Relaxin-Loaded Inhaled Porous Microspheres Inhibit Idiopathic Pulmonary Fibrosis and Improve Pulmonary Function Post-Bleomycin Challenges

Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeleta...

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Published in:Molecular pharmaceutics 2023-08, Vol.20 (8), p.3947-3959
Main Authors: Qiu, Shengnan, Fu, Xianglei, Shi, Yanbin, Zang, Hengchang, Zhao, Yunpeng, Qin, Zhilong, Lin, Guimei, Zhao, Xiaogang
Format: Article
Language:English
Subjects:
Animals
Bleomycin
Collagen
Fibrosis
Humans
Idiopathic Pulmonary Fibrosis - drug therapy
Idiopathic Pulmonary Fibrosis - pathology
Lung
Mice
Microspheres
Porosity
Relaxin - pharmacology
Relaxin - therapeutic use
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Summary:Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, due to its short circulating half-life, optimal efficacy requires continuous infusion or repeated injections. Here, we developed the porous microspheres loading RLX (RLX@PMs) and evaluated their therapeutic potential on IPF by aerosol inhalation. RLX@PMs have a large geometric diameter as RLX reservoirs for a long-term drug release, but smaller aerodynamic diameter due to their porous structures, which were beneficial for higher deposition in the deeper lungs. The results showed a prolonged release over 24 days, and the released drug maintained its peptide structure and activity. RLX@PMs protected mice from excessive collagen deposition, architectural distortion, and decreased compliance after a single inhalation administration in the bleomycin-induced pulmonary fibrosis model. Moreover, RLX@PMs showed better safety than frequent gavage administration of pirfenidone. We also found RLX-ameliorated human myofibroblast-induced collagen gel contraction and suppressed macrophage polarization to the M2 type, which may be the reason for reversing fibrosis. Hence, RLX@PMs represent a novel strategy for the treatment of IPF and suggest clinical translational potential.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.3c00111