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Nanodiamonds act as Trojan horse for intracellular delivery of metal ions to trigger cytotoxicity.

Zhu Y, Zhang Y, Shi G, Yang J, Zhang J, Li W, Li A, Tai R, Fang H, Fan C, Huang Q - Part Fibre Toxicol (2015)

Bottom Line: In addition, theoretical calculation and molecular dynamics (MD) computation were used to illustrate the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values.Detailed investigation of ND-Cu2+ interaction showed that the amount of released Cu2+ from ND-Cu2+ complexes at acidic lysosomal conditions was much higher than that at neutral conditions, leading to the elevation of intracellular ROS level, which triggered cytotoxicity.The present experimental and theoretical results provide useful insight into understanding of cytotoxicity triggered by nanoparticle-ion interactions, and open new ways in the interpretation of nanotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Division of Physical Biology, and Bioimaging Center, Shanghai Synchrotron Radiation Facility, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201800, China. zhuying@sinap.ac.cn.

ABSTRACT

Background: Nanomaterials hold great promise for applications in the delivery of various molecules with poor cell penetration, yet its potential for delivery of metal ions is rarely considered. Particularly, there is limited insight about the cytotoxicity triggered by nanoparticle-ion interactions. Oxidative stress is one of the major toxicological mechanisms for nanomaterials, and we propose that it may also contribute to nanoparticle-ion complexes induced cytotoxicity.

Methods: To explore the potential of nanodiamonds (NDs) as vehicles for metal ion delivery, we used a broad range of experimental techniques that aimed at getting a comprehensive assessment of cell responses after exposure of NDs, metal ions, or ND-ion mixture: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Trypan blue exclusion text, optical microscope observation, synchrotron-based scanning transmission X-ray microscopy (STXM) and micro X-ray fluorescence (μXRF) microscopy, inductively coupled plasma-mass spectrometry (ICP-MS), reactive oxygen species (ROS) assay and transmission electron microscopy (TEM) observation. In addition, theoretical calculation and molecular dynamics (MD) computation were used to illustrate the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values.

Results: The adsorption capacity of NDs for different metal ions was different, and the adsorption for Cu2+ was the most strong among divalent metal ions. These different ND-ion complexes then had different cytotoxicity by influencing the subsequent cellular responses. Detailed investigation of ND-Cu2+ interaction showed that the amount of released Cu2+ from ND-Cu2+ complexes at acidic lysosomal conditions was much higher than that at neutral conditions, leading to the elevation of intracellular ROS level, which triggered cytotoxicity. By theoretical approaches, we demonstrated that the functional carbon surface and cluster structures of NDs made them good vehicles for metal ions delivery.

Conclusions: NDs played the Trojan horse role by allowing large amounts of metal ions accumulate into living cells followed by subsequent release of ions in the interior of cells, which then led to cytotoxicity. The present experimental and theoretical results provide useful insight into understanding of cytotoxicity triggered by nanoparticle-ion interactions, and open new ways in the interpretation of nanotoxicity.

No MeSH data available.


Related in: MedlinePlus

Interactions of NDs with metal ions trigger cytotoxicity. a: Scheme of adsorption of metal ions on NDs leads to cellular responses. b: The adsorption amounts (blue) and adsorption energies (red) of metal ions on NDs obtained by ICP-MS measurements and theoretical computation, respectively. c: The IC50 values of metal ions and ND-ion mixture and the differences between them. d: Optical images of L929 cells after incubation with NDs, Cu2+ and NDs-Cu2+ mixture for 24 h.
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Fig1: Interactions of NDs with metal ions trigger cytotoxicity. a: Scheme of adsorption of metal ions on NDs leads to cellular responses. b: The adsorption amounts (blue) and adsorption energies (red) of metal ions on NDs obtained by ICP-MS measurements and theoretical computation, respectively. c: The IC50 values of metal ions and ND-ion mixture and the differences between them. d: Optical images of L929 cells after incubation with NDs, Cu2+ and NDs-Cu2+ mixture for 24 h.

Mentions: Here, we employed experimental approaches to investigate the various NDs-metal ion interactions and demonstrated that NDs acted as vehicles by allowing large amounts of metal ions accumulate into living cells followed by subsequent release of ions in the interior of cells, which then triggered cytotoxicity (Figure 1a). By theoretical approaches, the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values were well explored. A Trojan horse type effect has been proposed to explain the biological effects of nanoparticle-biomolecule interactions [22]. The present results are also in line with a Trojan horse-type mechanism, which opens new ways in the interpretation and understanding of nanoparticle-ion interactions and their bioeffects.Figure 1


Nanodiamonds act as Trojan horse for intracellular delivery of metal ions to trigger cytotoxicity.

Zhu Y, Zhang Y, Shi G, Yang J, Zhang J, Li W, Li A, Tai R, Fang H, Fan C, Huang Q - Part Fibre Toxicol (2015)

Interactions of NDs with metal ions trigger cytotoxicity. a: Scheme of adsorption of metal ions on NDs leads to cellular responses. b: The adsorption amounts (blue) and adsorption energies (red) of metal ions on NDs obtained by ICP-MS measurements and theoretical computation, respectively. c: The IC50 values of metal ions and ND-ion mixture and the differences between them. d: Optical images of L929 cells after incubation with NDs, Cu2+ and NDs-Cu2+ mixture for 24 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4374301&req=5

Fig1: Interactions of NDs with metal ions trigger cytotoxicity. a: Scheme of adsorption of metal ions on NDs leads to cellular responses. b: The adsorption amounts (blue) and adsorption energies (red) of metal ions on NDs obtained by ICP-MS measurements and theoretical computation, respectively. c: The IC50 values of metal ions and ND-ion mixture and the differences between them. d: Optical images of L929 cells after incubation with NDs, Cu2+ and NDs-Cu2+ mixture for 24 h.
Mentions: Here, we employed experimental approaches to investigate the various NDs-metal ion interactions and demonstrated that NDs acted as vehicles by allowing large amounts of metal ions accumulate into living cells followed by subsequent release of ions in the interior of cells, which then triggered cytotoxicity (Figure 1a). By theoretical approaches, the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values were well explored. A Trojan horse type effect has been proposed to explain the biological effects of nanoparticle-biomolecule interactions [22]. The present results are also in line with a Trojan horse-type mechanism, which opens new ways in the interpretation and understanding of nanoparticle-ion interactions and their bioeffects.Figure 1

Bottom Line: In addition, theoretical calculation and molecular dynamics (MD) computation were used to illustrate the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values.Detailed investigation of ND-Cu2+ interaction showed that the amount of released Cu2+ from ND-Cu2+ complexes at acidic lysosomal conditions was much higher than that at neutral conditions, leading to the elevation of intracellular ROS level, which triggered cytotoxicity.The present experimental and theoretical results provide useful insight into understanding of cytotoxicity triggered by nanoparticle-ion interactions, and open new ways in the interpretation of nanotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Division of Physical Biology, and Bioimaging Center, Shanghai Synchrotron Radiation Facility, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201800, China. zhuying@sinap.ac.cn.

ABSTRACT

Background: Nanomaterials hold great promise for applications in the delivery of various molecules with poor cell penetration, yet its potential for delivery of metal ions is rarely considered. Particularly, there is limited insight about the cytotoxicity triggered by nanoparticle-ion interactions. Oxidative stress is one of the major toxicological mechanisms for nanomaterials, and we propose that it may also contribute to nanoparticle-ion complexes induced cytotoxicity.

Methods: To explore the potential of nanodiamonds (NDs) as vehicles for metal ion delivery, we used a broad range of experimental techniques that aimed at getting a comprehensive assessment of cell responses after exposure of NDs, metal ions, or ND-ion mixture: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Trypan blue exclusion text, optical microscope observation, synchrotron-based scanning transmission X-ray microscopy (STXM) and micro X-ray fluorescence (μXRF) microscopy, inductively coupled plasma-mass spectrometry (ICP-MS), reactive oxygen species (ROS) assay and transmission electron microscopy (TEM) observation. In addition, theoretical calculation and molecular dynamics (MD) computation were used to illustrate the adsorption properties of different metal ion on NDs as well as release profile of ion from ND-ion complexes at different pH values.

Results: The adsorption capacity of NDs for different metal ions was different, and the adsorption for Cu2+ was the most strong among divalent metal ions. These different ND-ion complexes then had different cytotoxicity by influencing the subsequent cellular responses. Detailed investigation of ND-Cu2+ interaction showed that the amount of released Cu2+ from ND-Cu2+ complexes at acidic lysosomal conditions was much higher than that at neutral conditions, leading to the elevation of intracellular ROS level, which triggered cytotoxicity. By theoretical approaches, we demonstrated that the functional carbon surface and cluster structures of NDs made them good vehicles for metal ions delivery.

Conclusions: NDs played the Trojan horse role by allowing large amounts of metal ions accumulate into living cells followed by subsequent release of ions in the interior of cells, which then led to cytotoxicity. The present experimental and theoretical results provide useful insight into understanding of cytotoxicity triggered by nanoparticle-ion interactions, and open new ways in the interpretation of nanotoxicity.

No MeSH data available.


Related in: MedlinePlus