ROS-responsive nanoparticle-mediated delivery of CYP2J2 gene for therapeutic angiogenesis in severe hindlimb ischemia.
ROS-responsive nanoparticle-mediated delivery of CYP2J2 gene for therapeutic angiogenesis in severe hindlimb ischemia.
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ROS响应纳米颗粒介导的CYP2J2基因递送用于治疗严重后肢缺血的血管生成
DOI：
10.1016/j.mtbio.2021.100192
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Gui L;Chen Y;Diao Y;Chen Z;Duan J;Liang X;Li H;Liu K;Miao Y;Gao Q;Li Z;Yang J;Li Y
由于严重肢体缺血（CLI）是一种多因素疾病，越来越明显的是，基因治疗与多种生物功能的生长因子可以达到更好的治疗效果。细胞色素P450环氧合酶-2J2（CYP 2 J2）及其催化产物环氧二十碳三烯酸（Epoxyeicosatrienoicacids，ECO 2）具有促血管生成、抗炎和心血管保护等多种生物学活性，对逆转CLI缺血和恢复局部血流具有重要作用。本文设计了一种基于纳米颗粒的pcDNA3.1-CYP 2 J2质粒DNA（pDNA）递送系统（纳米颗粒/pDNA复合物），该系统由一种新型的三臂星形星星嵌段共聚物（3S-PLGA-po-PEG）组成，该共聚物通过过草酸酯键将三臂PLGA与PEG偶联而成。考虑到CYP 2 J2-雌二醇的多种生物功能和过草酸酯键对H2 O2的敏感性，这种基于纳米颗粒的基因递送系统有望表现出优异的促血管生成作用，同时改善缺血后肢的高氧化应激和炎症微环境。我们的研究报告了CYP 2 J2在CLI治疗的治疗性血管生成领域的首次应用，我们的研究结果表明CYP 2 J2纳米递送系统具有良好的生物相容性、稳定性和缓释特性。此外，这种基于纳米颗粒的基因递送系统在体外和体内显示出高转染效率和有效的VEGF表达。与用裸pDNA处理的小鼠相比，将纳米颗粒/pDNA复合物肌内注射到具有后肢缺血的小鼠中导致显著的快速血流恢复和改善的肌肉修复。综上所述，3S-PLGA-po-PEG/CYP 2 J2-pDNA复合物具有巨大的潜力，并为肢体缺血的治疗提供了一种实用的策略。此外，3S-PLGA-po-PEG纳米颗粒可能作为一种潜在的非病毒载体用于其他基因递送应用。细胞色素P450表氧化酶-2J2（CYP 2 J2）首次应用于治疗性血管生成领域，用于严重肢体缺血治疗。以过草酸酯为H2 O2响应性连接基，通过草酰氯与羟基的酯化反应，合成了具有ROS响应性的三臂星星型嵌段共聚物（3S-PLGA-po-PEG）。CYP 2 J2纳米递送系统具有高转染效率和显著的治疗性血管生成作用。
With critical limb ischemia (CLI) being a multi-factorial disease, it is becoming evident that gene therapy with a multiple bio-functional growth factor could achieve better therapeutic outcomes. Cytochrome P450 epoxygenase-2J2 (CYP2J2) and its catalytic products epoxyeicosatrienoic acids (EETs) exhibit pleiotropic biological activities, including pro-angiogenic, anti-inflammatory and cardiovascular protective effects, which are considerably beneficial for reversing ischemia and restoring local blood flow in CLI. Here, we designed a nanoparticle-based pcDNA3.1-CYP2J2 plasmid DNA (pDNA) delivery system (nanoparticle/pDNA complex) composed of a novel three-arm star block copolymer (3S-PLGA-po-PEG), which was achieved by conjugating three-armed PLGA to PEG via the peroxalate ester bond. Considering the multiple bio-functions of CYP2J2-EETs and the sensitivity of the peroxalate ester bond to H2O2, this nanoparticle-based gene delivery system is expected to exhibit excellent pro-angiogenic effects while improving the high oxidative stress and inflammatory micro-environment in ischemic hindlimb. Our study reports the first application of CYP2J2 in the field of therapeutic angiogenesis for CLI treatment and our findings demonstrated good biocompatibility, stability and sustained release properties of the CYP2J2 nano-delivery system. In addition, this nanoparticle-based gene delivery system showed high transfection efficiency and efficient VEGF expression in vitro and in vivo. Intramuscular injection of nanoparticle/pDNA complexes into mice with hindlimb ischemia resulted in significant rapid blood flow recovery and improved muscle repair compared to mice treated with naked pDNA. In summary, 3S-PLGA-po-PEG/CYP2J2-pDNA complexes have tremendous potential and provide a practical strategy for the treatment of limb ischemia. Moreover, 3S-PLGA-po-PEG nanoparticles might be useful as a potential non-viral carrier for other gene delivery applications. Cytochrome P450 epoxygenase-2J2 (CYP2J2) was first applied in the field of therapeutic angiogenesis for critical limb ischemia treatment. The ROS-responsive three-arm star block copolymer (3S-PLGA-po-PEG) was synthesized with peroxalate ester as H2O2-responsive linkages through the esterification reaction of oxalyl chloride and hydroxyl group. The CYP2J2 nano-delivery system achieved high transfection efficiency and significant therapeutic angiogenesis effect.
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影响因子：
4.4
作者：
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通讯作者：
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