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

Abstract

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.

• Authors: Shengnan Qiu, Xianglei Fu, Yanbin Shi, Hengchang Zang, Yunpeng Zhao, Zhilong Qin, Guimei Lin, Xiaogang Zhao
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 20 Issue 8 Pg. 3947-3959 (08 07 2023) ISSN: 1543-8392 [Electronic] United States
• PMID: 37358639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Relaxin
• Bleomycin
• Collagen

Topics

• Mice
• Humans
• Animals
• Relaxin (pharmacology, therapeutic use)
• Bleomycin
• Microspheres
• Porosity
• Lung
• Fibrosis
• Idiopathic Pulmonary Fibrosis (drug therapy, pathology)
• Collagen