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Abstract
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 r1 relaxivity with low fluorescence and fluorine magnetic resonance spectroscopic (19F-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 r1 relaxivity with compensatory enhancements in fluorescence and 19F-MRS. By combining in vivo magnetic resonance imaging (1H-MRI) with ex vivo fluorescence imaging and 19F-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.
Highlights
Acute hepatitis encompasses liver diseases that cause acute inflammation or damage to hepatocytes from various etiologies, which can lead to severe liver dysfunction and death [1, 2]
1-Gd is designed by covalently linking a paramagnetic Gd(III)-chelate for magnetic resonance imaging (MRI); 1-Gal is designed by conjugating a PEGylated β-Gal for liver targeting
The signal enhancement (% SE) in livers treated with GdNPs-Gal-Ctrl was ~70% at 4 h, ~2.4-folds higher than that treated with GdNPs-Gal (~29%) (Figure 5(b)). These results suggest that GdNPs-Gal can enter the liver and facilitate rapid disassembly triggered by abundant hepatic GSH in healthy mice, leading to a lower MRI contrast relative to that of GSH-inert GdNPs-Gal-Ctrl
Summary
Acute hepatitis encompasses liver diseases that cause acute inflammation or damage to hepatocytes from various etiologies (e.g., viral or bacterial infection, toxins, drugs, alcohol, and immunologic response), which can lead to severe liver dysfunction and death [1, 2]. Lee and colleagues reported a liver cell-targeting and GSH-activatable naphthalimide-based fluorescent probe to promote the detection of GSH fluctuations in liver cells [26] These probes can provide sensitive imaging signals to detect GSH in research settings, they have low tissue penetration depth and a limited signal-to-background ratio due to the inevitable absorption and scattering of light by tissues. In hepatitis cells, reduced GSH levels can slow the disulfide reduction and disassembly of GdNPs-Gal. The high r1 relaxivity and prolonged retention of GdNPsGal compared to its reduced small-molecule products generate higher MR contrast in inflammatory liver cells, enabling noninvasive visualization of LPS-induced liver inflammation [40, 41] via high-resolution MRI. Responsive molecular probes for noninvasive MRI of GSH levels in liver can be further applied for real-time monitoring of the antiinflammation efficacy of dexamethasone (DEX) [42, 43] in living mice
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