title: The prevention of restenosis in vivo with a VEGF gene and paclitaxel co-eluting stent.
abstract: Long-term clinical studies of drug-eluting stents (DES) have reported high incidence of late thrombosis. Given the growing concern over the clinical application of this technology, we have developed a stent coated with bi-layered PLGA nanoparticles (BL-PLGA NPs) containing VEGF plasmid in the outer layer and paclitaxel (PTX) in the inner core (VEGF/PTX NPs). We hypothesized that early release of VEGF gene would promote re-endothelialization, while slow release of PTX would suppress smooth muscle cell proliferation. Using Fc plasmid as a reporter gene, we observed that Fc/PTX NPs successfully expressed Fc protein, but did not show cytotoxicity or anti-proliferative effect during the first 7 days in cell culture. In contrast, PTX NPs showed strong anti-proliferative effect staring from day 1 in culture, suggesting sequential release of gene and PTX from the BL-PLGA NPs. In vivo effects of the treated stent were assessed in mini-swines. Implantation of GFP/PTX NP-coated stents revealed efficient local GFP gene transfection at day 7. VEGF/PTX NP-coated stents showed complete re-endothelialization and significantly suppressed in-stent restenosis after 1 month compared to commercial DES. In conclusion, the VEGF/PTX NP-coated stents promote early endothelium healing while inhibit smooth muscle cell proliferation through sequential release of the VEGF gene and paclitaxel.
authors.affiliation: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science, Tianjin 300192, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Yong-Xia
authors.initials: YX
authors.lastname: Chen
authors.forename: Ziying
authors.initials: Z
authors.lastname: Yang
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Li
authors.forename: Xigang
authors.initials: X
authors.lastname: Leng
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Wei
authors.forename: Hong-Fan
authors.initials: HF
authors.lastname: Sun
authors.forename: Cun-Xian
authors.initials: CX
authors.lastname: Song
mesh_terms: D000818:Animals; D016466:CHO Cells; D023903:Coronary Restenosis / Q000517:prevention & control*; D006224:Cricetinae; D003412:Cricetulus; D054855:Drug-Eluting Stents; D008855:Microscopy, Electron, Scanning; D017239:Paclitaxel / Q000008:administration & dosage*; D013552:Swine; D013556:Swine, Miniature; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel