The use of micelles to deliver potential hedgehog pathway inhibitor for the treatment of liver fibrosis.

Abstract

Rationale: Hedgehog (Hh) pathway plays an essential role in liver fibrosis by promoting the proliferation of hepatic stellate cells (HSCs) by enhancing their metabolism via yes-associated protein 1 (YAP1). Despite the presence of several inhibitors, Hh signaling cannot be controlled exclusively due to their poor efficacy and the lack of a suitable delivery system to the injury site. Therefore, it is rationale to develop new potent Hh inhibitors and suitable delivery carriers. Methods: Based on the structure and activity of Hh inhibitor GDC-0449, we replaced its sulfonamide group with two methylpyridine-2yl at amide nitrogen to synthesize MDB5. We compared the Hh pathway inhibition and anti-fibrotic effect of MDB5 with GDC-0449 in vitro. Next, we developed MDB5 loaded micelles using our methoxy poly(ethylene glycol)-blockpoly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (PEG-PCC-g-DC) copolymer and characterized for physicochemical properties. We evaluated the therapeutic efficacy of MDB5 loaded micelles in common bile duct ligation (CBDL) induced liver fibrosis, mouse model. We also determined the intrahepatic distribution of fluorescently labeled micelles after MDB5 treatment. Results: Our results show that MDB5 was more potent in inhibiting Hh pathway components and HSC proliferation in vitro. We successfully developed MDB5 loaded micelles with particle size of 40 ± 10 nm and drug loading up to 10% w/w. MDB5 loaded micelles at the dose of 10 mg/kg were well tolerated by mice, without visible sign of toxicity. The serum enzyme activities elevated by CBDL was significantly decreased by MDB5 loaded micelles compared to GDC-0449 loaded micelles. MDB5 loaded micelles further decreased collagen deposition, HSC activation, and Hh activity and its target genes in the liver. MDB5 loaded micelles also prevented liver sinusoidal endothelial capillarization (LSEC) and therefore restored perfusion between blood and liver cells. Conclusions: Our study provides evidence that MDB5 was more potent in inhibiting Hh pathway in HSC-T6 cells and showed better hepatoprotection in CBDL mice compared to GDC-0449.

• Authors: Virender Kumar, Yuxiang Dong, Vinod Kumar, Saud Almawash, Ram I Mahato
• Journal: Theranostics (Theranostics) Vol. 9 Issue 25 Pg. 7537-7555 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 31695785 (Publication Type: Journal Article)
• Copyright: © The author(s).

Chemical References

• Adaptor Proteins, Signal Transducing
• Anilides
• Benzene Derivatives
• Hedgehog Proteins
• HhAntag691
• MDB5
• Micelles
• Polyesters
• Pyridines
• poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-dodecanol)
• Dodecanol
• Polyethylene Glycols

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Anilides (pharmacology)
• Animals
• Benzene Derivatives (pharmacology)
• Cell Line
• Disease Models, Animal
• Dodecanol (pharmacology)
• Hedgehog Proteins (antagonists & inhibitors)
• Hepatic Stellate Cells (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Liver Cirrhosis (drug therapy, metabolism)
• Mice
• Mice, Inbred C57BL
• Micelles
• Polyesters (chemistry)
• Polyethylene Glycols (chemistry)
• Pyridines (pharmacology)
• Rats
• Signal Transduction (drug effects)