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

Bao-Ping Tian; Fangyuan Li; Ruiqing Li; Xi Hu; Tian-Wen Lai; Jingxiong Lu; Yun Zhao; Yang Du; Zeyu Liang; Chen Zhu; Wei Shao; Wen Li; Zhi-Hua Chen; Xiaolian Sun; Xiaoyuan Chen; Songmin Ying; Daishun Ling; Huahao Shen

doi:10.1016/j.biomaterials.2018.06.020

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

Biomaterials. 2019 Feb:192:429-439. doi: 10.1016/j.biomaterials.2018.06.020. Epub 2018 Jun 18.

Authors

Bao-Ping Tian¹, Fangyuan Li², Ruiqing Li², Xi Hu², Tian-Wen Lai³, Jingxiong Lu², Yun Zhao³, Yang Du², Zeyu Liang², Chen Zhu³, Wei Shao², Wen Li³, Zhi-Hua Chen³, Xiaolian Sun⁴, Xiaoyuan Chen⁴, Songmin Ying⁵, Daishun Ling⁶, Huahao Shen⁷

Affiliations

¹ Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang 310058, China; Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, Zhejiang 310009, China; Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
² Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
³ Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang 310058, China; Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, Zhejiang 310009, China.
⁴ Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.
⁵ Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang 310058, China; Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, Zhejiang 310009, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China. Electronic address: yings@zju.edu.cn.
⁶ Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: lingds@zju.edu.cn.
⁷ Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang 310058, China; Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, Zhejiang 310009, China; State Key Laboratory of Respiratory Diseases, Guangzhou, Guangdong 510120, China. Electronic address: huahaoshen@zju.edu.cn.

Abstract

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.

Keywords: ABT-199; Allergic airway inflammation; Bcl-2; Mitochondria; Nanotechnology; Targeted drug delivery.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Asthma / drug therapy*
Bridged Bicyclo Compounds, Heterocyclic / administration & dosage*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Cell Line
Drug Delivery Systems*
Hypersensitivity / drug therapy
Inflammation / drug therapy*
Mice
Mitochondrial Membranes / drug effects
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Sulfonamides / administration & dosage*
Sulfonamides / therapeutic use

Substances

Bridged Bicyclo Compounds, Heterocyclic
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
venetoclax

Abstract

Publication types

MeSH terms

Substances

Grants and funding