Open AccessDevelopment of nintedanib nanosuspension for inhaled treatment of experimental silicosis
Author(s) -
Andrade da Silva Luisa Helena,
Vieira Juliana Borges,
Cabral Marianna Ribeiro,
Antunes Mariana Alves,
Lee Daiheon,
Cruz Fernanda Ferreira,
Hanes Justin,
Rocco Patricia Rieken Macedo,
Morales Marcelo Marcos,
Suk Jung Soo
Publication year - 2023
Publication title -
bioengineering and translational medicine
Language(s) - English
Resource type - Journals
ISSN - 2380-6761
DOI - 10.1002/btm2.10401
Subject(s) - silicosis , inhalation , nintedanib , medicine , lung , pharmacology , fibrosis , occupational lung disease , dosing , pathology , idiopathic pulmonary fibrosis , anesthesia
Silicosis is an irreversible and progressive fibrotic lung disease caused by massive inhalation of crystalline silica dust at workplaces, affecting millions of industrial workers worldwide. A tyrosine kinase inhibitor, nintedanib (NTB), has emerged as a potential silicosis treatment due to its inhibitory effects on key signaling pathways that promote silica‐induced pulmonary fibrosis. However, chronic and frequent use of the oral NTB formulation clinically approved for treating other fibrotic lung diseases often results in significant side effects. To this end, we engineered a nanocrystal‐based suspension formulation of NTB (NTB‐NS) possessing specific physicochemical properties to enhance drug retention in the lung for localized treatment of silicosis via inhalation. Our NTB‐NS formulation was prepared using a wet‐milling procedure in presence of Pluronic F127 to endow the formulation with nonadhesive surface coatings to minimize interactions with therapy‐inactivating delivery barriers in the lung. We found that NTB‐NS, following intratracheal administration, provided robust anti‐fibrotic effects and mechanical lung function recovery in a mouse model of silicosis, whereas a 100‐fold greater oral NTB dose given with a triple dosing frequency failed to do so. Importantly, several key pathological phenotypes were fully normalized by NTB‐NS without displaying notable local or systemic adverse effects. Overall, NTB‐NS may open a new avenue for localized treatment of silicosis and potentially other fibrotic lung diseases.