Tunable leuko-polymersomes that adhere specifically to inflammatory markers.
The polymersome, a fully synthetic cell mimetic, is a tunable platform for drug delivery vehicles to detect and treat disease (theranostics). Here, we design a leuko-polymersome, a polymersome with the adhesive properties of leukocytes, which can effectively bind to inflammatory sites under flow. We hypothesize that optimal leukocyte adhesion can be recreated with ligands that mimic receptors of the two major leukocyte molecular adhesion pathways, the selectins and the integrins. Polymersomes functionalized with sialyl Lewis X and an antibody against ICAM-1 adhere avidly and selectively to surfaces coated with inflammatory adhesion molecules P-selectin and ICAM-1 under flow. We find that maximal adhesion occurs at intermediate densities of both sialyl Lewis X and anti-ICAM-1, owing to synergistic binding effects between the two ligands. Leuko-polymersomes bearing these two receptor mimetics adhere under physiological shear rates to inflamed endothelium in an in vitro flow chamber at a rate 7.5 times higher than those to uninflamed endothelium. This work clearly demonstrates that polymersomes bearing only a single ligand bind less avidly and with lower selectivity, thus suggesting proper mimicry of leukocyte adhesion requires contributions from both pathways. This work establishes a basis for the design of polymersomes for targeted drug delivery in inflammation.
Robbins
Gregory P
GP
Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Saunders
Randi L
RL
Haun
Jered B
JB
Rawson
Jeff
J
Therien
Michael J
MJ
Hammer
Daniel A
DA
D000906:Antibodies / Q000276:immunology; D000937:Antigen-Antibody Reactions; D015415:Biomarkers; D002070:Butadienes / Q000737:chemistry*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D020724:Elastomers / Q000737:chemistry*; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007962:Leukocytes / Q000737:chemistry* / Q000276:immunology; D008024:Ligands; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D008958:Models, Molecular; D009844:Oligosaccharides / Q000276:immunology; D019007:P-Selectin / Q000276:immunology; D011092:Polyethylene Glycols / Q000737:chemistry*; D000080506:Sialyl Lewis X Antigen; D013379:Substrate Specificity
D000906:Antibodies; D015415:Biomarkers; D002070:Butadienes; D004337:Drug Carriers; D020724:Elastomers; D008024:Ligands; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen; D018799:Intercellular Adhesion Molecule-1; D011092:Polyethylene Glycols; C028834:polybutadiene; C013411:biocytin; D008239:Lysine