Quantum dots: from cytotoxicity to metalloestrogenicity

The fields of Nanomedicine is rapidly expanding. Already numerous nanoparticles have entered clinical trials. However, certain nanostructures, though, therapeutically and diagnostically promising, can induce toxicity both in vitro and in vivo; cadmium telluride quantum dots fall into this category. Quantum dots (QDs) are highly fluorescent, semi-conducting nanocrystals, that consist of a metallic core. Compared to traditional fluorophores, QDs have superior optical qualities, including resistance to photobleaching, broad spectrum excitation and narrow emission. Cadmium telluride (CdTe) QDs were the first to be synthesized without organic solvents, and thus, considered suitable for biological application. However, early studies demonstrated that QDs induced cytotoxicity and oxidative stress. Although, this QD-toxicity was ascribed to cadmium (Cd) liberation from the QD-core, no empirical evidence was shown. Due to the attractiveness of QDs for biological applications, it was necessary that the mechanisms involved in QD-toxicity be understood so they may be prevented. Preliminary studies from our laboratory indicated that the antioxidant, N-acetlycysteine could prevent QD-toxicity. We, thus, hypothesized that QD-toxicity was not exclusively due to cadmium leaching from the QD. To evaluate this, an assay measuring free Cd was adapted for cellular use, to measure Cd present in both the cellular media and intracellularly. The cytotoxicity of various QDs was evaluated and correlated with the intracellular Cd. Results from this study showed no correlation between QD-toxicity and Cd release from QDs. We next questioned whether QD-toxicity could be explained as the sum of parts of the toxicity associated with core constituting metals, and whether the complexity of the model system used influences the cytotoxicity observed. We employed three model systems of the peripheral nervous system (an immortalized cell line, heterogeneous primary cultures and a three dimensional tissue model) and evaluated the toxicity of Cd, Te and QDs in each. Our findings showed that QDs are not a sum of parts and QD-toxicity is better ascribed to the induction of oxidative stress which is prevented by application of the multi-modal antioxidant, lipoic acid. Further, the model systems did not depict QD-toxicity comparably, stressing the need for standardization in nanotoxicological studies. Finally, it had been shown that Cd association with the estrogen receptor (ER) in ER expressing cells can activate estrogenic signalling. As such, Cd is considered a metalloestrogen. Given that QDs liberate Cd that can be detected in the cell, we investigated whether in ER expressing cells, QDs may act as metalloestrogens and induce estrogenic signalling. Results in vitro showed that QDs exert potent estrogenic signalling, comparable with estradiol, including cell proliferation, AKT phosphorylation, ERK phosphorylation and nuclear ER activation. These effects could be attenuated via pretreatment with the specific ER antagonist, ICI 182780, affirming that QD-induced estrogenic activity was mediated via the ER. To determine whether the estrogenic activity of QDs could also be demonstrated in vivo, ovariectomized mice were treated with QDs for two weeks, prior to being sacrificed. Subsequently, the wet weights of the mice uteruses were measured. In mice treated with QDs and estradiol a comparable 2.5 fold increase in uterine wet weight was observed. Taken together, these results indicate that CdTe QDs are both cytotoxic and endocrine disrupting, metalloestrogens. Though these nanocrystals may have valuable applications in biology the implications of QD-use are dangerous to plants, animals, humans and the environment. Therefore, it is imperative that Cd-free QDs be developed that retain the attractive qualities of QDs while preventing the detrimental side effects. Further, standardized testing of nanoparticles is imperative for the safe use of these novel tools.

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