Antioxidative Nanoparticles Significantly Enhance Therapeutic Efficacy of an Antibacterial Therapy against Listeria monocytogenes Infection
Antioxidative Nanoparticles Significantly Enhance Therapeutic Efficacy of an Antibacterial Therapy against Listeria monocytogenes Infection
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DOI：
10.1021/acs.molpharmaceut.7b00995
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发表时间：
2018-03-01
影响因子：
4.9
通讯作者：
Nagasaki, Yukio
中科院分区：
文献类型：
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作者：
Ikeda, Yutaka;Shoji, Kazuhiro;Nagasaki, Yukio
脓毒症等急性炎症会导致致命疾病，包括多器官衰竭。目前正在研究几种治疗方法，例如类固醇抗炎药，以降低显着增加的血液细胞因子水平。然而，这些治疗方法并不总是可靠和有效的。没有一个能够显着提高生存率，有些大多以失败告终。活性氧 (ROS) 是负责产生细胞因子和趋化因子的信号分子，这些细胞因子和趋化因子可以介导免疫反应的过度激活，称为细胞因子风暴。除了上述药物外，人们还探索了各种抗氧化剂来去除炎症过程中过量的ROS。然而，低分子量（LMW）抗氧化剂作为治疗剂的发展受到与毒性、药代动力学差、生物利用度低和快速代谢相关的几个问题的阻碍。在本研究中，我们旨在通过使用具有 2,2,6,6-四甲基哌啶-1-氧基 (TEMPO) 的抗氧化纳米颗粒来克服这些限制，该纳米颗粒与聚合物共价结合。尽管单独使用抗氧化纳米颗粒治疗并不能消除细菌，但与对照组相比，与抗菌剂联合治疗可显着提高治疗小鼠的存活率。更重要的是，抗氧化纳米颗粒减少了细菌感染引起的氧化组织损伤。因此，我们的研究结果强调了抗氧化纳米颗粒和抗菌剂联合治疗在预防细菌感染引起的严重炎症方面的有效性。
Acute inflammatory conditions such as sepsis lead to fatal conditions, including multiple organ failure. Several treatments such as steroidal anti-inflammatory drugs are currently being investigated in order to decrease the blood cytokine level, which increases remarkably. However, any of these therapeutic treatments are not always reliable and effective; none have drastically improved survival rates, and some have mostly ended with failure. Reactive oxygen species (ROS) are signaling molecules responsible for the production of cytokines and chemokines that can mediate hyperactivation of the immune response called cytokine storm. In addition to the above-mentioned agents, various antioxidants have been explored for the removal of excess ROS during inflammation. However, the development of low-molecular-weight (LMW) antioxidants as therapeutic agents has been hampered by several issues associated with toxicity, poor pharmacokinetics, low bioavailability, and rapid metabolism. In the present study, we aimed to overcome these limitations through the use of antioxidative nanoparticles possessing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) which are covalently conjugated to polymer. Although treatment with antioxidative nanoparticles alone did not eliminate bacteria, combined treatment with an antibacterial agent was found to significantly improve survival rate of the treated mice as compared to the control group. More importantly, the antioxidative nanoparticles reduced oxidative tissue injury caused by the bacterial infection. Thus, our findings highlighted the effectiveness of combination treatment with antioxidative nanoparticles and an antibacterial agent to prevent severe inflammation caused by bacterial infection.