Hepatocyte-Targeting Single Galactose-Appended Naphthalimide: A Tool for Intracellular Thiol Imaging in Vivo LeeMin Hee HanJi Hye KwonPil-Seung BhuniyaSankarprasad KimJin Young SesslerJonathan L. KangChulhun KimJong Seung 2012 We present the design, synthesis, spectroscopic properties, and biological evaluation of a single galactose-appended naphthalimide (<b>1</b>). Probe <b>1</b> is a multifunctional molecule that incorporates a thiol-specific cleavable disulfide bond, a masked phthalamide fluorophore, and a single galactose moiety as a hepatocyte-targeting unit. It constitutes a new type of targetable ligand for hepatic thiol imaging in living cells and animals. Confocal microscopic imaging experiments reveal that <b>1</b>, but not the galactose-free control system <b>2</b>, is preferentially taken up by HepG2 cells through galactose-targeted, ASGP-R-mediated endocytosis. Probe <b>1</b> displays a fluorescence emission feature at 540 nm that is induced by exposure to free endogenous thiols, most notably GSH. The liver-specificity of <b>1</b> was confirmed in vivo via use of a rat model. The potential utility of this probe in indicating pathogenic states and as a possible screening tool for agents that can manipulate oxidative stress was demonstrated in experiments wherein palmitate was used to induce lipotoxicity in HepG2 cells.