Preparation and Characterization of Silymarin-Conjugated Gold Nanoparticles with Enhanced Anti-Fibrotic Therapeutic Effects against Hepatic Fibrosis in Rats: Role of MicroRNAs as Molecular Targets

Abstract

Background: The main obstacles of silymarin (SIL) application in liver diseases are its low bioavailability, elevated metabolism, rapid excretion in bile and urine, and inefficient intestinal resorption. The study aimed to synthesize and characterize silymarin-conjugated gold nanoparticles (SGNPs) formulation to improve SIL bioavailability and release for potentiating its antifibrotic action. Methods: Both SGNPs and gold nanoparticles (GNPs) were prepared and characterized using standard characterization techniques. The improved formulation was assessed for in vitro drug release study and in vivo study on rats using CCl4 induced hepatic fibrosis model. SIL, SGNPs, and GNPs were administered by oral gavage daily for 30 days. At the end of the study, rats underwent anesthesia and were sacrificed, serum samples were collected for biochemical analysis. Liver tissues were collected to measure the genes and microRNAs (miRNAs) expressions. Also, histopathological and immunohistochemistry (IHC) examinations of hepatic tissues supported these results. Results: The successful formation and conjugation of SGNPs were confirmed by measurements methods. The synthesized nanohybrid SGNPs showed significant antifibrotic therapeutic action against CCl4-induced hepatic damage in rats, and preserved normal body weight, liver weight, liver index values, retained normal hepatic functions, lowered inflammatory markers, declined lipid peroxidation, and activated the antioxidant pathway nuclear factor erythroid-2-related factor 2 (NRF2). The antifibrotic activities of SGNPs mediated through enhancing the hepatic expression of the protective miRNAs; miR-22, miR-29c, and miR-219a which results in suppressed expression of the main fibrosis mediators; TGFβR1, COL3A1, and TGFβR2, respectively. The histopathology and IHC analysis confirmed the anti-fibrotic effects of SGNPs. Conclusions: The successful synthesis of SGNPs with sizes ranging from 16 up to 20 nm and entrapment efficiency and loading capacity 96% and 38.69%, respectively. In vivo studies revealed that the obtained nano-formulation of SIL boosted its anti-fibrotic effects.

Designing a Silymarin Nanopercolating System Using CME@ZIF-8: An Approach to Hepatic Injuries

“…The Fourier transform-infrared (FTIR) spectra of the free drug silymarin, CME@ZIF-8, and PEG-Sily@CME@ZIF-8 MOFs are presented in Figure b. The pure silymarin FTIR spectrum showed characteristic bands at 3428 cm –1 (O–H, phenols/alcohols), 2910 cm –1 (C–H, alkyl), 1629 cm –1 (–CO stretching), 1452 cm –1 (aromatic CC ring stretching), 1273 cm –1 (C–O stretching, polyols), and 973 cm –1 (C–H bending, alkenes) . For CME@ZIF-8 characteristics, peaks are at 2485 cm –1 (O–H, carboxylic acid), 2186 cm –1 (CC, alkynes), 1968 cm –1 (X = C = Y, isocyanate/isothiocyanate), 1628 cm –1 (CC, alkenes), 1341 cm –1 (S = O, sulfate/sulfonamide), 850 cm –1 (C–H, aromatic stretch out of plane bend), and 728 cm –1 (C–X, chloride) functional groups.…”

Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents

“…), 134 poor water solubility and low gastrointestinal absorption efficiency (such as luteolin, curcumin, silymarin, costuslactone, glycyrrhetinic acid, nilotinib, polydatin, etc. ), 135 and high side effects due to non-specific absorption (such as sorafenib, pirfenidone, carvedilol, dexamethasone, etc ). 136,137 In recent years, nanomaterial-based therapies have to some extent solved these difficulties faced by clinical drugs and have become an innovative and promising alternative to traditional drugs and are being explored for the treatment of liver fibrosis diseases.…”

Harnessing reactive oxygen/nitrogen species and inflammation: Nanodrugs for liver injury

“…12 A). The loaded small-molecule antioxidants can be divided into three categories: natural antioxidants (such as curcumin [ [221] , [222] , [223] , [224] , [225] ], silymarin [ [226] , [227] , [228] , [229] ], resveratrol [ 230 ], carvacrol [ 231 ], polydatin [ 232 ], carnosic acid [ 233 ], quercetin [ 234 , 235 ], and other compounds [ 231 , [236] , [237] , [238] , [239] , [240] , [241] , [242] , [243] , [244] , [245] , [246] , [247] , [248] , [249] , [250] , [251] , [252] ]), synthetic antioxidants (nitroxide 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl, tempol [ [253] , [254] , [255] , [256] , [257] , [258] ]), and human endogenous antioxidants (melatonin [ 259 , 260 ], bilirubin [ 261 ], ubiquinone (CoQ10) [ 262 ], and carbon monoxide (CO) [ 263 ]) ( Fig. 12 B–C).…”