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.

Recently, based on co-assembly and stimuli-response disassembly strategy, Deju Ye group from Nanjing University reported a liver-targeted and GSH-responsive 1H-MRI/19F-MRS/fluorescent trimodal probe (GdNPS-Gal) for noninvasive imaging of lipopolysaccharide-induced acute liver inflammation in vivo. The paper entitled "Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly" was recently published in Research (Research 2020 4087069, DOI: 10.34133/2020/4087069) https://spj.sciencemag.org/journals/research/2020/4087069/.

Image: Schematic illustration shows the structure and responsive mechanism of trimodal probe for in vivo imaging of liver inflammation.

The trimodal probe GdNPs-Gal was prepared via co-assembly of a GSH-responsive MRI probe (1-Gd) and liver-targeting probe (1-Gal). The 1-Gd/1-Gal ratio for building GdNPs-Gal was first optimized to 5, which ensured a small hydrodynamic size and large uptake of Gd(III). GdNPs-Gal functions as a uniform and stable nanoparticle in aqueous solution, demonstrating high relaxivity but quenched fluorescence and 19F-MRS signals. Upon interaction with GSH, the probe was disassembled into small molecules via disulfide-reduction, leading to greatly reduced 1H-MRI contrast and compensatory enhancement in fluorescence and 19F-MRS. The authors also demonstrated that GdNPs-Gal has fast response, high sensitivity and good specificity to biothiols.

After confirmed the capacity of GdNPs-Gal to detect endogenous GSH levels in HepG2 cells. The probe was then injected into living mice intravenously to investigate the ability to detect liver GSH in vivo. The results showed that GdNPs-Gal could specifically target and enter liver cells through efficient recognition between β-Gal ligands on the surface of GdNPs-Gal and ASGPR on cell membranes. In healthy hepatocytes, disulfide reduction and disassembly of GdNPs-Gal are initiated by abundant endogenous GSH, leading to lower 1H-MRI contrast but compensatory signal enhancement in fluorescence and 19F-MRS. In LPS-induced hepatitis parts, reduced GSH levels can slow the disulfide reduction and disassembly of GdNPs-Gal, producing generate higher MR contrast and enabling noninvasive visualization of liver inflammation via high-resolution MRI. The probe was also successfully applied to monitor the therapeutic efficiency of DEX against LPS-treated inflammatory mice, revealing efficient recovery of hepatic GSH concentration after anti-inflammation therapy with DEX.

In light of molecular co-assembly with precisely controlled composition, preferential liver accumulation, high biocompatibility, and GSH-driven disassembly with complementary changes in MRI contrast, fluorescence emission, and 19F-MRS intensity, GdNPs-Gal hold great promise for liver inflammation imaging. The reported co-self-assembly and disassembly approach to designing a liver-targeted and GSH-responsive trimodal probe could further inform the design of other biomarker-responsive probes for improved disease diagnosis.

Tag: Emerging materials research