Discovery of a potent nanoparticle P-selectin antagonist with anti-inflammatory effects in allergic airway disease.
The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P-selectin is known to play a role in the development of allergen-induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P-selectin-mediated leukocyte endothelial-cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P-selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P-selectin. The ligands acted as mimetics of the key binding elements responsible for the high-avidity adhesion of P-selectin to the physiologic ligand, PSGL-1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P-selectin-coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P-selectin blocking arrays were functionally active in vivo, significantly reducing allergen-induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma.
John
Alison E
AE
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Lukacs
Nicholas W
NW
Berlin
Aaron A
AA
Palecanda
Aiyappa
A
Bargatze
Robert F
RF
Stoolman
Lloyd M
LM
Nagy
Jon O
JO
D000485:Allergens / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001704:Biopolymers / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001991:Bronchitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000166:cytology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008863:Microspheres; D018448:Models, Immunological; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism
D000485:Allergens; D000893:Anti-Inflammatory Agents; D001704:Biopolymers; D008024:Ligands; D008055:Lipids; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein