Cytotoxicity of CdTe quantum dots in human umbilical vein endothelial cells: the involvement of cellular uptake and induction of pro-apoptotic endoplasmic reticulum stress

Abstract

Cadmium telluride quantum dots (CdTe QDs) have been proposed to induce oxidative stress, which plays a crucial role in CdTe QDs-mediated mitochondrial-dependent apoptosis in human umbilical vein endothelial cells (HUVECs). However, the direct interactions of CdTe QDs with HUVECs and their potential impairment of other organelles like endoplasmic reticulum (ER) in HUVECs are poorly understood. In this study, we reported that the negatively charged CdTe QDs (−21.63±0.91 mV), with good dispersity and fluorescence stability, were rapidly internalized via endocytosis by HUVECs, as the notable internalization could be inhibited up to 95.52% by energy depletion (NaN 3 /deoxyglucose or low temperature). The endocytosis inhibitors (methyl-β-cyclodextrin, genistein, sucrose, chlorpromazine, and colchicine) dramatically decreased the uptake of CdTe QDs by HUVECs, suggesting that both caveolae/raft- and clathrin-mediated endocytosis were involved in the endothelial uptake of CdTe QDs. Using immunocytochemistry, a striking overlap of the internalized CdTe QDs and ER marker was observed, which indicates that QDs may be transported to ER. The CdTe QDs also caused remarkable ER stress responses in HUVECs, confirmed by significant dilatation of ER cisternae, upregulation of ER stress markers GRP78/GRP94, and activation of protein kinase RNA-like ER kinase-eIF2α-activating transcription factor 4 pathway (including phosphorylation of both protein kinase RNA-like ER kinase and eIF2α and elevated level of activating transcription factor 4). CdTe QDs further promoted an increased C/EBP homologous protein expression, phosphorylation of c-JUN NH2-terminal kinase, and cleavage of ER-resident caspase-4, while the specific inhibitor (SP600125, Z-LEVD-fmk, or salubrinal) significantly attenuated QDs-triggered apoptosis, indicating that all three ER stress-mediated apoptosis pathways were activated and the direct participation of ER in the CdTe QDs-caused apoptotic cell death in HUVECs. Our findings provide important new insights into QDs toxicity and reveal potential cardiovascular risks for the future applications of QDs.

The use of human umbilical vein endothelial cells (HUVECs) as an in vitro model to assess the toxicity of nanoparticles to endothelium: a review

“…For example, ZnO NPs, which could dissolute to release high levels of Zn ions, have been shown to induce cytotoxicity of HUVECs as reduced mitochondrial viability and membrane integrity, inhibited proliferation as well as increased lysosomal destabilization and apoptosis (Tsou et al, 2010;Chen et al, 2014;Suzuki et al, 2014;Danielsen et al, 2015;Gong et al, 2016;Gu et al, 2017). Similar effects were also observed in HUVECs after exposure to Ag NPs, which can lead to intracellular Ag accumulation Ucciferri et al, 2014;Danielsen et al, 2015;Huo et al, 2015;Guo et al, 2016), as well as Cd-based QD, which can release the highly cytotoxic Cd ions (Yan et al, 2011(Yan et al, , 2016Soenen et al, 2014;). Some types of insoluble NPs, such as silica NPs (Corbalan et al, 2011;Blechinger et al, 2013;Duan et al, 2013b;Guo et al, 2015), carbon black NPs (Frikke-Schmidt et al, 2011;Vesterdal et al, 2012;Cao et al, 2014b) and MWCNT (Guo et al, 2011;Xu et al, 2012;Cao et al, 2014a), have also been reported to be cytotoxic to HUVECs, although the toxicity of these NPs appears to be more modest compared with the soluble, metal-based NPs.…”

Transport and release of colloidal 3-mercaptopropionic acid-coated CdSe–CdS/ZnS core-multishell quantum dots in human umbilical vein endothelial cells

“…Since our 3MPA-QDs did not reach the lysosomes, there was little chance that QDs could be degraded to release cytotoxic substances such as Cd 2+ . It is interesting to point out that it was reported before that 3MPA-QDs did not co-localize with the ER, 39 explaining the absence of cellular stress known to be triggered by certain QDs sequestered in ER.…”

Cationic carbon quantum dots derived from alginate for gene delivery: One-step synthesis and cellular uptake

“…The cytotoxicity of quantum dots depends on a combination of elements from the particle formulation, such as the core materials and modification ligands [58]. Compared with the eco-friendly CQDs, the semiconductor CdTe QDs may induce mitochondrial-dependent apoptosis of cells [59], with a relatively high cytotoxicity. This result indicated that the developed CQDs possess negligible toxicity and superior safety advantage over the CdTe QDs (see Fig.…”