Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Elmorsy E.A.; Saber S.; Kira A.Y.; Alghasham A.; Abdel-Hamed M.R.; Amer M.M.; Mohamed E.A.; AlSalloom A A.; Alkhamiss A.S.; Hamad R.S.; Abdel-Reheim M.A.; Ellethy A.T.; Elsisi H.A.; Alsharidah M.; Elghandour S.R.; Elnawawy T.; Abdelhady R.

Journal: Frontiers in Pharmacology

Publisher: Frontiers Media SA

Publication Date: 14 May 2024

Volume / Issue: Volume 15

Article No.: 1377980

ISSN: 16639812

DOI: 10.3389/fphar.2024.1377980

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Elmorsy E.A., Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraydah, Saudi Arabia, Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Kira A.Y., Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Alghasham A., Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraydah, Saudi Arabia; Abdel-Hamed M.R., Department of Anatomy, College of Medicine, Qassim University, Buraydah, Saudi Arabia, Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Amer M.M., Department of Anatomy, College of Medicine, Qassim University, Buraydah, Saudi Arabia, Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Mohamed E.A., Department of Anatomy, College of Medicine, Qassim University, Buraydah, Saudi Arabia, Department of Anatomy, Faculty of Medicine, Cairo University, Cairo, Egypt; AlSalloom A A., Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia; Alkhamiss A.S., Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia; Hamad R.S., Biological Sciences Department, College of Science, King Faisal University, Saudi Arabia, Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt; Abdel-Reheim M.A., Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt; Ellethy A.T., Department of Oral and Medical Basic Sciences, Biochemistry Division, College of Dentistry, Qassim University, Buraydah, Saudi Arabia; Elsisi H.A., Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia, Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; Alsharidah M., Department of Physiology, College of Medicine, Qassim University, Buraydah, Saudi Arabia; Elghandour S.R., Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah, Saudi Arabia; Elnawawy T., Department of Pharmaceutics, Egyptian Drug Authority, Cairo, Egypt; Abdelhady R., Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt

Abstract

Liver fibrosis is a disease with a great global health and economic burden. Existing data highlights itraconazole (ITRCZ) as a potentially effective anti-fibrotic therapy. However, ITRCZ effect is hindered by several limitations, such as poor solubility and bioavailability. This study aimed to formulate and optimize chitosan nanoparticles (Cht NPs) loaded with ITRCZ as a new strategy for managing liver fibrosis. ITRCZ-Cht NPs were optimized utilizing a developed 22 full factorial design. The optimized formula (F3) underwent comprehensive in vitro and in vivo characterization. In vitro assessments revealed that F3 exhibited an entrapment efficiency of 89.65% ± 0.57%, a 169.6 ± 1.77 nm particle size, and a zeta potential of +15.93 ± 0.21 mV. Furthermore, in vitro release studies indicated that the release of ITRCZ from F3 adhered closely to the first-order model, demonstrating a significant enhancement (p-value < 0.05) in cumulative release compared to plain ITRCZ suspension. This formula increased primary hepatocyte survival and decreased LDH activity in vitro. The in vivo evaluation of F3 in a rat model of liver fibrosis revealed improved liver function and structure. ITRCZ-Cht NPs displayed potent antifibrotic effects as revealed by the downregulation of TGF-β, PDGF-BB, and TIMP-1 as well as decreased hydroxyproline content and α-SMA immunoexpression. Anti-inflammatory potential was evident by reduced TNF-α and p65 nuclear translocation. These effects were likely ascribed to the modulation of Hedgehog components SMO, GLI1, and GLI2. These findings theorize ITRCZ-Cht NPs as a promising formulation for treating liver fibrosis. However, further investigations are deemed necessary. Copyright © 2024 Elmorsy, Saber, Kira, Alghasham, Abdel-Hamed, Amer, Mohamed, AlSalloom A., Alkhamiss, Hamad, Abdel-Reheim, Ellethy, Elsisi, Alsharidah, Elghandour, Elnawawy and Abdelhady.

Keywords

anti-fibrotic; hedgehog signaling; inflammation; itraconazole; liver fibrosis; nanotechnolody; alanine aminotransferase; aspartate aminotransferase; chitosan nanoparticle; gamma glutamyltransferase; hydroxyproline; lactate dehydrogenase; nanoparticle; platelet derived growth factor; platelet derived growth factor BB; superoxide dismutase; tissue inhibitor of metalloproteinase 1; transforming growth factor beta; tumor necrosis factor; adult; animal cell; animal experiment; animal model; animal tissue; Article; bioavailability; cell viability; controlled study; cytotoxicity; differential scanning calorimetry; dispersity; down regulation; encapsulation; factorial design; fibrogenesis; fluorescence intensity; histopathology; hydrolysis; in vitro study; in vivo study; liver cell; liver function; male; molecularly targeted therapy; nanotechnology; nonhuman; oxidative stress; particle size; rat; reproducibility; transmission electron microscopy; zeta potential

Citation Information

Scopus Citations: 13

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