Enhanced Adhension of Biodegradable Drug Delivery Vehicles to Inflamed Endothelium
The expression of endothelial cell adhesion molecules (ECAMs), known to play a role in leukocyte recruitment (e.g. P-selectin, E-selectin, ICAM-1 and VCAM-1), is increased at sites of pathological inflammation. Various studies have sought to exploit the up-regulation of ECAMs for vascular targeted drug delivery. Drug carriers made from biodegradable polymers complement and expand the possibilities of drug delivery afforded by other carriers. Here, we report the development of targeted biodegradable drug delivery vehicles that exhibit selective adhesion to inflamed endothelium. We initially sought to determine whether biodegradable particles conjugated with ligands to inducible ECAMs could exhibit selective adhesion to inflamed endothelium in vitro and in vivo. We successfully conjugated ligands to the surface of biodegradable particles at very high densities to generate anti(?)–VECAM leukocyte-endothelial cell adhesive particles (LEAPs). These particles possess adhesion efficiencies similar to that of leukocytes, can target each of the major inducible ECAMs and can be engineered to exhibit distinct adhesive phenotypes. Next, we used a well accepted model of human inflammatory bowel disease, the dextran sulfate sodium (DSS)-induced murine model of colitis, to investigate the behavior of LEAPs in a setting of pathological inflammation. We found that VCAM-1 is up-regulated in the inflamed vasculature of DSS treated mice. We hence probed the adhesion of ?-VCAM-1(V) LEAPs in this model. Our findings demonstrate that ?-V LEAPs exhibit selective adhesion to the inflamed vasculature of colitic mice and that their targeting efficiency is a complex function of the dose regime. In many cases, it would be desirable for the LEAPs to be internalized by endothelial cells. Since nanometer sized (200-300 nm) cargoes are known to be readily internalized by endothelial cells, we investigated the adhesion of nanosized LEAPs to inflamed endothelium. Our results indicate that ?-E-selectin nanoLEAPs exhibit selective adhesion to inflamed endothelium in vivo. Finally, we developed a mathematical model to account for the diffusion resistance that the particles flowing in the blood stream will probably encounter to reach the surface of endothelial cells. Collectively, the findings of this work represent a major step towards the rational development of targeted vascular drug delivery schemes.
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:inflammation endothelial celladhension molecules targeted drug delivery microparticles naboparticles
Date of Publication:01/01/2005