NSTI BioNano 2010

Enhanced Cytotoxicity of Doxorubicin Conjugated to Ultrasmall Au Nanoparticles

E. Zhang, K. Ntumba, J. Nadeau
McGill University, CA

Keywords: gold, doxorubicin, apoptosis, cancer, targeting, nucleus

Abstract:

In this study we find that ultra-small (mean diameter, 2.8 nm) Au nanoparticles conjugated to doxorubicin (Au-Dox) are up to five-fold more cytotoxic to B16 melanoma cells than Dox alone. The particles enter the cell nucleus, as observed by fluorescence confocal, reflectance, and transmission electron microscopy. At these concentrations, cell death with Dox alone is apoptotic, whereas with Au-Dox, both necrosis and apoptosis occur. The Au particles themselves are non-toxic. We also report quantitative comparisons of reactive oxygen species generation, oxidative DNA damage, and caspase-3 reactivity in cells exposed to Dox alone, Au alone, and Au-Dox. These results have implications for the design of chemotherapeutic nanoparticles. They indicate that very small particles can enter cell nuclei and react with DNA, and that doxorubicin remains highly active when conjugated to Au, without the need for cleavable linkers to the particle. It is expected that these particles will accumulate in tumors without further targeting, and future animal studies will determine its efficacy in mouse models of melanoma and breast cancer. Results will be immediately translatable to clinical studies as all the elements of the formulation are FDA approved.
 
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