Journal
RESEARCH
Volume 2020, Issue -, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.34133/2020/4087069
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Funding
- National Key R&D Program of China [2017YFA0701301]
- National Natural Science Foundation of China [21922406, 21775071, 21632008]
- Natural Science Foundation of Jiangsu Province [BK20190055]
- CAS Key Laboratory of Receptor Research [SIMM1904YKF-03]
- Fundamental Research Funds for the Central Universities [020514380185]
- Excellent Research Program of Nanjing University [ZYJH004]
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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 (F-19-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 F-19-MRS. By combining in vivo magnetic resonance imaging (H-1-MRI) with ex vivo fluorescence imaging and F-19-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.
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