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

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.

• Authors: 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
• Journal: Biomaterials (Biomaterials) Vol. 192 Pg. 429-439 (02 2019) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 30500724 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Ltd.

Chemical References

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

Topics

• Animals
• Apoptosis (drug effects)
• Asthma (drug therapy)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, 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, therapeutic use)