Design and in vitro characterization of biodegradable, drug delivery vehicle with the adhesive properties of leukocytes
The site-specific expression of selectins (E- and P-selectin) on endothelial cells of blood vessels during inflammation provides an opportunity for the targeted delivery of anti-inflammatory drugs to the vascular endothelium for the purpose of reducing inflammation in chronic inflammatory diseases. Previous work in our laboratory has shown that artificial capsules with the adhesive properties of leukocytes can be made by attaching leukocyte adhesive ligands to polystyrene microspheres. We adapted this technology to create a targeted delivery system using biodegradable, poly-lactic-co-glycolic-acid (PLGA) microspheres. Biotinylated-Sialyl Lewis X (sLeX) a carbohydrate that serves as a ligand to selectins, was attached to the surface of avidin-linked PLGA microspheres. These carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on P-selectin in flow chambers, displaying slow rolling under flow. The rolling velocities displayed by sLeX-coated microspheres were similar to those displayed by leukocytes rolling on P- or E-selectin coated surfaces, and rolling velocity can be tuned by changing the density of carbohydrate residues on microsphere surfaces. Using in vitro degradation assays, we show that the time scale in which sLeX-coated microspheres continued to recognize selectin in flow depends on the rate of microsphere degradation. Therefore, factors affecting degradation such as type of polymer, type of drug, extent of drug loading and microsphere size, provide an opportunity for engineering the time-scale of activity for the delivery system. Since the selectin-ligand bond is weak, it cannot sufficiently maintain either firm leukocyte-endothelial interaction or cell transmigration. Firm arrest of leukocytes to the endothelium in vivo is mediated by intercellular and vascular adhesion molecules (ICAMs and VCAMs) binding to activated β2-integrin. Similarly, it is expected that selectin-ligand interaction alone would not support firm binding of targeted, drug delivery vehicle to the endothelium. To this end, I explored the possibility of two-receptor, selectin and ICAM-1, targeting by functionalizing microspheres with both sLeX and anti-ICAM-1. I show that at particular sLeX/anti-ICAM-1 ratios, these two-receptor microspheres must roll via selectin-sLeX interaction prior to firm binding, mimicking the in vivo leukocyte adhesion in inflammation.
Chemical engineering|Biomedical research|Biophysics
Eniola, Adetokunbo Omolola, "Design and in vitro characterization of biodegradable, drug delivery vehicle with the adhesive properties of leukocytes" (2004). Dissertations available from ProQuest. AAI3129438.