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

Virender Kumar, Vaibhav Mundra, Ram I Mahato

Research output: Contribution to journalArticle

33 Citations (Scopus)

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
StatePublished - May 2014

Fingerprint

rosiglitazone
Nanomedicine
Medical nanotechnology
Peroxisome Proliferator-Activated Receptors
Hedgehogs
Liver Cirrhosis
Liver
Nanoparticles
Pharmaceutical Preparations
Common Bile Duct
HhAntag691
Particle Size
Ducts
Rats
Particle size
Nuclear magnetic resonance
Hepatic Stellate Cells
Emulsification
PPAR gamma
Carbonates

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)

Cite this

Nanomedicines of hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis. / Kumar, Virender; Mundra, Vaibhav; Mahato, Ram I.

In: Pharmaceutical Research, Vol. 31, No. 5, 05.2014, p. 1158-1169.

Research output: Contribution to journalArticle

Kumar, Virender ; Mundra, Vaibhav ; Mahato, Ram I. / Nanomedicines of hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis. In: Pharmaceutical Research. 2014 ; Vol. 31, No. 5. pp. 1158-1169.
@article{cf135d52186c44d9beae3ea5a450fb0b,
title = "Nanomedicines of hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis",
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.",
keywords = "PPAR-γ agonist, common bile duct ligation, hedgehog inhibitor, liver fibrosis",
author = "Virender Kumar and Vaibhav Mundra and Mahato, {Ram I}",
year = "2014",
month = "5",
doi = "10.1007/s11095-013-1239-5",
language = "English (US)",
volume = "31",
pages = "1158--1169",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "5",

}

TY - JOUR

T1 - Nanomedicines of hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis

AU - Kumar, Virender

AU - Mundra, Vaibhav

AU - Mahato, Ram I

PY - 2014/5

Y1 - 2014/5

N2 - 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.

AB - 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.

KW - PPAR-γ agonist

KW - common bile duct ligation

KW - hedgehog inhibitor

KW - liver fibrosis

UR - http://www.scopus.com/inward/record.url?scp=84902289285&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902289285&partnerID=8YFLogxK

U2 - 10.1007/s11095-013-1239-5

DO - 10.1007/s11095-013-1239-5

M3 - Article

C2 - 24249038

AN - SCOPUS:84902289285

VL - 31

SP - 1158

EP - 1169

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 5

ER -