Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis
Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis
复制标题
纳米配方 ABT-199 可有效靶向线粒体膜上的 Bcl-2，通过诱导细胞凋亡减轻气道炎症
DOI：
10.1016/j.biomaterials.2018.06.020
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发表时间：
2019
期刊：
影响因子：
14
通讯作者：
Shen Huahao
中科院分区：
文献类型：
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作者：
Tian Bao-Ping;Li Fangyuan;Li Ruiqing;Hu Xi;Lai Tian-Wen;Lu Jingxiong;Zhao Yun;Du Yang;Liang Zeyu;Zhu Chen;Shao Wei;Li Wen;Chen Zhi-Hua;Sun Xiaolian;Chen Xiaoyuan;Ying Songmin;Ling Daishun;Shen Huahao
清除呼吸道炎症细胞是控制哮喘的关键。由于Bcl2蛋白在炎症细胞的线粒体外膜上高表达，我们选择了一种Bcl2抑制剂ABT-199，它可以通过诱导炎症细胞凋亡来抑制气道炎症和气道高反应性。在此，我们合成了一种对pH敏感的纳米制剂Bcl-2抑制剂(NF-ABT-199)，它可以特异性地将ABT-199运送到支气管炎细胞的线粒体。使用NF-ABT-199的炎性细胞线粒体靶向治疗的概念验证研究在过敏性哮喘的小鼠模型中得到了验证。核因子-ABT-199可有效诱导嗜酸性粒细胞凋亡，抑制炎症细胞的浸润和粘液的高分泌，从而显著减轻气道炎症。此外，纳米载体或核因子-ABT-199对细胞存活率、呼吸道上皮屏障和肝功能无明显影响，具有良好的生物相容性和无毒作用。纳米制剂的Bcl-2抑制剂NF-ABT-199积聚在炎症细胞的线粒体中，有效地缓解过敏性哮喘。
Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma.