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

作　　者：Marit ten Hove Andreas Smyris Richell Booijink Lydia Wachsmuth Uwe Hansen Lejla Alic Cornelius Faber Carsten Hӧltke Ruchi Bansal 

机构地区：[1]Personalized Diagnostics and Therapeutics,Department of Bioengineering Technologies,Technical Medical Centre,Faculty of Science and Technology,University of Twente,Enschede,the Netherlands [2]Clinic of Radiology,University Hospital Muenster,Muenster,Germany [3]Institute for Musculoskeletal Medicine,University Hospital Muenster,Muenster,Germany [4]Department of Magnetic Detection and Imaging,Technical Medical Centre,Faculty of Science and Technology,University of Twente,Enschede,the Netherlands

出　　处：《Bioactive Materials》2024年第9期406-426,共21页生物活性材料（英文）

摘　　要：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,andα-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.

关 键 词：Endothelin A receptor SPIONs Hepatic stellate cells Liver fibrosis 

分 类 号：R575.2[医药卫生—消化系统]