Surface Functionalization of Nanodiamonds Can Induce Endothelial Barrier Leakiness
Intravenous injection is a popular route of entry for many nanomedicine formulations. As such, interaction between the nanomedicine and the vasculature would inevitably occur during their transport in the vasculature. Despite its obvious importance, testing for side effects or toxicity of nanomedicine on the endothelial cells that line the vasculature is often overlooked. Nanodiamonds (ND), a promising cancer nanomedicine, could induce endothelial leakiness in this study. Amine functionalized ND was found to cause the highest degree of vascular barrier leakiness compared to the non-functionalized ND and carboxylate functionalized ND. In vitro dosimetry measurements confirmed that the ND-induced leakiness was not caused by any difference in the actual dose delivered to the endothelial cells, suggesting that the ND-induced leakiness was caused by the activation of intracellular processing. In depth mechanistic study showed that the ND-induced leakiness was mediated by the increase in intracellular reactive oxygen species (ROS) and Ca2+. These in turn triggers the activation of Akt/eNOS signalling pathway and induce the dissociation of adherens junction protein, VE-cadherin, from actin cytoskeleton. Moreover, the increase in ROS and Ca2+ level also brought about the activation of ERK pathway that responsible to induce the cytoskeleton remodelling. Blocking either one of the pathway was proven to partially reduce the ND-induced leakiness, suggesting that both pathways work hand-in-hand to result with the leakiness. This understanding is important as it enables material scientists to re-assess the safety of their nanomedicine and if need be, re-design the nanomedicine to negate their unintended adverse effects.
M. I. Setyawati et al., "Surface Functionalization of Nanodiamonds Can Induce Endothelial Barrier Leakiness," Toxicology Letters, vol. 258, Supplement, pp. S263, Elsevier, Sep 2016.
The definitive version is available at http://dx.doi.org/10.1016/j.toxlet.2016.06.1926
52nd Congress of the European Societies of Toxicology (2016: Sep. 4-7, Seville, Spain)
Center for High Performance Computing Research
Article - Conference proceedings
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