Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis

Virender Kumar, Goutam Mondal, Rinku Dutta, Ram I Mahato

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

In liver fibrosis, secretion of growth factors and hedgehog (Hh) ligands by hepatic parenchyma upon repeated insults results in transdifferentiation of quiescent hepatic stellate cells (HSCs) into active myofibroblasts which secrete excessive amounts of extracellular matrix (ECM) proteins. An Hh inhibitor GDC-0449 and miR-29b1 can play an important role in treating liver fibrosis by inhibiting several pro-fibrotic genes. Our in-silico analysis indicate that miR-29b1 targets several profibrotic genes like collagen type I & IV, c-MYC, PDGF-β and PI3K/AKT which are upregulated in liver fibrosis. Common bile duct ligation (CBDL) resulted in an increase in Ptch-1, Shh and Gli-1 expression. miR-29b1 and GDC-0449 were co-formulated into micelles using methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-tetraethylenepentamine) (mPEG-b-PCC-g-DC-g-TEPA) copolymer, and injected systemically into CBDL mice. High concentrations of GDC-0449 and miR-29b1 were delivered to liver cells as determined by in situ liver perfusion at 30 min post systemic administration of their micelle formulation. There was a significant decrease in collagen deposition in the liver and serum injury markers, leading to improvement in liver morphology. Combination therapy was more effective in providing hepatoprotection, lowering liver injury related serum enzyme levels, reducing fibrotic protein markers such as collagen, α-SMA, FN-1 and p-AKT compared to monotherapy. In conclusion, inhibition of Hh pathway and restoration of miR-29b1 have the potential to act synergistically in treating CBDL-induced liver fibrosis in mice.

Original languageEnglish (US)
Pages (from-to)144-156
Number of pages13
JournalBiomaterials
Volume76
DOIs
StatePublished - Jan 1 2016

Fingerprint

Hedgehogs
MicroRNAs
HhAntag691
Liver Cirrhosis
Liver
Molecules
Common Bile Duct
Ligation
Micelles
Collagen
Ducts
Triethylenephosphoramide
Dodecanol
Transplants
Grafts
Hepatic Stellate Cells
Myofibroblasts
Ethylene Glycol
Extracellular Matrix Proteins
Wounds and Injuries

Keywords

  • CBDL
  • GDC-0449
  • Hedgehog
  • Liver fibrosis
  • MiR-29b1
  • MiRNA delivery
  • Micelles

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis. / Kumar, Virender; Mondal, Goutam; Dutta, Rinku; Mahato, Ram I.

In: Biomaterials, Vol. 76, 01.01.2016, p. 144-156.

Research output: Contribution to journalArticle

Kumar, Virender ; Mondal, Goutam ; Dutta, Rinku ; Mahato, Ram I. / Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis. In: Biomaterials. 2016 ; Vol. 76. pp. 144-156.
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