Endogenous H₂S-Activated Orthogonal Second Near-Infrared Emissive Nanoprobe for In Situ Ratiometric Fluorescence Imaging of Metformin-Induced Liver Injury

Abstract

Metformin as a hypoglycemic drug for antidiabetic treatment has emerged as a multipotential drug for many disease treatments such as cognitive disorders, cancers, promoting weight loss. However, overdose uptake may upregulate the hepatic H 2 S level, subsequently leading to serious liver injury and toxicity. Therefore, developing intelligent second near-infrared (NIR-II) emitting nanoprobes by using endogenous H 2 S as a smart trigger for noninvasive highly specific in situ monitoring of the metformin-induced hepatotoxicity is highly desirable, which is rarely explored. Herein, an endogenous H 2 S activated orthogonal NIR-II emitting myrica rubra-like nanoprobe based on NaYF 4 :Gd/ Yb/Er@NaYF 4 :Yb@SiO 2 coated with Ag nanodots was explored for highly specific in vivo ratiometrically monitoring of hepatotoxicity. The designed nanoprobes were mainly uptaken by the liver and subsequently converted to NaYF 4 :Gd/Yb/Er@NaYF 4 :Yb@SiO 2 @Ag 2 S via in situ sulfuration reaction triggered by the overexpressed endogenous H 2 S in the injured liver tissues, finally leading to a turn-on orthogonal emission centered at 1053 nm (irradiation by 808 nm laser) and 1525 nm (irradiation by 980 nm laser). The designed nanoprobe presents a high detection limit down to 0.7 nM of H 2 S. More importantly, the in situ highly specific ratiometric imaging of the metformininduced hepatotoxicity was successfully achieved by using the activatable orthogonal NIR-II emitting probe. Our results provide an NIR-II ratiometric fluorescence imaging strategy for highly sensitive/specific diagnosis of hepatotoxicity levels induced by metformin.

Variables associated with increased incidence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes

“…Metformin might have hepatotoxic effects on injured livers and therefore promote NAFLD, which could potentially explain that a weight loss-inducing agent is associated with a higher incidence of NAFLD. 20 Nevertheless, data regarding the effect of different antidiabetics on the development of NAFLD are conflicting and the pathophysiology leading to NAFLD in T2D is complex and only poorly understood. While our analysis cannot elucidate molecular mechanism, our data should trigger further functional studies in this context.…”

Near infrared bioimaging and biosensing with semiconductor and rare-earth nanoparticles: recent developments in multifunctional nanomaterials

“…Furthermore, the detection of hepatocellular carcinoma lesions within the liver of mice was demonstrated using this strategy. ONOOinduced a change in the lifetime of the RENPs specifically within the tumor regions, which permitted to visualize tumor areas that could not be otherwise detected using traditional steadystate PL imaging (Figure9 -A4).Similar in vivo multivariate diagnosis has been pursued by other authors, but relying on analyte quantification through steady-state ratiometric PL strategies: one emission band of the RENPs may remain constant and is used as a reference, while another one varies in intensity due to the presence of the target analyte 93,[98][99][100][101]. It is important to highlight that these works focus on detecting analytes that can cause cellular oxidative stress (e.g.…”

“…Similar in vivo multivariate diagnosis has been pursued by other authors, but relying on analyte quantification through steady-state ratiometric PL strategies: one emission band of the RENPs may remain constant and is used as a reference, while another one varies in intensity due to the presence of the target analyte. 93,[98][99][100][101] It is important to highlight that these works focus on detecting analytes that can cause cellular oxidative stress (e.g. metformin) or are result-products of it, such as: peroxynitrite, hypochlorous acid, or hydrogen peroxide.…”

“…metformin) or are result-products of it, such as: peroxynitrite, hypochlorous acid, or hydrogen peroxide. 93,[98][99][100][101] As a consequence, their oxidative properties are used to chemically modify the FRET acceptor, usually a cyanine dye that acts by quenching one of the RENPs emission bands. Upon oxidation, the optical properties (e.g., absorbance) of the FRET acceptor change and the otherwise quenched emission band from RENPs is restored.…”

“…It is important to highlight that these works focus on detecting analytes that can cause cellular oxidative stress (e.g. metformin) or are result-products of it, such as: peroxynitrite, hypochlorous acid, or hydrogen peroxide 93,[98][99][100][101]. As a consequence, their oxidative properties are used to chemically modify the FRET acceptor, usually a cyanine dye that acts by quenching one of the RENPs emission bands.…”