一鍋法製備具有抗氧化和抗發炎活性的 FeP-Ti/MXene 奈米複合材料以減輕小鼠急性腎損傷

One-pot Preparation of FeP-Ti/MXene Nanocomposites with Anti-oxidant and Anti-inflammatory Activities to Alleviate Acute Kidney Injury in Mice

余慧玲(Hui-Ling Yu)

指導教授 ： 張煥宗

國立臺灣大學/理學院/化學研究所/碩士(2022年)

https://doi.org/10.6342/NTU202201969

摘要

急性腎損傷 (Acute kidney injury, AKI) 是一種常見的臨床疾病，具有高發病率、高死亡率和高醫療成本無幾的特點，每年至少導致170萬人死亡，平均每百萬人就有將近五千人患此疾病，在美國每年與AKI相關的醫療支出高達240億美元。AKI的臨床特徵包含代謝功能障礙、腎小管損傷、嚴重發炎反應及氧化壓力積累；其中發炎反應過程中會產生一系列的生物事件，如活性氧類 (reactive oxygen species, ROS) 的過量產生、組織缺氧及巨噬細胞促發炎極化；因而引發一系列病理過程，包括細胞凋亡和腎纖維化，從而導致腎臟排泄功能迅速下降、尿量減少和氮代謝累積增加。目前，在腎功能完全喪失的情況下，除了腎臟替代療法，如血液透析、腹膜透析及腎臟移植三種方法外尚無有效的臨床治療方法。鑒於前述事實，本研究中致力於開發具有抗氧化和抗發炎特性的人工奈米酶，作為AKI的有效治療策略。本研究將磷酸鐵及二氧化鈦組成的異質結構藉由一步法修飾於Ti3C2Tx (MXene) 奈米片上，形成複合材料FeP-Ti/MXene；該複合材料具有廣譜 ROS 清除能力和仿過氧化氫酶的活性，可用於治療由橫紋肌溶解引起AKI的白化小鼠。在體外試驗中，我們發現FeP-Ti/MXene可有效避免人胚胎腎細胞 (HEK-293T) 氧化壓力積累及緩解由脂多醣誘發引起巨噬細胞 (Raw 264.7) 的發炎反應。在動物實驗中，FeP-Ti/MXene顯著改善了 AKI小鼠的存活率，同時尿素氮 (BUN)、肌酸酐 (CRE)、發炎因子及腎組織切片評估得知FeP-Ti/MXene對AKI具有顯著的治療效果。總的來說，將廣譜抗氧化劑結合仿過氧化氫酶能有效減緩AKI導致的臨床病徵，並為開發AKI治療手段提供一個新穎的研究方向。

關鍵字

急性腎損傷 ； 活性氧類 ； 抗氧化劑 ； 仿過氧化氫酶 ； 抗發炎

並列摘要

Acute kidney injury (AKI) is a common syndrome with very high morbidity, mortality and cost, involving more than 5000 cases per million people and causing at least 1.7 million deaths per year. The cost is as high as $24 billion. AKI features as metabolism dysfunction, tubular damage, inflammatory events, and oxidative stress. Moreover, a series of biological events would generate during the inflammatory response process, such as the excessive production of reactive oxygen species (ROS), the absence of oxygen situation, and the regulation of macrophages, triggering a series of pathological processes, including cellular apoptosis and renal fibrosis. Herein, we reported a FePO4/TiO2 heterostructure decorated Ti3C2Tx (FeP-Ti/MXene) nanocomposites that has broad-spectrum ROS scavenging activity and catalase-mimic activity for the treatment of AKI in mice. FeP-Ti/MXene showed anti-inflammatory properties in reducing the accumulation of ROS in human embryonic kidney cells (HEK-293T) and the inflammation of LPS induced macrophage (Raw264.7). Most importantly, we found that FeP-Ti/MXene alleviated oxidative stress-induced cellular apoptosis and significantly improved the treatment outcomes of AKI. Meanwhile, which was evaluated by the expression of blood urea nitrogen, creatinine, inflammatory factors, and tissue analyses showed that FeP-Ti/MXene is effective and efficient for the treatment of AKI. These findings open an avenue to the use of FeP-Ti/MXene as a novel nanodrug to treat AKI.

並列關鍵字

Acute kidney injury ； Reactive oxygen species ； FeP-Ti/MXene ； ROS scavenging activity ； catalase-like activity

參考文獻

[1] Yin, M., Jiang, N., Guo, L., Ni, Z., Al-Brakati, A. Y., Othman, M. S., Abdel Moneim, A. E., Kassab, R. B., Oleuropein suppresses oxidative, inflammatory, and apoptotic responses following glycerol-induced acute kidney injury in rats. Life Sci. 2019, 232, 116634.

[2] Chawla, L. S., Eggers, P. W., Star, R. A., Kimmel, P. L., Acute kidney injury and chronic kidney disease as interconnected syndromes. N. Engl. J. Med. 2014, 371 (1), 58-66.

[3] Makris, K., Spanou, L., Acute kidney injury: definition, pathophysiology and clinical phenotypes. Clin. Biochem. Rev. 2016, 37 (2), 85-98.

[4] AlBasher, G., Alfarraj, S., Alarifi, S., Alkhtani, S., Almeer, R., Alsultan, N., Alharthi, M., Alotibi, N., Al-Dbass, A., Abdel Moneim, A. E., Nephroprotective role of selenium nanoparticles against glycerol-Induced acute kidney injury in rats. Biol. Trace Elem. Res. 2020, 194 (2), 444-454.

[5] Zuk, A., Bonventre, J. V., Acute kidney injury. Annu. Rev. Med. 2016, 67, 293-307.