title: In vivo hepatocyte MR imaging using lactose functionalized magnetoliposomes.
abstract: The aim of this study was to assess a novel lactose functionalized magnetoliposomes (MLs) as an MR contrast agent to target hepatocytes as well as to evaluate the targeting ability of MLs for in vivo applications. In the present work, 17 nm sized iron oxide cores functionalized with anionic MLs bearing lactose moieties were used for targeting the asialoglycoprotein receptor (ASGP-r), which is highly expressed in hepatocytes. Non-functionalized anionic MLs were tested as negative controls. The size distribution of lactose and anionic MLs was determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). After intravenous administration of both MLs, contrast enhancement in the liver was observed by magnetic resonance imaging (MRI). Label retention was monitored non-invasively by MRI and validated with Prussian blue staining and TEM for up to eight days post MLs administration. Although the MRI signal intensity did not show significant differences between functionalized and non-functionalized particles, iron-specific Prussian blue staining and TEM analysis confirmed the uptake of lactose MLs mainly in hepatocytes. In contrast, non-functionalized anionic MLs were mainly taken up by Kupffer and sinusoidal cells. Target specificity was further confirmed by high-resolution MR imaging of phantoms containing isolated hepatocytes, Kupffer cell (KCs) and hepatic stellate cells (HSCs) fractions. Hypointense signal was observed for hepatocytes isolated from animals which received lactose MLs but not from animals which received anionic MLs. These data demonstrate that galactose-functionalized MLs can be used as a hepatocyte targeting MR contrast agent to potentially aid in the diagnosis of hepatic diseases if the non-specific uptake by KCs is taken into account.
authors.affiliation: Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, Katholieke Universiteit Leuven, Herestraat 49, B3000 Leuven, Belgium.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Ketkar-Atre
authors.forename: Tom
authors.initials: T
authors.lastname: Struys
authors.forename: Tom
authors.initials: T
authors.lastname: Dresselaers
authors.forename: Michael
authors.initials: M
authors.lastname: Hodenius
authors.forename: Inge
authors.initials: I
authors.lastname: Mannaerts
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
authors.forename: Ivo
authors.initials: I
authors.lastname: Lambrichts
authors.forename: Leo A
authors.initials: LA
authors.lastname: Van Grunsven
authors.forename: Marcel
authors.initials: M
authors.lastname: De Cuyper
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
mesh_terms: D000818:Animals; D000838:Anions / Q000737:chemistry; D037263:Asialoglycoprotein Receptor / Q000032:analysis*; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry; D022781:Hepatocytes / Q000166:cytology* / Q000473:pathology / Q000648:ultrastructure; D007785:Lactose / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D008107:Liver Diseases / Q000175:diagnosis; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice
chemical_list: D000838:Anions; D037263:Asialoglycoprotein Receptor; D003287:Contrast Media; D005290:Ferric Compounds; D008081:Liposomes; C000499:ferric oxide; D007785:Lactose
keywords: Asialoglycoprotein receptor (ASGPr-1); Hepatocyte; Lactose; Liver; MRI; Magnetoliposomes