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Long-term intravenous administration of carboxylated single-walled carbon nanotubes induces persistent accumulation in the lungs and pulmonary fibrosis via the nuclear factor-kappa B pathway

Authors Qin Y, Li S, Zhao G, Fu X, Xie X, Huang Y, Cheng X, Wei J, Liu H, Lai Z

Received 4 October 2016

Accepted for publication 21 November 2016

Published 30 December 2016 Volume 2017:12 Pages 263—277

DOI https://doi.org/10.2147/IJN.S123839

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 2

Editor who approved publication: Dr Linlin Sun


Yue Qin,1,* Suning Li,2,* Gan Zhao,2,* Xuanhao Fu,1 Xueping Xie,1 Yiyi Huang,1 Xiaojing Cheng,3 Jinbin Wei,1 Huagang Liu,1 Zefeng Lai1

1Pharmaceutical College, Guangxi Medical University, 2Department of Pharmacy, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, 3Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China

*These authors contributed equally to this work

Abstract: Numerous studies have demonstrated promising application of single-walled carbon nanotubes (SWNTs) in drug delivery, diagnosis, and targeted therapy. However, the adverse health effects resulting from intravenous injection of SWNTs are not completely understood. Studies have shown that levels of “pristine” or carboxylated carbon nanotubes are very high in mouse lungs after intravenous injection. We hypothesized that long-term and repeated intravenous administration of carboxylated SWNTs (c-SWNTs) can result in persistent accumulation and induce histopathologic changes in rat lungs. Here, c-SWNTs were administered repeatedly to rats via tail-vein injection for 90 days. Long-term intravenous injection of c-SWNTs caused sustained embolization in lung capillaries and granuloma formation. It also induced a persistent inflammatory response that was regulated by the nuclear factor-kappa B signaling pathway, and which resulted in pulmonary fibrogenesis. c-SWNTs trapped within lung capillaries traversed capillary walls and injured alveolar epithelial cells, thereby stimulating production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and pro-fibrotic growth factors (transforming growth factor-beta 1). Protein levels of type-I and type-III collagens, matrix metalloproteinase-2, and the tissue inhibitor of metalloproteinase-2 were upregulated after intravenous exposure to c-SWNTs as determined by immunohistochemical assays and Western blotting, which suggested collagen deposition and remodeling of the extracellular matrix. These data suggest that chronic and cumulative toxicity of nanomaterials to organs with abundant capillaries should be assessed if such nanomaterials are applied via intravenous administration.

Keywords: lung fibrosis, carbon nanotubes, capillary embolization, inflammation, NF-κB

Corrigendum for this paper has been published.

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