Discoidal PLGA particles used for delivery of nintedanib in development of therapy for pulmonary fibrosis (lung-scarring)

 

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which scar tissue forms along the inner lining of the lung preventing oxygen uptake. Recently, researchers at Yonsei University (Korea) used PLGAs (AP040, AP091, AP259) from PolySciTech Division of Akina, Inc. (www.polyscitech.com) to create disc-shaped nanoparticles. These were tested for use in treatment of lung-scarring. This research holds promise to improve treatment of this lethal disease. Read More: Park, S., J. Y. Park, J. H. Nahm, G. Kim, Y. L. Cho, W. J. Kang, and J. Key. "Systemic delivery of nintedanib using PLGA-based discoidal polymeric particles for idiopathic pulmonary fibrosis treatment." Materials Today Chemistry 26 (2022): 101181. https://www.sciencedirect.com/science/article/pii/S2468519422004104

“Highlights: Fabricated biodegradable discoidal polymeric particles containing nintedanib. Stability was improved by increasing the lactide/glycolide ratio of PLGA. Nintedanib-loaded PLGA-DPPs significantly reduced severity of pulmonary fibrosis. Nib-PLGA-DPPs have potential for improving the bioavailability of anti-fibrotic drugs. Abstract: Nintedanib is an approved tyrosine kinase inhibitor for the treatment of idiopathic pulmonary fibrosis (IPF); however, the bioavailability is low due to low solubility. In this study, nintedanib-loaded poly (lactic-co-glycolic acid)-based discoidal polymeric particles (Nib-PLGA-DPPs) were prepared, and their effectiveness was evaluated for the treatment of IPF. Nib-PLGA-DPPs with a uniform size and shape were manufactured using a top-down method by adjusting the lactide:glycolide molar ratio (50:50, 75:25, and 85:15) of PLGA. The physicochemical properties, drug loading content, and in vitro nintedanib release behavior were characterized; ex vivo biodistribution was performed in mice. The therapeutic efficacy of Nib-PLGA-DPPs was evaluated in a murine model of IPF induced by bleomycin (BLM). The synthesized Nib-PLGA-DPP showed an average size of 2.8 ± 0.2 μm with a zeta potential value of approximately −23.5 mV and 15.7% drug loading content. Approximately 40% of the nintedanib was initially released from Nib-PLGA (50:50)-DPPs during the first 24 h; however, the initial burst was significantly reduced to 18% by increasing the lactide:glycolide ratio from 50:50 to 85:15. Nib-PLGA (50:50)-DPPs showed rapid nintedanib release reaching completion within 3 days; however, Nib-PLGA (85:15)-DPPs sustained drug release over 7 days. Notably, ex vivo imaging showed that lung accumulation of fluorescent-labeled PLGA-DPPs in BLM-treated mice was approximately 2-fold higher than that in normal mice at early time points. In the IPF murine model, Nib-PLGA-DPPs showed a greater reduction in the total BALF cell numbers and severity of pulmonary fibrosis than nintedanib alone. In addition, the higher lactide content of the PLGA polymer exhibited a lower degree of pulmonary inflammation and fibrosis. Our findings indicate that the lactide ratio of the PLGA composition could enhance the bioavailability of drug molecules and that micro sized Nib-PLGA-DPPs could be a promising systemic delivery vehicle for treating IPF. Keywords: Idiopathic pulmonary fibrosis Nintedanib Discoidal polymeric particles PLGA Therapeutic efficacy”