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Nat Mater. 2016 Nov;15(11):1212-1221. doi: 10.1038/nmat4718. Epub 2016 Aug 15.

Mechanism of hard-nanomaterial clearance by the liver.

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Institute of Biomaterials and Biomedical Engineering, University of Toronto, Rosebrugh Building, Room 407, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
Division of Orthopaedic Surgery, University of Toronto, 149 College Street, Toronto, Ontario M5T 1P5, Canada.
Department of Immunology, University of Toronto, Medical Sciences Building, Room 6271, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Multi Organ Transplant Program, Toronto General Research Institute, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
Department of Orthopaedic Surgery, Duke University, Duke University Medical Center, Room 2888, 200 Trent Drive, Durham, North Carolina 27710, USA.
Department of Pathology, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
Department of Physics, University of Toronto, 60 St. George Street, Toronto, Ontario M5S 1A7, Canada.
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Room 230, Toronto, Ontario M5S 3E1, Canada.
Department of Chemical Engineering, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5, Canada.
Department of Chemistry, University of Toronto, 80 St George Street, Toronto, Ontario M5S 3H6, Canada.
Department of Material Science and Engineering, University of Toronto, 160 College Street, Room 450, Toronto, Ontario M5S 3E1, Canada.


The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

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