TY - JOUR
T1 - Development of nintedanib nanosuspension for inhaled treatment of experimental silicosis
AU - Andrade da Silva, Luisa Helena
AU - Vieira, Juliana Borges
AU - Cabral, Marianna Ribeiro
AU - Antunes, Mariana Alves
AU - Lee, Daiheon
AU - Cruz, Fernanda Ferreira
AU - Hanes, Justin
AU - Rocco, Patricia Rieken Macedo
AU - Morales, Marcelo Marcos
AU - Suk, Jung Soo
N1 - Funding Information:
The authors thank Mr. Andre Benedito da Silva for animal care, Ms. Arlete Fernandes for histological processing, Ms. Paloma Meireles for assistance in X‐ray diffraction analysis, Prof. Dr. Tatiana Ferreira for assistance in image acquisition, Dr. Siddharth Shenoy for assistance in NTB‐NS nebulization experiments, and Dr. Karina Negrón and Dr. Namho Kim for assistance in transmission electron microscopy analysis. This study was supported by the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES, no. 88881.132639/2016‐01, granted to L.H.A.S.), the Brazilian Council for Scientific and Technological Development (CNPq, no. 159568/2018‐8, granted to L.H.A.S.), Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro, FAPERJ (grant number: E‐26/010.000983/2019, P.R.M.R), PRONEX, CNPq/FAPERJ (26/210.910/2016, P.R.M.R.), Cystic Fibrosis Foundation (SUK18I0), and National Institute of Health (R01HL136617).
Funding Information:
Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Number: 159568/2018‐8; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Grant/Award Number: 88881.132639/2016‐01; Cystic Fibrosis Foundation, Grant/Award Numbers: SUK1810, SUK18I0; Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Grant/Award Numbers: 26/210.910/2016, E‐26/010.000983/2019; National Institutes of Health, Grant/Award Number: R01HL136617; PRONEX, CNPq/FAPERJ; Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro, FAPERJ; Brazilian Council for Scientific and Technological Development; Brazilian Coordination for the Improvement of Higher Education Personne Funding information
Publisher Copyright:
© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - localized treatment
KW - lung function
KW - nanosuspension
KW - pulmonary fibrosis
KW - tyrosine kinase inhibitor
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U2 - 10.1002/btm2.10401
DO - 10.1002/btm2.10401
M3 - Article
C2 - 36925690
AN - SCOPUS:85138229264
SN - 2380-6761
VL - 8
JO - Bioengineering and Translational Medicine
JF - Bioengineering and Translational Medicine
IS - 2
M1 - e10401
ER -