Pulmonary delivery of polyplexes for combined PAI-1 gene silencing and CXCR4 inhibition to treat lung fibrosis

This report describes the development of polyplexes based on CXCR4-inhibiting poly(ethylenimine) derivative (PEI-C) for pulmonary delivery of siRNA to silence plasminogen activator inhibitor-1 (siPAI-1) as a new combination treatment of pulmonary fibrosis (PF). Safety and delivery efficacy of the PEI-C/siPAI-1 polyplexes was investigated in vitro in primary lung fibroblasts isolated from mice with bleomycin-induced PF. Biodistribution analysis following intratracheal administration of fluorescently labeled polyplexes showed prolonged retention in the lungs. Treatment of mice with bleomycin-induced PF using the PEI-C/siPAI-1 polyplexes resulted in a significant down-regulation of the PAI-1 expression and decreased collagen deposition in the lung. The results of this study provide first evidence of the potential benefits of combined inhibition of CXCR4 and PAI-1 in the pulmonary treatment of PF.Graphical AbstractPulmonary fibrosis (PF) is a chronic inflammatory fibrotic disorder with limited therapeutic approaches. If left untreated, PF progresses into a fatal disease within several years of medical diagnosis. Here, we report development of novel combination nanomedicine pulmonary treatment based on inhibition of PAI-1 and CXCR4 - two relevant targets in the pathophysiology of PF. The developed nanomedicines are based on CXCR4-inhibiting polymer (PEI-C22) that delivers siRNA to silence PAI-1 expression in fibrotic lungs.
Source: Nanomedicine: Nanotechnology, Biology and Medicine - Category: Nanotechnology Source Type: research