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Nanomedicines of Hedgehog Inhibitor and PPAR-γ Agonist for Treating Liver Fibrosis

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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.

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Abbreviations

ALT:

serum alanine transaminase

AST:

serum aspartate transaminase

CBDL:

common bile duct ligation

EMT:

epithelial to mesenchymal transition

GDC:

vismodegib

Hh:

Hedgehog

HSCs:

hepatic stellate cells

IL-6:

interleukin-6

mPEG-b-p(CB-co-LA):

Methoxy-polyethylene-glycol-b-poly(carbonate-co-lactide)

NFκB:

nuclear factor κB

PPAR-γ:

peroxisome proliferator-activated receptor gamma

Ptch-1:

Patched-1

ROS:

reactive oxygen species

RSG:

rosiglitazone

Shh:

Sonic hedgehog

TGF-β1:

transforming growth factor beta 1

TNF-α:

tumor necrosis factor α

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by The University of Tennessee Health Science Center.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA

    Virender Kumar, Vaibhav Mundra & Ram I. Mahato

  2. Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA

    Ram I. Mahato

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  1. Virender Kumar
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Correspondence to Ram I. Mahato.

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Kumar, V., Mundra, V. & Mahato, R.I. Nanomedicines of Hedgehog Inhibitor and PPAR-γ Agonist for Treating Liver Fibrosis. Pharm Res 31, 1158–1169 (2014). https://doi.org/10.1007/s11095-013-1239-5

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