Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury.
Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury.
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DOI：
10.1038/srep16592
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发表时间：
2015-11-13
影响因子：
4.6
通讯作者：
Kang PM
中科院分区：
文献类型：
--
作者：
Lee D;Park S;Bae S;Jeong D;Park M;Kang C;Yoo W;Samad MA;Ke Q;Khang G;Kang PM
过氧化氢(H_2O_2)的过量产生导致氧化应激，是缺血/再灌注(I/R)损伤发生的主要原因。因此，抑制氧化应激在I/R损伤的治疗中至关重要。在这里，我们报告了过氧化氢激活的抗氧化剂前药(BRAP)，它能够特异性地靶向氧化应激部位，并发挥抗炎和抗细胞凋亡的活性。BRAP带有自焚的硼酸酯保护基团，具有清除过氧化氢和释放HBA(对羟基苯甲醇)的作用，具有抗氧化和抗炎活性。BRAP通过抑制ROS和促炎细胞因子的产生，在脂多糖(LPS)和过氧化氢刺激的细胞中发挥强大的抗氧化和抗炎活性。在小鼠肝脏I/R和心脏I/R模型中，BRAP通过清除过氧化氢的硼酸酯和治疗性HBA的协同作用而发挥出强大的抗氧化、抗炎和抗细胞凋亡活性。此外，每天服用大剂量BRAP 7天，未发现肾或肝功能异常。因此，BRAP作为H_2O_2激活的抗氧化剂前体药物治疗I/R损伤具有巨大的治疗潜力。
Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries.