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.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154265/1/fsb2fj030166fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154265/2/fsb2fj030166fje.pd