery to the activated vascular endothelium, suggesting their application in the treatment of diseases with an inflammatory component such as rheumatoid arthritis and cancer.
Banquy
Xavier
X
Faculte de Pharmacie, Ecole d'Optometrie, Universite de Montreal, Quebec, Canada.
Leclair
Grégoire
G
Rabanel
Jean-Michel
JM
Argaw
Anteneh
A
Bouchard
Jean-François
JF
Hildgen
Patrice
P
Giasson
Suzanne
S
D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry; D009928:Organ Specificity; D011091:Polyesters; D011108:Polymers / Q000737:chemistry; D051381:Rats; D019087:Selectins / Q000378:metabolism*; D013379:Substrate Specificity; D013499:Surface Properties
D002264:Carboxylic Acids; D004337:Drug Carriers; D008024:Ligands; D011091:Polyesters; D011108:Polymers; D019087:Selectins; D019344:Lactic Acid; C033616:poly(lactide)