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

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.

Redox-Activated Contrast-Enhanced T1-Weighted Imaging Visualizes Glutathione-Mediated Biotransformation Dynamics in the Liver

“…g ., Gd 3+ , Fe 2+/3+ , and Mn 2+ ) can significantly accelerate 1 H relaxation, which substantially increases the difference (contrast) between regions of interest and surrounding tissues in MR images. − Though gadolinium-based contrast agents (GBCAs) currently dominate in contrast-enhanced (CE) 1 H MRI, recent findings on the correlation between nephrogenic systemic fibrosis (NSF) and the use of GBCAs have rejuvenated the development of iron-based and manganese-based contrast agents, which are of relatively higher biosafety. − The high resolution and excellent soft tissue penetration render 1 H MRI appealing as an imaging technique for in vivo real-time visualization of GSH-mediated biotransformation . Despite some reports on in vivo imaging of GSH with 1 H MRI, , the attempts on continuous in vivo monitoring of the dynamics of GSH-mediated biotransformation are rare.…”

“…25−31 The high resolution and excellent soft tissue penetration render 1 H MRI appealing as an imaging technique for in vivo real-time visualization of GSH-mediated biotransformation. 32 Despite some reports on in vivo imaging of GSH with 1 H MRI, 33,34 the attempts on continuous in vivo monitoring of the dynamics of GSH-mediated biotransformation are rare.…”

Activatable Nanoparticles: Recent Advances in Redox-Sensitive Magnetic Resonance Contrast Agent Candidates Capable of Detecting Inflammation

“…The most recent advancement of GSH-mediated trimodal imaging investigated the use of a GSH sensitive, liver-targeted probe for the real-time visualization of hepatic GSH levels for the diagnosis and prognosis of acute hepatitis. Hu and coworkers aim to create a better method for measuring hepatic GSH levels than existing GSH-responsive fluorescent imaging probes, which are limited by the low penetration depth of light in the liver [ 38 ]. GdNPs-Gal were formed via the molecular coassembly of a GSH-responsive Gd(III) MR probe and a liver targeting probe (1-Gal).…”

Scratching the Surface of Unventured Possibilities with In Situ Self-Assembly: Protease-Activated Developments for Imaging and Therapy

“…1 Such examples include the cell membrane made up mainly of lipids and proteins maintaining the integrity of cells, 2 the deoxyribonucleic acid (DNA) double helix comprising nucleic acids storing genetic information, 3 and enzymes consisting of amino acids and peptides catalyzing a wide array of vital chemical reactions in the body. 4 Inspired by these self-assembling building blocks of life, self-assembled nanoscale materials have garnered increased research interest in recent years and have been utilized widely in the design of structures for diagnostic 5,6 and therapeutic purposes. 7,8 A specific category of proteins known as enzymes act as catalysts to accelerate a myriad of chemical reactions in the biological environment with high specificity and efficiency, 9 one of which is self-assembly, an ubiquitous process in life playing various biological roles from maintaining cellular functions and integrity to causing numerous abnormalities in diseases.…”

“…Such examples include the cell membrane made up mainly of lipids and proteins maintaining the integrity of cells, the deoxyribonucleic acid (DNA) double helix comprising nucleic acids storing genetic information, and enzymes consisting of amino acids and peptides catalyzing a wide array of vital chemical reactions in the body . Inspired by these self-assembling building blocks of life, self-assembled nanoscale materials have garnered increased research interest in recent years and have been utilized widely in the design of structures for diagnostic , and therapeutic purposes. , …”