RGD-Modified Nanocarrier-Mediated Targeted Delivery of HIF-1α-AA Plasmid DNA to Cerebrovascular Endothelial Cells for Ischemic Stroke Treatment
RGD-Modified Nanocarrier-Mediated Targeted Delivery of HIF-1α-AA Plasmid DNA to Cerebrovascular Endothelial Cells for Ischemic Stroke Treatment
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RGD 修饰的纳米载体介导的 HIF-1 α-AA 质粒 DNA 靶向递送至脑血管内皮细胞用于缺血性中风治疗
DOI：
10.1021/acsbiomaterials.9b01362
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发表时间：
2019-11-01
影响因子：
5.8
通讯作者：
Deng, David Y. B.
中科院分区：
文献类型：
--
作者：
Deng, Lingna;Zhang, Fang;Deng, David Y. B.
研究表明，使用促血管生成基因可以通过促进损伤部位的血管生成来改善缺血性卒中的预后。例如，在这项研究中，缺氧诱导因子1- α (HIF-1 α)显示出血管生成作用。我们之前的研究报道了一种更稳定的HIF-1 α突变形式（HIF-1 α - aa），将其转染到间充质干细胞中，可对缺血性中风提供神经保护作用。非病毒基因载体的安全性一直是研究人员关注的问题。本研究将HIF-1 α - aa质粒DNA封装到一个新合成的有效的非病毒基因载体中，即超支化阳离子支链淀粉衍生物（DMAPA-Amyp）纳米载体。此外，采用靶向策略选择RGD肽，并结合设计的纳米载体作为靶向内皮细胞的分子。靶向策略用于将纳米载体直接递送到脑梗死周围的血管内皮细胞。本研究强调纳米载体的靶向性及其对脑缺血的治疗作用。结果表明，RGD-DMAPA-Amyp具有良好的生物相容性和较高的细胞摄取率，是一种可被人细胞内吞的安全的非病毒基因载体。在大鼠缺血性卒中模型中，与非靶向纳米载体组相比，更多的RGD-DMAPA-Amyp纳米颗粒聚集在梗死周围区血管内皮细胞中，显著促进了神经功能的恢复。结果表明，rgd修饰的纳米药物能更有效地促进神经功能的恢复。对RGD-DMAPA-Amyp/HIF-1 α - aa治疗脑缺血机制的进一步研究显示，RGD-DMAPA-Amyp/HIF-1 α - aa在体内有显著促进新血管形成的潜力。我们的研究结果表明，rgd修饰的含有HIF-1 α - aa的非病毒基因载体似乎是一种安全且有前景的缺血性卒中基因治疗策略。
Studies have shown that the use of proangiogenic genes can improve the prognosis of ischemic stroke by promoting angiogenesis at the injury site. For example, within this study, hypoxia-inducible factor 1-alpha (HIF-1 alpha) has exhibited an angiogenic effect. Our previous study reported a more stable HIF-1 alpha mutant form (HIF-1 alpha-AA), which was transfected into mesenchymal stem cells to provide neuroprotective effects against ischemic stroke. The safety of nonviral gene vectors has attracted researchers' attention. This study encapsulated the HIF-1 alpha-AA plasmid DNA into a newly synthesized effective nonviral gene vector, a hyperbranched cationic amylopectin derivative (DMAPA-Amyp) nanocarrier. In addition, a targeting strategy was applied to select the RGD peptides and bind to the designed nanocarrier as a molecule targeting endothelial cells. The targeting strategy is used to directly deliver the nanocarriers to the vascular endothelial cells of the brain peri-infarct site. This study emphasizes the targeting ability of nanocarrier and its therapeutic effect on cerebral ischemia. The results showed that RGD-DMAPA-Amyp had good biocompatibility and a high cell uptake rate, indicating that it is a safe nonviral gene vector that can be endocytosed by human cells. In rat models of ischemic stroke, compared with the nontargeted nanocarrier group, more RGD-DMAPA-Amyp nanoparticles aggregated in vascular endothelial cells of the peri-infarct region and significantly improved the recovery of neurological function. It is indicated that the RGD-modified nanomedicine promotes the recovery of nerve function more efficiently. Further study on the mechanism of RGD-DMAPA-Amyp/HIF-1 alpha-AA in the treatment of cerebral ischemia displayed potential to significantly promote the formation of new blood vessels in vivo. Our findings suggest that the RGD-modified nonviral gene vector containing HIF-1 alpha-AA appears to be a safe and promising therapeutic strategy for ischemic stroke gene therapy.