Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly

Noninvasive in vivo imaging of hepatic glutathione(GSH)levels is essential to early diagnosis and prognosis of acute hepatitis.Although GSH-responsive fluorescence imaging probes have been reported for evaluation of hepatitis conditions,the low penetration depth of light in liver tissue has impeded reliable GSH visualization in the human liver.We present a liver-targeted and GSH-responsive trimodal probe(GdNPs-Gal)for rapid evaluation of lipopolysaccharide-(LPS-)induced acute liver inflammation via noninvasive,real-time in vivo imaging of hepatic GSH depletion.GdNPs-Gal are formed by molecular coassembly of a GSH-responsive Gd(III)-based MRI probe(1-Gd)and a liver-targeted probe(1-Gal)at a mole ratio of 5/1(1-Gd/1-Gal),which shows high r_(1) relaxivity with low fluorescence and fluorine magnetic resonance spectroscopic(^(19)F-MRS)signals.Upon interaction with GSH,1-Gd and 1-Gal are cleaved and GdNPs-Gal rapidly disassemble into small molecules 2-Gd,2-Gal,and 3,producing a substantial decline in r_(1) relaxivity with compensatory enhancements in fluorescence and ^(19)F-MRS.By combining in vivo magnetic resonance imaging(^(1)H-MRI)with ex vivo fluorescence imaging and ^(19)F-MRS analysis,GdNPs-Gal efficiently detect hepatic GSH using three independent modalities.We noninvasively visualized LPS-induced liver inflammation and longitudinally monitored its remediation in mice after treatment with an anti-inflammatory drug,dexamethasone(DEX).Findings highlight the potential of GdNPs-Gal for in vivo imaging of liver inflammation by integrating molecular coassembly with GSH-driven disassembly,which can be applied to other responsive molecular probes for improved in vivo imaging.