The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury.
The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury.
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DOI：
10.1016/j.biomaterials.2009.10.045
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发表时间：
2010-02
期刊：
影响因子：
14
通讯作者：
Davis, Michael E.
中科院分区：
文献类型：
--
作者：
Seshadri, Gokulakrishnan;Sy, Jay C.;Brown, Milton;Dikalov, Sergey;Yang, Stephen C.;Murthy, Niren;Davis, Michael E.
氧化应激在心肌梗死后增加，并在心肌细胞死亡中起重要作用，导致心功能障碍。心肌梗死后内源性抗氧化剂Cu/Zn-超氧化物歧化酶（SOD 1）水平降低。虽然SOD 1基因治疗研究显示出希望，但由于药物动力学较差，SOD 1蛋白的试验几乎没有成功，因此需要新的运载工具。在这项工作中，聚缩酮颗粒，最近开发的运载工具，用于制造SOD 1-酯化微粒（PKSOD）。我们对培养的巨噬细胞的研究表明，PKSOD处理清除细胞内和细胞外的超氧化物，这表明SOD 1蛋白质有效地传递到细胞内部。在缺血/再灌注（IR）损伤的大鼠模型中，梗死后3天注射PKSOD而不是游离SOD 1或空颗粒能够清除IR诱导的过量超氧化物。此外，只有PKSOD治疗显着减少心肌细胞凋亡。此外，PKSOD治疗能够改善心脏功能，如通过基线超声心动图缩短分数的急性变化所测量的，这表明在心脏修复的早期阶段持续递送SOD 1是至关重要的。这些数据表明，用聚缩酮递送SOD 1上级游离SOD 1蛋白治疗，并可能具有潜在的临床意义。
Oxidative stress is increased in the myocardium following infarction and plays a significant role in death of cardiac myocytes, leading to cardiac dysfunction. Levels of the endogenous antioxidant Cu/Zn-superoxide dismutase (SOD1) decrease following myocardial infarction. While SOD1 gene therapy studies show promise, trials with SOD1 protein have had little success due to poor pharmacokinetics and thus new delivery vehicles are needed. In this work, polyketal particles, a recently developed delivery vehicle, were used to make SOD1-encapsulated-microparticles (PKSOD). Our studies with cultured macrophages demonstrated that PKSOD treatment scavenges both intracellular and extracellular superoxide, suggesting efficient delivery of SOD1 protein to the inside of cells. In a rat model of ischemia/reperfusion (IR) injury, injection of PKSOD, and not free SOD1 or empty particles was able to scavenge IR-induced excess superoxide 3 days following infarction. In addition, only PKSOD treatment significantly reduced myocyte apoptosis. Further, PKSOD treatment was able to improve cardiac function as measured by acute changes in fractional shortening from baseline echocardiography, suggesting that sustained delivery of SOD1 is critical during the early phase of cardiac repair. These data demonstrate that delivery of SOD1 with polyketals is superior to free SOD1 protein therapy and may have potential clinical implications.
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