The attenuation of restenosis following arterial gene transfer using carbon nanotube coated stent incorporating TAT/DNA(Ang1+Vegf) nanoparticles

Abstract

This study report the development of a nanobiohybrid hydrogel based endovascular stent device capable of preventing postangioplasty in-stent restenosis (ISR) by promoting significant vascular endothelial recovery in a site-specific manner. The hydrogel is comprised of fibrin matrices, assembled layer-by-layer (LbL) on stent surface with alternate layers carrying endosomolytic Tat peptide/DNA nanoparticles (NPs) or NPs hybridized to polyacrylic acid (PAA) wrapped single-walled carbon nanotubes (NP-CNT). Here, the hydrogel works as a reservoir to carry, protect, and simultaneously deliver pro-angiogenic, vascular endothelial growth factor (Vegf) and Angiopoietin-1(Ang1), gene carrying NPs to the target site. In vitro results demonstrated that CNTs incorporated in the hydrogel layers play a major role in tuning the bioactivity of the stent. In addition, the developed stent formulation can significantly reduce the loss of therapeutics while traversing through the vessel and during deployment. In vivo experiments in balloon-injured canine femoral artery demonstrated that the NCS (+) group, carrying NP(vegf+Ang1), can significantly enhance re-endothelialization of injured artery compared to control NCS (-), carrying NP(Null), and bare metal stent (BMS) groups, attenuate stenosis (18.5±9.03% vs 39.56±13.8 vs 45.34±8.3%; n=8, p<0.05) and prevent neointima formation (1.53±0.36 mm(2) vs 2.51±0.27 mm(2) vs 2.66±0.14 mm(2); n=8, p<0.05) as analyzed angiography and histomorphometric analysis. These data collectively implicate that this new technology can be useful for stent and other biomedical devices through controlled delivery of multiple biotherapeutics.