Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries
Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries
复制标题
DOI：
10.1161/circulationaha.107.746412
复制
发表时间：
2008-04-22
期刊：
影响因子：
37.8
通讯作者：
Levy, Robert J.
中科院分区：
文献类型：
--
作者：
Fishbein, Ilia;Alferiev, Ivan;Levy, Robert J.
背景-聚合物涂层支架的局部药物释放已被证明对预防支架内再狭窄有效;然而，聚合物涂层的炎症效应和对药物洗脱支架使用的晚期结局的担忧都表明需要研究创新方法，例如将局部基因治疗与支架血管成形术相结合。因此，我们研究了腺病毒载体（Ad）可以用用于可逆载体结合的合成复合物从支架的裸金属表面递送的假设。（1）具有潜在硫醇基团的聚烯丙基胺二膦酸盐（PABT），（2）具有吡啶基二硫基的聚乙烯亚胺（PEI），用于扩增连接位点[PEI（PDT）]，和（3）具有不稳定酯键（HL）的双功能（胺和硫醇反应性）交联剂。HL修饰的Ad附着在PABT/PEI（PDT）处理的钢表面上，在体外持续释放超过30天，并在大鼠动脉平滑肌细胞培养物中局部表达绿色荧光蛋白，这些细胞对中和抗Ad抗体的抑制或37 ℃储存后的灭活不敏感。在大鼠颈动脉研究中，配置有PABT/PEI（PDT）/HL系留的腺病毒载体的钢支架的部署证明了每个光学成像的位点特异性动脉Ad（GFP）表达和腺病毒荧光素酶转基因活性。大鼠颈动脉支架输送腺病毒编码诱导型一氧化氮合酶导致显着抑制restenosis. Conclusions可逆固定的腺病毒载体的裸金属表面的血管内支架通过合成复合物代表了一种有效的，可调的方法持续释放的基因载体的血管。
Background-Local drug delivery from polymer-coated stents has demonstrated efficacy for preventing in-stent restenosis; however, both the inflammatory effects of polymer coatings and concerns about late outcomes of drug-eluting stent use indicate the need to investigate innovative approaches, such as combining localized gene therapy with stent angioplasty. Thus, we investigated the hypothesis that adenoviral vectors (Ad) could be delivered from the bare-metal surfaces of stents with a synthetic complex for reversible vector binding.Methods and Results-We synthesized the 3 components of a gene vector binding complex: (1) A polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethyleneimine (PEI) with pyridyldithio groups for amplification of attachment sites [PEI(PDT)], and (3) a bifunctional (amine-and thiol-reactive) cross-linker with a labile ester bond (HL). HL-modified Ad attached to PABT/PEI(PDT)-treated steel surfaces demonstrated both sustained release in vitro over 30 days and localized green fluorescent protein expression in rat arterial smooth muscle cell cultures, which were not sensitive to either inhibition by neutralizing anti-Ad antibodies or inactivation after storage at 37 degrees C. In rat carotid studies, deployment of steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated both site-specific arterial Ad(GFP) expression and adenovirus-luciferase transgene activity per optical imaging. Rat carotid stent delivery of adenovirus encoding inducible nitric oxide synthase resulted in significant inhibition of restenosis.Conclusions-Reversible immobilization of adenovirus vectors on the bare-metal surfaces of endovascular stents via a synthetic complex represents an efficient, tunable method for sustained release of gene vectors to the vasculature.