Treatment of acute lung injury and early- and late-stage pulmonary fibrosis with combination emulsion siRNA polyplexes

Yixin Wang, Ling Ding, Zhaoting Li, Gang Chen, Minjie Sun, David Oupicky

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are severe lung diseases causing irreversible lung damage and premature death. Both diseases share multiple pathological features, including overexpression of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of plasminogen activator inhibitor-1 (PAI-1). The goal of the present study was to evaluate therapeutic potential of pulmonary treatment with combined inhibition of CXCR4 and PAI-1 in ALI and various disease stages of IPF. We report preparation of perfluorocarbon emulsion polyplexes containing a fluorinated polymeric CXCR4 antagonist (F-PAMD) as an siRNA carrier suitable for pulmonary delivery. In vitro testing of the emulsion polyplexes in primary lung fibroblasts from IPF mice showed high cellular uptake and promising antifibrotic effect as indicated by the decreased expression of α smooth muscle actin, when compared with conventional siRNA polyplexes. Biodistribution analysis in mice with IPF showed prolonged lung retention and widespread lung distribution following intratracheal administration of the formulations. The emulsion polyplexes showed promising therapeutic efficacy in ALI and in early fibrinogenic stage of IPF. Increased survival was observed in the model of late-stage IPF. The use of perfluorocarbon emulsion polyplexes to achieve combined CXCR4 antagonism and PAI-1 inhibition is a promising strategy for treatment of ALI and IPF.

Original languageEnglish (US)
Pages (from-to)12-24
Number of pages13
JournalJournal of Controlled Release
Volume314
DOIs
StatePublished - Nov 28 2019

Keywords

  • Acute lung injury
  • CXCR4
  • Emulsion
  • Idiopathic pulmonary fibrosis
  • PAI-1
  • siRNA

ASJC Scopus subject areas

  • Pharmaceutical Science

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