Novel IMB16-4 Compound Loaded into Silica Nanoparticles Exhibits Enhanced Oral Bioavailability and Increased Anti-Liver Fibrosis In Vitro.

Xia Niu,Guoqing Li,Xiaomei Wang,Xinyi Yang,Guiling Li,Bingyu Niu,Yucheng Wang

doi:10.3390/molecules26061545

Abstract

Background: Liver fibrosis, as a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. However, IMB16-4 is water-insoluble and has very low bioavailability. Methods: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. The physical states of IMB16-4 and IMB16-4-MSNs were investigated using nitrogen adsorption, thermogravimetric analysis (TGA), HPLC, UV-Vis, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results: The results show that MSNs enhanced the dissolution rate of IMB16-4 significantly. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530% compared with raw IMB16-4 on Sprague–Dawley (SD) rats. In addition, IMB16-4-MSNs repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers, including α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β1) and matrix metalloproteinase-2 (MMP2) in LX-2 cells. Conclusions: These results provided powerful information on the use of IMB16-4-MSNs for the treatment of liver fibrosis in the future.

Highlights

Liver fibrosis is a global health problem and is characterized as cholestasis, hepatitis and nonalcoholic fatty liver disease [1,2,3,4]
The morphology and particle size of Mesoporous silica nanoparticles (MSNs) and IMB16-4-MSNs were analyzed by SEM
Antibody for glyceraldehyde-3-antiphosphate dehydrogenase (GAPDH) and horseradish peroxidase (HRP)-conjugated secondary antibodies against mouse or rabbit IgG were obtained from Proteintech (Wuhan, China)

Summary

Introduction

Liver fibrosis is a global health problem and is characterized as cholestasis, hepatitis and nonalcoholic fatty liver disease [1,2,3,4]. A quiescent state of hepatic stellate cells (HSCs) in healthy liver is activated. Numerous studies have elucidated the various factors and cell signaling pathways that regulate HSC activation, including transforming growth factor-beta (TGF-β) [10]. As a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. We have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. Methods: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530%

Methods

Results

Conclusion