Nanoparticle based delivery of hypoxia-regulated VEGF transgene system combined with myoblast engraftment for myocardial repair
Nanoparticle based delivery of hypoxia-regulated VEGF transgene system combined with myoblast engraftment for myocardial repair
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DOI：
10.1016/j.biomaterials.2010.12.008
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发表时间：
2011-03-01
期刊：
影响因子：
14
通讯作者：
Sim, Eugene K. W.
中科院分区：
文献类型：
--
作者：
Ye, Lei;Zhang, Wei;Sim, Eugene K. W.
一种控制基因表达的调控启动子系统是安全有效的治疗性转基因过表达所需要的。联合骨骼肌母细胞（SkMs），我们报道了缺氧调节的VEGF基因递送对急性心肌梗死（AM!）期间心肌修复的疗效。制备了一种缺氧调节的VEGF质粒（pHRE-VEGF）。优化后，用聚乙烯亚胺（PEI）纳米颗粒转染约30%的SkMs。缺氧条件下pHRE-VEGF转染SkMs （VEGF）的VEGF表达峰值（151.34 +/- 8.59 ng/ml）高于缺氧条件下（16.92 +/- 2.74 ng/ml）。在家兔急性心肌梗死模型中评价缺氧调控基因表达系统的作用。各组接受不含细胞的基础M199（1组）或含未转染SkMs（2组）或（VEGF）SkMs（3组）。第4组，将VEGF SkMs注入正常心脏，作为正常缺氧对照。移植后第3天和第7天，3组和-4组SkM存活率均有所提高（p < 0.05， vs 2组）。治疗后2周，3组血管密度为20.1 +/- 1.3，显著高于其他各组（p < 0.05）。3组左室前壁血流量（ml/min/g）显著高于1组（0.76 +/- 0.05）和2组（0.96 +/- 0.06），与4组（1.26 +/- 0.05）比较，差异无统计学意义（p < 0.05）。左室射血分数保存最好的是3组（58.4 +/- 1.75%），与4组（61.1 +/- 1.8%）和2组（52.8 +/- 1.4%）差异无统计学意义，但与1组（44.7 +/- 2.2%）相比有显著改善（p < 0.05）。研究表明，在AMI期间，基于纳米颗粒的低氧调节VEGF转基因联合SkMs有效地保留了左室区域血流量和心脏收缩功能。(C) 2010 Elsevier Ltd.版权所有。
A regulated promoter system to control gene expression is desirable for safe and efficacious overexpression of therapeutic transgene. Combined with skeletal myoblast (SkMs), we report the efficacy of hypoxia-regulated VEGF gene delivery for myocardial repair during acute myocardial infarction (AM!). A hypoxia-regulated VEGF plasmid (pHRE-VEGF) was developed. After optimization, similar to 30% SkMs were transfected using polyethyleneimine (PEI) nanoparticles. The peak VEGF expression was higher in pHRE-VEGF transfected SkMs ((VEGF)SkMs) under hypoxia (151.34 +/- 8.59 ng/ml) than that with normoxia (16.92 +/- 2.74 ng/ml). The efficacy of hypoxia-regulated gene expression system was assessed in a rabbit model of AMI. The animals were grouped to receive basal M199 without cells (group-1) or containing non-transfected SkMs (group-2) or (VEGF)SkMs (group-3). In group-4, (VEGF)SkMs were injected into normal heart to serve as normoxia control. Improved SkM survival was observed in group-3 and -4 (p < 0.05 vs group-2) at day-3 and 7 after transplantation. Blood vessel density was 20.1 +/- 1.3 in group-3 which was significantly higher than any other groups (p < 0.05) at 2 weeks after treatment. Improved blood flow (ml/min/g) in the left ventricle (LV) anterior wall was observed in group-3 (1.28 +/- 0.09, p < 0.05) as compared with group-1 (0.76 +/- 0.05) and group-2 (0.96 +/- 0.06), and similar to group-4 (1.26 +/- 0.05). LV ejection fraction was best preserved in group-3 (58.4 +/- 1.75%) which was insignificantly different from group-4 (61.1 +/- 1.8%), and group-2 (52.8 +/- 1.4%), but significantly improved compared with group-1 (44.7 +/- 2.2%, p < 0.05). The study demonstrates that nanoparticle based delivery of hypoxia-regulated VEGF transgene combined with SkMs during AMI effectively preserves LV regional blood flow and contractile function of the heart. (C) 2010 Elsevier Ltd. All rights reserved.