title: Detection of hepatocellular carcinoma in transgenic mice by Gd-DTPA- and rhodamine 123-conjugated human serum albumin nanoparticles in T1 magnetic resonance imaging.
abstract: Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd-Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI, which currently provides the most sensitive detection of HCC in patients. Immunohistochemical analyses revealed that the Gd-Rho-HSA-NPs were localized to macrophages, which were - similar to HCC in patients - fewer in number in HCC as compared to the liver tissue, which is in agreement with the negative contrasting of HCC in Gd-Rho-HSA-NP-enhanced MRI. Poloxamine-coated NPs showed lower accumulation in the tumor macrophages and caused a longer lasting enhancement of the MRI signal. These data indicate that Gd-Rho-HSA-NPs enable sensitive detection of HCC by T1-weighted MRI in mice with endogenous HCC through their uptake by macrophages. Poloxamine coating of the NPs delayed the tumor localization of the NPs.
authors.affiliation: Institute for Pharmaceutical Technology, Goethe-University of Frankfurt, Max-von-Laue-Straße 7, D-60438 Frankfurt, Germany.
authors.forename: Waralee
authors.initials: W
authors.lastname: Watcharin
authors.affiliation: Department of Medicine 1, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmithals
authors.affiliation: Department of Medicine 1, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pleli
authors.affiliation: Department of Medicine 1, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Köberle
authors.affiliation: Department of Nuclear Medicine, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Hüdayi
authors.initials: H
authors.lastname: Korkusuz
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Hospital of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Hübner
authors.affiliation: Department of Medicine 1, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Waidmann
authors.affiliation: Department of Medicine 1, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Institute of Anatomy 2, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
authors.affiliation: Institute for Inorganic and Analytic Chemistry, Goethe-University of Frankfurt, Max-von-Laue-Straße 7, D-60438 Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Terfort
authors.affiliation: Nanosystem Ltd., 115193 Moscow, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gelperina
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Hospital of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Vogl
authors.affiliation: Institute for Pharmaceutical Technology, Goethe-University of Frankfurt, Max-von-Laue-Straße 7, D-60438 Frankfurt, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.affiliation: Department of Medicine 1, University Hospital of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. Electronic address: piiper@med.uni-frankfurt.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Piiper
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media; D005029:Ethylenediamines; D005079:Excipients; D019786:Gadolinium DTPA; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles; D010316:Particle Size; D011092:Polyethylene Glycols; D020112:Rhodamine 123; D012709:Serum Albumin; D014018:Tissue Distribution; D016211:Transforming Growth Factor alpha / Q000235:genetics
chemical_list: D003287:Contrast Media; D005029:Ethylenediamines; D005079:Excipients; D012709:Serum Albumin; D016211:Transforming Growth Factor alpha; D020112:Rhodamine 123; C012571:tetronic 701; D011092:Polyethylene Glycols; D019786:Gadolinium DTPA
keywords: Gadolinium; HCC; MRI; Macrophages; Nanoparticle; Targeting