Development of Drug-Eluting Stents on the Basis of Genistein and Poly(L-lactide)

Abstract

Stent-based local drug release at the site of vascular injury via a polymer-coated drug-eluting stent (DES) is an attractive therapeutic approach to prevent in-stent restenosis. Estrogens were discussed as active agents for second generation DES due to their differential effects on human coronary artery endothelial (HCAEC) and smooth muscle cells (HCASMC). We have tested the effects of genistein and 17β-estradiol on HCAEC and HCASMC in vitro, and developed genistein DES prototypes with a biodegradable poly(L-lactide) (PLLA) matrix which were tested in vitro and in vivo. In vitro, genistein showed a concentration dependent inhibition of HCASMC proliferation, whereas 17β-estradiol was less effective. Proliferation of HCAEC was markedly stimulated by genistein, but barely stimulated by 17β-estradiol. The genistein release profile showed an initial burst and subsequent steady release over more than 3 months. After stent expansion, the PLLA/genistein coating exhibited structural integrity and a smooth surface. In vivo, the PLLA/genistein DES showed complete re-endothelialization after 4 weeks and a reduction in stenosis diameter, and reduced stenosis area in comparison to the PLLA coated control group (QCA data). In contrast, the histomorphometrical evaluation showed no significant differences regarding coronary stenosis and neointimal area between both groups, and thus has not confirmed the QCA data. The conducted in vitro and in vivo studies indicate the potential of PLLA/genistein DES for enhanced re-endothelialization. However, for the prevention of the restenosis process via a chain of different immunological and biochemical reactions combined DES concepts with genistein and antiproliferative drugs, such as sirolimus are essential.