Engineered SPIONs functionalized with endothelin a receptor antagonist ameliorate liver fibrosis by inhibiting hepatic stellate cell activation

• Published in: Bioactive materials 2024-09, Vol.39, p.406-426
• Main Authors: ten Hove, Marit, Smyris, Andreas, Booijink, Richell, Wachsmuth, Lydia, Hansen, Uwe, Alic, Lejla, Faber, Cornelius, Hӧltke, Carsten, Bansal, Ruchi
• Format: Article
• Language: English
• Subjects: Attenuation; Bioavailability; Biocompatibility; Body weight; Carbon tetrachloride; Cell activation; Cirrhosis; Collagen; Contractility; Effectiveness; Endothelin 1; Endothelin A receptor; Endothelin ETA receptors; Extracellular matrix; Fibrosis; Gene expression; Growth factors; Hepatic stellate cells; Hepatocytes; In vivo methods and tests; Kinases; Liver; Liver cancer; Liver cirrhosis; Liver fibrosis; Localization; Magnetic resonance imaging; Nanoparticles; Pathogenesis; Polyethylene glycol; Receptors; SPIONs; Stellate cells
• ISSN: 2452-199X; 2097-1192; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.05.034

Endothelin-1/endothelin A receptor (ET-1/ETAR) pathway plays an important role in the progression of liver fibrosis by activating hepatic stellate cells (HSCs) - a key cell type involved in the pathogenesis of liver fibrosis. Inactivating HSCs by blocking the ET-1/ETAR pathway using a selective ETAR antagonist (ERA) represents a promising therapeutic approach for liver fibrosis. Unfortunately, small-molecule ERAs possess limited clinical potential due to poor bioavailability, short half-life, and rapid renal clearance. To improve the clinical applicability, we conjugated ERA to superparamagnetic iron-oxide nanoparticles (SPIONs) and investigated the therapeutic efficacy of ERA and ERA-SPIONs in vitro and in vivo and analyzed liver uptake by in vivo and ex vivo magnetic resonance imaging (MRI), HSCs-specific localization, and ET-1/ETAR-pathway antagonism in vivo. In murine and human liver fibrosis/cirrhosis, we observed overexpression of ET-1 and ETAR that correlated with HSC activation, and HSC-specific localization of ETAR. ERA and successfully synthesized ERA-SPIONs demonstrated significant attenuation in TGFβ-induced HSC activation, ECM production, migration, and contractility. In an acute CCl4-induced liver fibrosis mouse model, ERA-SPIONs exhibited higher liver uptake, HSC-specific localization, and ET-1/ETAR pathway antagonism. This resulted in significantly reduced liver-to-body weight ratio, plasma ALT levels, and α-SMA and collagen-I expression, indicating attenuation of liver fibrosis. In conclusion, our study demonstrates that the delivery of ERA using SPIONs enhances the therapeutic efficacy of ERA in vivo. This approach holds promise as a theranostic strategy for the MRI-based diagnosis and treatment of liver fibrosis. [Display omitted] •ET-1/ETAR pathway plays a key role in the activation of HSCs and liver fibrosis.•ETAR antagonists (ERAs) have shown to ameliorate liver fibrosis.•The clinical application of small-molecule ERAs is hindered due to short half-life.•Delivery of ERAs using SPIONs showed higher liver uptake and therapeutic efficacy.•We present versatile nano-theranostic for imaging and treatment of liver fibrosis.