TY - JOUR
T1 - Deconvoluting hepatic processing of carbon nanotubes
AU - Alidori, Simone
AU - Bowman, Robert L.
AU - Yarilin, Dmitry
AU - Romin, Yevgeniy
AU - Barlas, Afsar
AU - Mulvey, J. Justin
AU - Fujisawa, Sho
AU - Xu, Ke
AU - Ruggiero, Alessandro
AU - Riabov, Vladimir
AU - Thorek, Daniel L.J.
AU - Ulmert, Hans David S.
AU - Brea, Elliott J.
AU - Behling, Katja
AU - Kzhyshkowska, Julia
AU - Manova-Todorova, Katia
AU - Scheinberg, David A.
AU - McDevitt, Michael R.
N1 - Funding Information:
We acknowledge the expert advice and technical assistance of Dr Pat Zanzonico and Ms Valerie Longo for PET imaging experiments; Dr Bard Smedsrd for expert advice on isolating primary LSEC from mice; Ms Amy Carol McDevitt for graphic design and layout; Ms Ning Fan and Mr Mesru Turkekul for tissue processing and sectioning; Mr Brad Beattie for PET/CT configuration and analyses; Drs Sebastien Monette, Smitha Pankajavally Somanathan Pillai, and Julie R. White for clinical pathology; Ms Christina Schmuttermaier for technical assistance in the endocytosis experiments. This work was supported by the Office of Science (BER), US Department of Energy (Award DESC0002456), NIH MSTP Grant GM07739, R21 CA128406, R01 CA166078, R01 CA55349, R25T CA046945, R24 CA83084, P30 CA008748, P01 CA33049, F31 CA167863, the Memorial Sloan-Kettering Center for Molecular Imaging and Nanotechnology (CMINT), Mr William H. and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research, and The Center for Experimental Therapeutics of Memorial Sloan-Kettering Cancer Center.
PY - 2016/7/29
Y1 - 2016/7/29
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms12343
DO - 10.1038/ncomms12343
M3 - Article
C2 - 27468684
AN - SCOPUS:84982701885
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 12343
ER -