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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. Lastly, the pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans.

Authors:
 [1];  [2];  [3];  [3];  [3];  [2];  [3];  [3];  [4];  [5];  [6];  [1];  [2];  [1];  [7];  [3];  [8]; ORCiD logo [9]
  1. Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Dept. of Radiology
  2. Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Dept. of Molecular Pharmacology and Chemistry
  3. Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Molecular Cytology Core Facility
  4. Papworth Hospital NHS Foundation Trust, Cambridge (United Kingdom). Dept. of Radiology
  5. Ruprecht-Karls Univ. of Heidelberg, Mannheim (Germany). Inst. of Transfusion Medicine and Immunology; Tomsk State Univ., Tomsk (Russia). Lab. for Translational Cellular and Molecular Biomedicine
  6. Johns Hopkins Univ., Baltimore, MD (United States). Department of Radiology and Radiological Sciences
  7. Ruprecht-Karls Univ. of Heidelberg, Mannheim (Germany). Inst. of Transfusion Medicine and Immunology; Tomsk State Univ., Tomsk (Russia). Lab. for Translational Cellular and Molecular Biomedicine; Red Cross Blood Service Baden-Wurttemberg-Hessen, Mannheim (Germany)
  8. Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Dept. of Molecular Pharmacology and Chemistry; Weill Cornell Medical College, New York, NY (United States). Dept. of Pharmacology
  9. Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Dept. of Radiology; Weill Cornell Medical College, New York, NY (United States). Dept. of Medicine
Publication Date:
Research Org.:
Sloan-Kettering Inst. For Cancer Research, Inc. (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH); CMINT; Commonwealth Foundation for Cancer Research; Center for Experimental Therapeutics of Memorial Sloan-Kettering Cancer Center
OSTI Identifier:
1326670
Grant/Contract Number:
SC0002456; GM07739; R21 CA128406; R01 CA166078; R24 CA83084; R01 CA55349; R25T CA046945; P30 CA008748; P01 CA33049; F31 CA167863
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 77 NANOSCIENCE AND NANOTECHNOLOGY; nanotube

Citation Formats

Alidori, Simone, Bowman, Robert L., Yarilin, Dmitry, Romin, Yevgeniy, Barlas, Afsar, Mulvey, J. Justin, Fujisawa, Sho, Xu, Ke, Ruggiero, Alessandro, Riabov, Vladimir, Thorek, Daniel L. J., Ulmert, Hans David S., Brea, Elliott J., Behling, Katja, Kzhyshkowska, Julia, Manova-Todorova, Katia, Scheinberg, David A., and McDevitt, Michael R. Deconvoluting hepatic processing of carbon nanotubes. United States: N. p., 2016. Web. doi:10.1038/ncomms12343.
Alidori, Simone, Bowman, Robert L., Yarilin, Dmitry, Romin, Yevgeniy, Barlas, Afsar, Mulvey, J. Justin, Fujisawa, Sho, Xu, Ke, Ruggiero, Alessandro, Riabov, Vladimir, Thorek, Daniel L. J., Ulmert, Hans David S., Brea, Elliott J., Behling, Katja, Kzhyshkowska, Julia, Manova-Todorova, Katia, Scheinberg, David A., & McDevitt, Michael R. Deconvoluting hepatic processing of carbon nanotubes. United States. doi:10.1038/ncomms12343.
Alidori, Simone, Bowman, Robert L., Yarilin, Dmitry, Romin, Yevgeniy, Barlas, Afsar, Mulvey, J. Justin, Fujisawa, Sho, Xu, Ke, Ruggiero, Alessandro, Riabov, Vladimir, Thorek, Daniel L. J., Ulmert, Hans David S., Brea, Elliott J., Behling, Katja, Kzhyshkowska, Julia, Manova-Todorova, Katia, Scheinberg, David A., and McDevitt, Michael R. 2016. "Deconvoluting hepatic processing of carbon nanotubes". United States. doi:10.1038/ncomms12343. https://www.osti.gov/servlets/purl/1326670.
@article{osti_1326670,
title = {Deconvoluting hepatic processing of carbon nanotubes},
author = {Alidori, Simone and Bowman, Robert L. and Yarilin, Dmitry and Romin, Yevgeniy and Barlas, Afsar and Mulvey, J. Justin and Fujisawa, Sho and Xu, Ke and Ruggiero, Alessandro and Riabov, Vladimir and Thorek, Daniel L. J. and Ulmert, Hans David S. and Brea, Elliott J. and Behling, Katja and Kzhyshkowska, Julia and Manova-Todorova, Katia and Scheinberg, David A. and McDevitt, Michael R.},
abstractNote = {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. Lastly, the pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans.},
doi = {10.1038/ncomms12343},
journal = {Nature Communications},
number = ,
volume = 7,
place = {United States},
year = 2016,
month = 7
}

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