Antioxidative Nanoparticles Significantly Enhance Therapeutic Efficacy of an Antibacterial Therapy against Listeria monocytogenes Infection

Yutaka Ikeda, Kazuhiro Shoji, Chitho P. Feliciano, Shinji Saito, Yukio Nagasaki

Index: 10.1021/acs.molpharmaceut.7b00995

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Abstract

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.