Nanoparticle coatings for controlled release of quercetin from an angioplasty balloon

Abstract

Peripheral artery disease (PAD) is a systemic vascular disease of the legs that results in a blockage of blood flow from the heart to the lower extremities. Now one of the most common causes of mortality in the U.S., the first line of therapy for PAD is to mechanically open the blockages using balloon angioplasty. Coating the balloons with antiproliferative agents can potentially reduce vessel re-narrowing, or restenosis after surgical intervention, but current drug-coated balloons releasing chemotherapy agents like paclitaxel have in some cases shown increased mortality long-term. Our aim was to design a novel drug-coated balloon using a polymeric nanodelivery system for a sustained release of polyphenols that reduce restenosis but with reduced toxicity compared to chemotherapy agents. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles with entrapped quercetin, a dimethoxy quercetin (rhamnazin), as well as quercetin conjugated to PLGA, were developed. Balloon catheters were coated with polymeric nanoparticles using an ultrasonic method, and nanoparticle characteristics, drug loading, coating uniformity and drug release were determined. The adhesion of nanoparticles to vascular smooth muscle cells and the antiproliferative effect of nano-delivered polyphenols were also assessed. Of the nanoparticle systems tested, those with covalently attached quercetin provided the most sustained release over a 6-day period. Although these particles adhered to cells to a smaller extent compared to other nanoparticle formulations, their attachment was resistant to washing. These particles also exhibited the greatest anti-proliferative effect. In addition, their attachment was not altered when the cells were grown in calcifying conditions, and in PAD tissue calcification is typically a condition that impedes drug delivery. Moreover, the ultrasonic coating method generated a uniform balloon coating. The polymeric nanoparticle system with covalently attached quercetin developed herein is thus proposed as a promising platform to reduce restenosis post-angioplasty.