Limits...
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

Release profile of Cu2+from ND-Cu2+complex at different pH values. a: Desorption amount of Cu2+ from ND-Cu2+ complexes in different pH values: pH 7.4 and pH 5.5 within 24 h. b: The most stable structures of the ND-Cu2+ complex at high and low pH (denoted by ND-Cu2+ and NDH-Cu2+, respectively) obtained by theoretical computation. c: Molecular modeling illustrations for the adsorption of Cu2+ on ND aggregates at high pH and low pH.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Release profile of Cu2+from ND-Cu2+complex at different pH values. a: Desorption amount of Cu2+ from ND-Cu2+ complexes in different pH values: pH 7.4 and pH 5.5 within 24 h. b: The most stable structures of the ND-Cu2+ complex at high and low pH (denoted by ND-Cu2+ and NDH-Cu2+, respectively) obtained by theoretical computation. c: Molecular modeling illustrations for the adsorption of Cu2+ on ND aggregates at high pH and low pH.

Mentions: Several studies have shown that NDs uptake in a variety of cells was by endocytosis [10,35]. After entering the cytoplasm of the cells, many of NDs often store in endosomes, which subsequently fuse with lysosomes that contain many different hydrolytic enzymes [36]. Thus, we then examined the release profile of Cu2+ from ND-Cu2+ complex at extracellular pH (at typical cell culture medium pH of 7.4) and mildly acidic conditions (at typical lososomal pH of 5). The release curve (Figure 4a) showed that at neutral pH, a very small amount of Cu2+ (only about 2%) could release from ND-Cu2+ complex and confirmed the stability of ND-Cu2+ complex in cell culture medium. On the contrary, at acidic conditions, Cu2+ absorbed on NDs released very quickly. The amount of released Cu2+, presented by a weight percentage of the total Cu2+ adsorbed, was approximately 15 times higher than that at neutral conditions.Figure 4


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)

Release profile of Cu2+from ND-Cu2+complex at different pH values. a: Desorption amount of Cu2+ from ND-Cu2+ complexes in different pH values: pH 7.4 and pH 5.5 within 24 h. b: The most stable structures of the ND-Cu2+ complex at high and low pH (denoted by ND-Cu2+ and NDH-Cu2+, respectively) obtained by theoretical computation. c: Molecular modeling illustrations for the adsorption of Cu2+ on ND aggregates at high pH and low pH.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Release profile of Cu2+from ND-Cu2+complex at different pH values. a: Desorption amount of Cu2+ from ND-Cu2+ complexes in different pH values: pH 7.4 and pH 5.5 within 24 h. b: The most stable structures of the ND-Cu2+ complex at high and low pH (denoted by ND-Cu2+ and NDH-Cu2+, respectively) obtained by theoretical computation. c: Molecular modeling illustrations for the adsorption of Cu2+ on ND aggregates at high pH and low pH.
Mentions: Several studies have shown that NDs uptake in a variety of cells was by endocytosis [10,35]. After entering the cytoplasm of the cells, many of NDs often store in endosomes, which subsequently fuse with lysosomes that contain many different hydrolytic enzymes [36]. Thus, we then examined the release profile of Cu2+ from ND-Cu2+ complex at extracellular pH (at typical cell culture medium pH of 7.4) and mildly acidic conditions (at typical lososomal pH of 5). The release curve (Figure 4a) showed that at neutral pH, a very small amount of Cu2+ (only about 2%) could release from ND-Cu2+ complex and confirmed the stability of ND-Cu2+ complex in cell culture medium. On the contrary, at acidic conditions, Cu2+ absorbed on NDs released very quickly. The amount of released Cu2+, presented by a weight percentage of the total Cu2+ adsorbed, was approximately 15 times higher than that at neutral conditions.Figure 4

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