Multi-Walled Carbon Nano-Tubes (MWCNTs) Accelerate Leukaemia Development in Mice: Implications for Drug Development in Humans

Biomedical applications of nano-technology including carbon nano-tubes (CNTs) are of considerable recent interest. However, relatively little attention is given to potential biological effects including cancer-induction or acceleration resulting from long-term exposures. We investigated whether and how multi-walled carbon nano-tubes (MWCNTs) affected leukaemia development in a mouse model. We found injections of MWCNTs accelerated murine leukaemia virus (MLV)-induced leukaemia development in normal mice with the magnitude of acceleration correlated with extent of MWCNT exposure. In contrast, injection of MWCNTs to immune-deficient mice caused no acceleration. Co-treatment of normal mice with MWCNTs and rapamycin reduced or eliminated accelerated leukaemia development. We found exposure to MWCNTs induced phagocytosis by macrophages and production of pro-inflammatory cytokines in normal mice and in cultured RAW264.7 cells. Methoxy-polyethylene glycol amine modified MWCNTs (PEG-MWCNTs) did not accelerate leukaemia development in normal mice, an effect correlated with reduced macrophage phagocytosis and reduced production of pro-inflammatory cytokines. We also found increased levels of pro-inflammatory cytokines induced by exposure to MWCNTs in normal mice increased intra-cellular reactive oxide species (ROS) levels resulting in increased cell proliferation and enhanced survival of the leukaemia cells. Our data indicate exposure to MWCNTs accelerates leukaemia development in a virus-induced leukaemia model. This effect is associated with activation of macrophages and increased levels of pro-inflammatory cytokines resulting in increased intra-cellar ROS levels. Our data have implications for the application of nano-technology to drug development in humans. For example, some MWCNTs are of the same size as asbestos fibers proved to cause mesothelioma in mice and humans. Also, increased macrophage phagocytosis and production of pro-inflammatory cytokines are reported in these settings. Our data also suggest interventions which might reduce a theoretical increased cancer-risk or acceleration of cancer development resulting from MWCNT exposures.