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Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis

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
Biomaterials 2019 v.192 pp. 429-439
animal models, apoptosis, asthma, biocompatibility, cell viability, epithelium, hypersecretion, inflammation, liver function, mitochondria, mitochondrial membrane, mucus, nanocarriers
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.