Development of nintedanib nanosuspension for inhaled treatment of experimental silicosis.

Autor: Andrade da Silva LH; Laboratory of Pulmonary Investigation Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro Brazil.; Rio de Janeiro Innovation Network in Nanosystems for Health - NanoSAÚDE/FAPERJ Rio de Janeiro Brazil., Vieira JB; Laboratory of Pulmonary Investigation Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro Brazil., Cabral MR; Laboratory of Pulmonary Investigation Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro Brazil., Antunes MA; Laboratory of Pulmonary Investigation Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro Brazil., Lee D; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine Baltimore Maryland USA.; Department of Ophthalmology Johns Hopkins University School of Medicine Baltimore Maryland USA., Cruz FF; Laboratory of Pulmonary Investigation Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro Brazil., Hanes J; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine Baltimore Maryland USA.; Department of Ophthalmology Johns Hopkins University School of Medicine Baltimore Maryland USA.; Department of Chemical and Biomolecular Engineering Johns Hopkins University Baltimore Maryland USA., Rocco PRM; Laboratory of Pulmonary Investigation Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro Rio de Janeiro Brazil.; Rio de Janeiro Innovation Network in Nanosystems for Health - NanoSAÚDE/FAPERJ Rio de Janeiro Brazil., Morales MM; Laboratory of Cellular and Molecular Physiology Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro Rio de Janeiro Brazil., Suk JS; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine Baltimore Maryland USA.; Department of Ophthalmology Johns Hopkins University School of Medicine Baltimore Maryland USA.; Department of Chemical and Biomolecular Engineering Johns Hopkins University Baltimore Maryland USA.
Jazyk: angličtina
Zdroj: Bioengineering & translational medicine [Bioeng Transl Med] 2022 Sep 19; Vol. 8 (2), pp. e10401. Date of Electronic Publication: 2022 Sep 19 (Print Publication: 2023).
DOI: 10.1002/btm2.10401
Abstrakt: 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.
(© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)
Databáze: MEDLINE
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