Harnessing the pleiotropic effects of atorvastatin-fenofibrate combination for cardiovascular stents

Highlights: • The combination of atorvastatin and fenofibrate is reported for the first time for stent application. • Dual drug loaded PLCL film retards smooth muscle cell proliferation and promoting endothelialization. • Dual drug loaded PLCL film also has anti-thrombotic and anti-inflammatory effects. - Abstract: Atorvastatin and fenofibrate have been conventionally employed as lipid-lowering agents. They also exhibit beneficial effects in the treatment of endothelial dysfunction, oxidative stress and vascular inflammation due to their pleiotropic effects that include vasodilatory and anti-inflammatory effects. These pleiotropic effects may serve to overcome the drawbacks of late stent thrombosis and delayed endothelialization that plague conventional drug eluting stents. However, the combination has not been explored yet as therapeutic coatings in drug eluting stents. The present study aims to investigate the potential of atorvastatin-fenofibrate combination loaded in a biodegradable poly(l-lactide-co-caprolactone) polymer film to inhibit thrombus formation and macrophage activation apart from exploring their effect on the proliferation of smooth muscle cells and endothelial cells. The dual drug-loaded polymer films were characterized by spectroscopy and calorimetry. In vitro studies revealed that the combination effectively retarded the proliferation of only smooth muscle cells but not the endothelial cells which augers well for stent applications where rapid re-endothelialization is preferred. Further, the dual drug-loaded films exhibited a marked decrease in the adhesion and activation of platelets and macrophages revealing the potent anti-thrombogenic and anti-inflammatory effects of the combination. The pleiotropic effects of the combination may be attributed to their ability to activate nitric oxide synthase in endothelial cells while mTOR levels remained unaltered by the combination.