Abciximab-Krueppel-like factor 4-plasmid-titanium dioxide coated coronary stent for inhibition of neointimal hyperplasia

Purpose: We developed dual system in delivery of gene and drug for coronary stent. For local gene delivery, denatured polymer coating was used. For drug delivery, titanium dioxide (TiO2) thin film which was non-polymer and had a high blood compatibility was used. In this study, we hypothesized whether dual delivery system of gene and drug for coronary stent was useful in preventing in-stent restenosis (ISR). Methods and results: The coating and modification of TiO2 thin film were manipulated by plasma enhanced chemical vapor deposition (PECVD) method. In vitro study, TiO2-Drug (Abciximab) coating stainless steel (SS) plate catch a larger amount of gWIZ-beta gal (beta-gal) plasmid compared with TiO2-only coating SS plate (2.70±0.32 vs. 7.17±0.38 mg/cm2, p<0.05). Also, the binding plasmid (Krueppel-Like Factor 4, KLF4) was effectively transfected into 293 cells after detachment using plasmid elution buffer. The reverse transfection using direct attachment of pig coronary artery smooth muscles showed the X-gal stain positive cells after 5 days. For analysis of in vivo gene delivery, we used animal models of rat abdominal skin and pig coronary artery. At 5 days after implantation of TiO2-Drug-beta-gal plasmid SS plate in rat abdominal skin, the expression of the beta-gal plasmid was observed. At 5 days after implantation of TiO2-Drug-beta-gal plasmid binding coronary stent in balloon-injured porcine coronary artery restenosis model, X-gal stained linear area was observed. To analyze the inhibitory effect of ISR, we used both TiO2-Abciximab-KLF4-plasmid-cobalt chromium (TAK-CC) and TiO2-only coating CC (T-CC) stent. Four weeks after implantation in porcine coronary artery, in histomorphometric analysis, TAK-CC stent group decreased ISR compared with T-CC group (TAK-CC group: 26.38±10.79% vs. T-CC group: 48.59±20.17%, n=6 in each, p<0.05). Also, both TAK-CC and T-CC stent group did not show the fibrin deposition at Castars' stain and accelerated re-endothelialization indicated by detectable anti-CD31 positive stained cells compared with commercial available paclitaxel-eluting stent. Conclusions: Our study implicate that this novel new system could be useful for coronary stent and other biomedical devices through dual delivery of gene and drug.