Action at a distance: lengthening adhesion bonds with poly(ethylene glycol) spacers enhances mechanically stressed affinity for improved vascular targeting of microparticles.
Poly(ethylene glycol) (PEG) chains were used to decorate microparticles with long adhesion ligands to emulate the efficacy of selectin-mediated leukocyte homing mechanisms. Ligands for P-selectin, an endothelial cell inflammatory marker, were coupled to PEG spacers of two sizes (MW 3400 and 10,000 Da) to investigate the effects on adhesion kinetics to P-selectin substrates. Under shear flow 80 nm PEG spacers improved P-selectin-antibody adhesion frequency by up to 4.5-fold and bond lifetimes by 7-fold compared to microparticles bearing chemisorbed antibody. Presentation of the glycosulfopeptide P-selectin ligands (2-GSP-6) and its nonsulfated low affinity form (2-GP-6) by long PEG spacers led to improved lifetimes of stressed bonds formed with P-selectin in shear flow and the rolling fluxes. Thus, structural features far removed from the binding pocket of a receptor that increase molecular contour length may enhance affinity in mechanically stressed environments such as those existing within the confines of the blood vessel. Such features may be useful for improving the performance of vascular-targeted micro- and nanoparticles used for drug, gene, and image contrast delivery. Ligand presentation on molecularly extended stalks may also serve to enhance any particle-surface interaction that takes place in laminar shear flow.
Ham
Anthony S
AS
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
Klibanov
Alexander L
AL
Lawrence
Michael B
MB
D000268:Adhesiveness; D000818:Animals; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism; D006020:Glycopeptides / Q000737:chemistry; D006801:Humans; D008024:Ligands; D051379:Mice; D008863:Microspheres; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods; D019007:P-Selectin / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D013314:Stress, Mechanical; D013499:Surface Properties
D006020:Glycopeptides; D008024:Ligands; D019007:P-Selectin; D011092:Polyethylene Glycols