Inhibition of intimal hyperplasia from epigallocatechin-3-O-gallate released by exovascular treatment of electrospun poly(L-lactide glycolic acid) fiber sheets containing epigallocatechin-3-O-gallate in injured abdominal aorta

摘要

Introduction: Intimal hyperplasia is the major cause of failure in invasive treatments for vascular diseases, occurring in arterial catheter-based and endovascular surgical interventions. It signifies an increase in the number of cells and the amount of ECM and these induce the more intimal thickening. Electrospun fibers have exhibited many advantages as a potential drug delivery. The drug loading is very easy to implement in electrospinning process, and the high applied voltage had little influence on the drug activity. Epigallocatechin gallate (EGCG) is most prevalent polyphenol contained in green tea. These have been reported to have antioxidant, anti-proliferative and anti-thrombogenic effect. Recent experiments have suggested that green tea cathechins reduce atherosclerotic lesions in various animal models and can prevent cardiovascular diseases. In the present study, we were to develop a polymeric local drug delivery device by electrospun methods for delivery of EGCG with poly(lactic-co-glycolic acid) (PLGA) polymer. Also, we investigated whether exovascularly local delivery device contained EGCG that wrapped around the sites of vascular damage inhibited intimal hyperplasia and prevented luminal narrowing in endothelium denuding rabbit model by balloon injury. Materials and Methods: PLGA sheet containing EGCG was fabricated by electrospinning. The morphology of the composite sheets was characterized using scanning electron microscopy (SEM) and Fourier transform-infrared spectroscopy (FTIR). Release profile of EGCG-loaded PLGA sheets was determined by measuring the absorbance of the PBS buffer immersed PLGA sheets using a UV-Vis spectrophotometer. In vivo study, the abdominal aorta of male New Zealand White rabbits was injured by a 3F Fogarty embolectomy catheter and wrapped with PLGA sheets containing EGCG. To quantify neointimal hyperplasia, fixed tissue segments were embedded in paraffin blocks and with hematoxylin and eosin (H&E). Results and Discussion: From SEM and FTIR analysis, EGCG was loaded and dispersed into the PLGA-based electrospun fibers. Also, EGCG-loaded PLGA sheets exhibited sustained EGCG release following the initial 24 h of burst release in phosphate-buffered saline. We investigated the effect of locally administered EGCG on the formation of neointima at day 28 post aorta injury. In vivo studies demonstrated significant inhibition of decreased intima/media (I/M) ratio following the treatment of EGCG-containing PLGA fiber sheets, compared with vehicle PLGA controls. EGCG released from sheets was observed to suppress neointima formation following adventitial administration in injured arteries. Local drug delivery throughout the outer surface of blood vessel is readily accessible, making application of drug more direct and easily achievable at the time of open surgery. From the therapeutic point of view, these results suggest that EGCG can be a potential agent for the prevention of VSMC dedifferentiation and their local release from electrospun PLGA fiber sheet can be applicable as a method to prevent intimal hyperplasia in stent, catheter, and vascular bypass and graft.