Nanomedicines of hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis

Virender Kumar, Vaibhav Mundra, Ram I Mahato

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Purpose: Hedgehog (Hh) and peroxisome proliferator-activated receptor gamma (PPAR-γ) are major signaling pathways involved in the pathogenesis of liver fibrosis. Since Hh inhibitor, vismodegib (GDC) and PPAR-γ agonist, rosiglitazone (RSG) have poor water solubility, our objective was to formulate biodegradable polymeric nanoparticles encapsulating GDC and RSG for treating liver fibrosis. Methods: Methoxy-polyethylene-glycol-b-poly(carbonate-co- lactide) [mPEG-b-p(CB-co-LA)] was synthesized and characterized using 1H NMR. Nanoparticles were prepared using this polymer by emulsification/solvent evaporation method to encapsulate GDC and RSG either alone or in combination. Nanoparticles were characterized for particle size, drug loading, drug release, and anti-fibrotic efficacy after tail vein injection into common bile duct ligated (CBDL) fibrotic rats. Results: mPEG-b-p(CB-co-LA) copolymer has molecular weight of 30,000 Da as determined by 1H NMR. Nanoparticles were monodisperse with a mean particle size of 120-130 nm. Drug loading was 5% and 2% w/w for GDC and RSG, respectively. Nanoparticles carrying both GDC and RSG were formulated at half of their individual drug loading. Systemic administration of drug loaded nanoparticles protected liver injury in CBDL rats by suppressing the activation of hepatic stellate cells, and decreasing inflammatory cytokines. Conclusion: Polymeric nanoparticles for co-delivery of Hh inhibitor and PPAR-γ agonist have the potential to treat liver fibrosis by intervening complex fibrotic cascade.

Original languageEnglish (US)
Pages (from-to)1158-1169
Number of pages12
JournalPharmaceutical Research
Volume31
Issue number5
DOIs
Publication statusPublished - May 2014

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Keywords

  • PPAR-γ agonist
  • common bile duct ligation
  • hedgehog inhibitor
  • liver fibrosis

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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