Targeted ultrasound enhanced drug delivery to foam cell spheroids

Abstract

Atherosclerosis is a chronic vascular disorder marked by the accumulation of foam cells in the intimal space of the artery. Foam cells are macrophages that reside in the arterial wall after internalizing excessive cholesterol. Though many strategies to remove cholesterol from foam cells have been put forward, delivering these agents at the site of the lesion remains a challenge. Here, we investigated the ability of our previously reported multi-cavity poly-co-lactic-co-glycolic acid microparticles (mc-PLGA MPs) to penetrate into a model for early stage atherosclerosis, a 3D foam cell spheroid, and deliver hydroxyl beta cyclodextrin (HBCD) and sirolimus. HBCD is a polysaccharide that solubilizes cholesterol and promotes cholesterol efflux from foam cells. First, the drug release capability of mcPLGA MPs was tested using DAPI dye as a model drug. Sustained release of DAPI from mcPLGA MPs was observed in foam cell nuclei three days after implantation. We found that DAPI released from mcPLGA MPs distributed evenly throughout the spheroid even though mcPLGA MPs were implanted predominantly at the periphery. FITC conjugated HBCD was co-administered with sirolimus loaded mc-PLGA MPs and was also found to be implanted only under ultrasound exposure. Foam cell viability and the inflammatory response of the ultrasound treatment were also monitored across a week. In conclusion, this study shows the possibility of atherosclerosis treatment with targeted ultrasound enhanced drug delivery.