title: Deconvoluting hepatic processing of carbon nanotubes.
abstract: Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans.
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Alidori
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bowman
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Yarilin
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Romin
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Afsar
authors.initials: A
authors.lastname: Barlas
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: J Justin
authors.initials: JJ
authors.lastname: Mulvey
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Sho
authors.initials: S
authors.lastname: Fujisawa
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Radiology, Papworth Hospital NHS Foundation Trust, Cambridge University Health Partners, Cambridge CB23 3RE, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ruggiero
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim 68167, Germany.|Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Riabov
authors.affiliation: Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Daniel L J
authors.initials: DL
authors.lastname: Thorek
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Hans David S
authors.initials: HD
authors.lastname: Ulmert
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Brea
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Behling
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim 68167, Germany.|Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.|Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim 68167, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kzhyshkowska
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.|Department of Pharmacology, Weill Cornell Medical College, New York 10065, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York 10065, USA.
authors.forename: Michael R
authors.identifier: 0000-0002-8855-0917
authors.initials: MR
authors.lastname: McDevitt
mesh_terms: D000818:Animals; D004705:Endocytosis; D005260:Female; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D037742:Nanotubes, Carbon / Q000633:toxicity; D010599:Pharmacokinetics
chemical_list: D037742:Nanotubes, Carbon