Molecular MRI quantification of extracellular aldehyde pairs for early detection of liver fibrogenesis and response to treatment

Abstract

Liver fibrosis plays a critical role in the evolution of most chronic liver diseases and is characterized by a buildup of extracellular matrix, which can progress to cirrhosis, hepatocellular carcinoma, liver failure, or death. Now, there are no noninvasive methods available to accurately assess disease activity (fibrogenesis) to sensitively detect early onset of fibrosis or to detect early response to treatment. Here, we hypothesized that extracellular allysine aldehyde (Lys Ald ) pairs formed by collagen oxidation during active fibrosis could be a target for assessing fibrogenesis with a molecular probe. We showed that molecular magnetic resonance imaging (MRI) using an extracellular probe targeting these Lys Ald pairs acts as a noninvasive biomarker of fibrogenesis and demonstrated its high sensitivity and specificity in detecting fibrogenesis in toxin- and dietary-induced mouse models, a cholestasis rat model of liver fibrogenesis, and in human fibrotic liver tissues. Quantitative molecular MRI was highly correlated with fibrogenesis markers and enabled noninvasive detection of early onset fibrosis and response to antifibrotic treatment, showing high potential for clinical translation.

Tailored chemical reactivity probes for systemic imaging of aldehydes in fibroproliferative diseases

“…However, these methods are insensitive to detecting fibrosis at earlier stages and do not assess fibrotic disease activity 50 . Prior work in animal models showed that imaging liver fibrogenesis may enable the detection of the earliest stages of liver fibrosis and that imaging disease activity can provide an early readout of response to therapy 12 .…”

“…However, if the tissue is damaged then LOX is upregulated while the tissue is being remodeled 10 . We have found that lung and liver tissue allysine concentrations can be in the hundreds of micromolar during such pathological processes 11,12 .…”

“…The high concentration of allysine during fibrogenesis makes it amenable to detection by a targeted magnetic resonance (MR) probe molecule 12,[23][24][25][26] . The general absence of aldehydes in the ECM of healthy tissue suggests that an extracellular, aldehyde-targeted probe would have high specificity for fibroproliferative disease activity.…”

The Application of Bio-orthogonality for In Vivo Animal Imaging

“…To overcome the problem of low concentrations of bio-orthogonal products in the target-of-interest, one approach is to aim for proteins that are abundant in the targets. In recent years, Ning and Caravan et al approved that liver fibrogenesis could be an excellent target. , Extracellular matrix proteins are abundant in many tissues, such as the liver, while lysyl oxidase enzymes can catalyze the oxidation of lysine ε-amino groups on the extracellular matrix proteins to form the aldehyde containing the amino acid allysine (Lys Ald ). Notably, liver fibrogenesis is normally accompanied by the upregulation of lysyl oxidase.…”

“…In vivo MRI imaging showed that Mn-2CHyd could be used to in vivo detect liver fibrogenesis in CCl 4 -injured mice. 61 Furthermore, they showed that the probe had the capacity for early detection of liver fibrogenesis and response to treatment. 61 Hyperpolarized magnetic resonance (HP-MR), a powerful, sensitive, and noninvasive imaging approach, has been broadly applied in recent years in both preclinical and clinical imaging studies, particularly for metabolic imaging.…”