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Nano Research 2018, 11(5): 2746-2755 https://doi.org/10.1007/s12274-017-1905-8
Research Article | Issue | Published: 12 May 2018

Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism

Show Author's Information Lu Wang1,§,  Zejun Wang1,§,  Xiaoming Li2,  Yi Zhang1,  Min Yin1,  Jiang Li1,  Haiyun Song3,  Jiye Shi1,4,  Daishun Ling5,  Lihua Wang1,  Nan Chen1( ),  Chunhai Fan1,2( )
Division of Physical Biology and Bioimaging CenterShanghai Synchrotron Radiation FacilityCAS Key Laboratory of Interfacial Physics and TechnologyShanghai Institute of Applied PhysicsChinese Academy of SciencesShanghai201800China
School of Life Science and TechnologyShanghai Tech UniversityShanghai201210China
Key Laboratory of Food Safety ResearchInstitute for Nutritional SciencesShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai200031China
UCB Pharma208 Bath RoadSloughSL1 3WEUK
College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China

§Lu Wang and Zejun Wang contributed equally to this work.

Keywords:
cytotoxicity, reactive oxygen species, iron oxide nanoparticles, catalase-like activity, autophagy
Cite this article:
Wang L, Wang Z, Li X, et al. Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism. Nano Research, 2018, 11(5): 2746-2755. https://doi.org/10.1007/s12274-017-1905-8
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Abstract Full text Electronic supplementary material About this article

Magnetite nanoparticles (Fe3O4 NPs) are a well proven biocompatible nanomaterial, which hold great promise in various biomedical applications. Interestingly, unlike conventional biocompatible materials (e.g., polyethylene glycol (PEG)) that are chemically and biologically inert in nature, Fe3O4 NPs are known to be catalytically active and exhibit prominent physiological effects. Herein, we report an "active", dynamic equilibrium mechanism for maintaining the cellular amenity of Fe3O4 NPs. We examined the effects of two types of iron oxide (magnetite and hematite) NPs in rat pheochromocytoma (PC12) cells and found that both induced stress responses. However, only Fe2O3 NPs caused significant programmed cell death; whereas Fe3O4 NPs are amenable to cells. We found that intrinsic catalase-like activity of Fe3O4 NPs antagonized the accumulation of toxic reactive oxygen species (ROS) induced by themselves, and thereby modulated the extent of cellular oxidative stress, autophagic activity, and programmed cell death. In line with this observation, we effectively reversed severe autophagy and cell death caused by Fe2O3 NPs via co-treatment with natural catalase. This study not only deciphers the distinct intrinsic antagonism of Fe3O4 NPs, but opens new routes to designing biocompatible theranostic nanoparticles with novel mechanisms.


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Electronic supplementary material
About this article

Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism

Show Author's information Lu Wang1,§, Zejun Wang1,§, Xiaoming Li2, Yi Zhang1, Min Yin1, Jiang Li1, Haiyun Song3, Jiye Shi1,4, Daishun Ling5, Lihua Wang1, Nan Chen1( ), Chunhai Fan1,2( )
Division of Physical Biology and Bioimaging CenterShanghai Synchrotron Radiation FacilityCAS Key Laboratory of Interfacial Physics and TechnologyShanghai Institute of Applied PhysicsChinese Academy of SciencesShanghai201800China
School of Life Science and TechnologyShanghai Tech UniversityShanghai201210China
Key Laboratory of Food Safety ResearchInstitute for Nutritional SciencesShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai200031China
UCB Pharma208 Bath RoadSloughSL1 3WEUK
College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China

§Lu Wang and Zejun Wang contributed equally to this work.

Abstract

Magnetite nanoparticles (Fe3O4 NPs) are a well proven biocompatible nanomaterial, which hold great promise in various biomedical applications. Interestingly, unlike conventional biocompatible materials (e.g., polyethylene glycol (PEG)) that are chemically and biologically inert in nature, Fe3O4 NPs are known to be catalytically active and exhibit prominent physiological effects. Herein, we report an "active", dynamic equilibrium mechanism for maintaining the cellular amenity of Fe3O4 NPs. We examined the effects of two types of iron oxide (magnetite and hematite) NPs in rat pheochromocytoma (PC12) cells and found that both induced stress responses. However, only Fe2O3 NPs caused significant programmed cell death; whereas Fe3O4 NPs are amenable to cells. We found that intrinsic catalase-like activity of Fe3O4 NPs antagonized the accumulation of toxic reactive oxygen species (ROS) induced by themselves, and thereby modulated the extent of cellular oxidative stress, autophagic activity, and programmed cell death. In line with this observation, we effectively reversed severe autophagy and cell death caused by Fe2O3 NPs via co-treatment with natural catalase. This study not only deciphers the distinct intrinsic antagonism of Fe3O4 NPs, but opens new routes to designing biocompatible theranostic nanoparticles with novel mechanisms.

Keywords: cytotoxicity, reactive oxygen species, iron oxide nanoparticles, catalase-like activity, autophagy

References(44)

1

Krug, H. F. Nanosafety research—Are we on the right track? Angew. Chem., Int. Ed. 2014, 53, 12304–12319.
DOI Google Scholar
2

Yu, Y.; Cui, C.; Liu, X. H.; Petrik, I. D.; Wang, J. Y.; Lu, Y. A designed metalloenzyme achieving the catalytic rate of a native enzyme. J. Am. Chem. Soc. 2015, 137, 11570–11573.
DOI Google Scholar
3

Zhao, Z.; Fu, J. L.; Dhakal, S.; JohnsonBuck, A.; Liu, M. H.; Zhang, T.; Woodbury, N. W.; Liu, Y.; Walter, N. G.; Yan, H. Nanocaged enzymes with enhanced catalytic activity and increased stability against protease digestion. Nat. Commun. 2016, 7, 10619.
DOI Google Scholar
4

Liu, J. L.; Yang, Y.; Zhu, W. W.; Yi, X.; Dong, Z. L.; Xu, X. N.; Chen, M. W.; Yang, K.; Lu, G.; Jiang, L. et al. Nanoscale metal-organic frameworks for combined photodynamic & radiation therapy in cancer treatment. Biomaterials 2016, 97, 1–9.
DOI Google Scholar
5

Li, M. Y.; Li, L. L.; Zhan, C. Y.; Kohane, D. S. Core–shell nanostars for multimodal therapy and imaging. Theranostics 2016, 6, 2306–2313.
DOI Google Scholar
6

Xu, M.; Zhu, J. Q.; Wang, F. F.; Xiong, Y. J.; Wu, Y. K.; Wang, Q. Q.; Weng, J.; Zhang, Z. H.; Chen, W.; Liu, S. J. Improved in vitro and in vivo biocompatibility of graphene oxide through surface modification: Poly(acrylic acid)- functionalization is superior to pegylation. ACS Nano 2016, 10, 3267–3281.
DOI Google Scholar
7

Li, Y. J.; Feng, L. Z.; Shi, X. Z.; Wang, X. J.; Yang, Y. L.; Yang, K.; Liu, T.; Yang, G. B.; Liu, Z. Surface coatingdependent cytotoxicity and degradation of graphene derivatives: Towards the design of non-toxic, degradable nano-graphene. Small 2014, 10, 1544–1554.
DOI Google Scholar
8

Liu, Q.; Wang, W. P.; Zhan, C. Y.; Yang, T. S.; Kohane, D. S. Enhanced precision of nanoparticle phototargeting in vivo at a safe irradiance. Nano Lett. 2016, 16, 4516–4520.
DOI Google Scholar
9

Lee, D. H.; Kang, M.; Lee, H. J.; Kim, J. A.; Choi, Y. K.; Cho, H.; Park, J. K.; Park, T. H.; Jung, H. Enhanced cellular uptake of silica-coated magnetite nanoparticles compared with peg-coated ones in stem cells. J. Nanosci. Nanotechnol. 2015, 15, 5512–5519.
DOI Google Scholar
10

Walczyk, D.; Bombelli, F. B.; Monopoli, M. P.; Lynch, I.; Dawson, K. A. What the cell "sees" in bionanoscience. J. Am. Chem. Soc. 2010, 132, 5761–5768.
DOI Google Scholar
11

Shi, M.; Cheng, L.; Zhang, Z. B.; Liu, Z.; Mao, X. L. Ferroferric oxide nanoparticles induce prosurvival autophagy in human blood cells by modulating the beclin 1/Bcl-2/ VPS34 complex. Int. J. Nanomedicine 2015, 10, 207–216.
DOI Google Scholar
12

Chen, N.; Wang, H.; Huang, Q.; Li, J.; Yan, J.; He, D. N.; Fan, C. H.; Song, H. Y. Long-term effects of nanoparticles on nutrition and metabolism. Small 2014, 10, 3603–3611.
DOI Google Scholar
13

Vernet, E.; Popa, G.; Pozdnyakova, I.; Rasmussen, J. E.; Grohganz, H.; Giehm, L.; Jensen, M. H.; Wang, H. B.; Plesner, B.; Nielsen, H. M. et al. Large-scale biophysical evaluation of protein pegylation effects: In vitro properties of 61 protein entities. Mol. Pharm. 2016, 13, 1587–1598.
DOI Google Scholar
14

Harrison, E.; Coulter, J. A.; Dixon, D. Gold nanoparticle surface functionalization: Mixed monolayer versus hetero bifunctional peg linker. Nanomedicine 2016, 11, 851–865.
DOI Google Scholar
15

Lee, N.; Yoo, D.; Ling, D. S.; Cho, M. H.; Hyeon, T.; Cheon, J. Iron oxide based nanoparticles for multimodal imaging and magnetoresponsive therapy. Chem. Rev. 2015, 115, 10637–10689.
DOI Google Scholar
16

Yoo, D.; Lee, J. H.; Shin, T. H.; Cheon, J. Theranostic magnetic nanoparticles. Acc. Chem. Res. 2011, 44, 863–874.
DOI Google Scholar
17

Colombo, M.; Carregal-Romero, S.; Casula, M. F.; Gutierrez, L.; Morales, M. P.; Böhm, I. B.; Heverhagen, J. T.; Prosperi, D.; Parak, W. J. Biological applications of magnetic nanoparticles. Chem. Soc. Rev. 2012, 41, 4306–4334.
DOI Google Scholar
18

Kong, S. D.; Lee, J.; Ramachandran, S.; Eliceiri, B. P.; Shubayev, V. I.; Lal, R.; Jin, S. Magnetic targeting of nanoparticles across the intact blood-brain barrier. J. Control Release 2012, 164, 49–57.
DOI Google Scholar
19

Yi, P. W.; Chen, G. C.; Zhang, H. L.; Tian, F.; Tan, B.; Dai, J. W.; Wang, Q. B.; Deng, Z. W. Magnetic resonance imaging of Fe3O4@SiO2-labeled human mesenchymal stem cells in mice at 11.7 T. Biomaterials 2013, 34, 3010–3019.
DOI Google Scholar
20

Mo, A. H.; Landon, P. B.; Gomez, K. S.; Kang, H.; Lee, J.; Zhang, C.; Janetanakit, W.; Sant, V.; Lu, T. Y.; Colburn, D. A. et al. Magnetically-responsive silica-gold nanobowls for targeted delivery and sers-based sensing. Nanoscale 2016, 8, 11840–11850.
DOI Google Scholar
21

Han, J.; Kim, B.; Shin, J. Y.; Ryu, S.; Noh, M.; Woo, J.; Park, J. S.; Lee, Y.; Lee, N.; Hyeon, T. et al. Iron oxide nanoparticle-mediated development of cellular gap junction crosstalk to improve mesenchymal stem cells' therapeutic efficacy for myocardial infarction. ACS Nano 2015, 9, 2805–2819.
DOI Google Scholar
22

Ling, D. S.; Lee, N.; Hyeon, T. Chemical synthesis and assembly of uniformly sized iron oxide nanoparticles for medical applications. Acc. Chem. Res. 2015, 48, 1276–1285.
DOI Google Scholar
23

Gao, L. Z.; Zhuang, J.; Nie, L.; Zhang, J. B.; Zhang, Y.; Gu, N.; Wang, T. H.; Feng, J.; Yang, D. L.; Perrett, S. et al. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles. Nat. Nanotechnol. 2007, 2, 577–583.
DOI Google Scholar
24

Chen, Z. E.; Yin, J. J.; Zhou, Y. T.; Zhang, Y.; Song, L. N.; Song, M. J.; Hu, S. L.; Gu, N. Dual enzyme-like activities of iron oxide nanoparticles and their implication for diminishing cytotoxicity. ACS Nano 2012, 6, 4001–4012.
DOI Google Scholar
25

Zhang, Y.; Wang, Z. Y.; Li, X. J.; Wang, L.; Yin, M.; Wang, L. H.; Chen, N.; Fan, C. H.; Song, H. Y. Dietary iron oxide nanoparticles delay aging and ameliorate neurodegeneration in drosophila. Adv. Mater. 2016, 28, 1387–1393.
DOI Google Scholar
26

Zhong, W. Y.; Lü, M.; Liu, L. Y.; Sun, J. L.; Zhong, Z. T.; Zhao, Y.; Song, H. Y. Autophagy as new emerging cellular effect of nanomaterials. Chin. Sci. Bull. 2013, 58, 4031–4038.
DOI Google Scholar
27

Peynshaert, K.; Manshian, B. B.; Joris, F.; Braeckmans, K.; De Smedt, S. C.; Demeester, J.; Soenen, S. J. Exploiting intrinsic nanoparticle toxicity: The pros and cons of nanoparticle-induced autophagy in biomedical research. Chem. Rev. 2014, 114, 7581–7609.
DOI Google Scholar
28

Popp, L.; Segatori, L. Differential autophagic responses to nano-sized materials. Curr. Opin. Biotechnol. 2015, 36, 129–136.
DOI Google Scholar
29

Wan, B.; Wang, Z. X.; Lv, Q. Y.; Dong, P. X.; Zhao, L. X.; Yang, Y.; Guo, L. H. Single-walled carbon nanotubes and graphene oxides induce autophagosome accumulation and lysosome impairment in primarily cultured murine peritoneal macrophages. Toxicol. Lett. 2013, 221, 118–127.
DOI Google Scholar
30

Scherz-Shouval, R.; Shvets, E.; Fass, E.; Shorer, H.; Gil, L.; Elazar, Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of atg4. EMBO J. 2007, 26, 1749–1760.
DOI Google Scholar
31

Luo, Y. H.; Wu, S. B.; Wei, Y. H.; Chen, Y. C.; Tsai, M. H.; Ho, C. C.; Lin, S. Y.; Yang, C. S.; Lin, P. P. Cadmium-based quantum dot induced autophagy formation for cell survival via oxidative stress. Chem. Res. Toxicol. 2013, 26, 662–673.
DOI Google Scholar
32

Lewinski, N.; Colvin, V.; Drezek, R. Cytotoxicity of nanoparticles. Small 2008, 4, 26–49.
DOI Google Scholar
33

Chen, N.; He, Y.; Su, Y. Y.; Li, X. M.; Huang, Q.; Wang, H. F.; Zhang, X. Z.; Tai, R. Z.; Fan, C. H. The cytotoxicity of cadmium-based quantum dots. Biomaterials 2012, 33, 1238–1244.
DOI Google Scholar
34

Wang, B.; Chen, N.; Wei, Y. L.; Li, J.; Sun, L.; Wu, J. R.; Huang, Q.; Liu, C.; Fan, C. H.; Song, H. Y. Akt signaling- associated metabolic effects of dietary gold nanoparticles in drosophila. Sci. Rep. 2012, 2, 563.
DOI Google Scholar
35

Ma, P. A.; Xiao, H. H.; Yu, C.; Liu, J. H.; Cheng, Z. Y.; Song, H. Q.; Zhang, X. Y.; Li, C. X.; Wang, J. Q.; Gu, Z. et al. Enhanced cisplatin chemotherapy by iron oxide nanocarrier- mediated generation of highly toxic reactive oxygen species. Nano Lett. 2017, 17, 928–937.
DOI Google Scholar
36

Scherz-Shouval, R.; Elazar, Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol. 2007, 17, 422–427.
DOI Google Scholar
37

Li, C. G.; Liu, H. L.; Sun, Y.; Wang, H. L.; Guo, F.; Rao, S.; Deng, J. J.; Zhang, Y. L.; Miao, Y. F.; Guo, C. Y. et al. Pamam nanoparticles promote acute lung injury by inducing autophagic cell death through the akt-tsc2-mtor signaling pathway. J. Mol. Cell. Biol. 2009, 1, 37–45.
DOI Google Scholar
38

Guan, Y. J.; Li, M.; Dong, K.; Gao, N.; Ren, J. S.; Zheng, Y. C.; Qu, X. G. Ceria/poms hybrid nanoparticles as a mimicking metallopeptidase for treatment of neurotoxicity of amyloid-beta peptide. Biomaterials 2016, 98, 92–102.
DOI Google Scholar
39

White, E.; DiPaola, R. S. The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 2009, 15, 5308–5316.
DOI Google Scholar
40

Levine, B.; Mizushima, N.; Virgin, H. W. Autophagy in immunity and inflammation. Nature 2011, 469, 323–335.
DOI Google Scholar
41

Mariño, G.; Niso-Santano, M.; Baehrecke, E. H.; Kroemer, G. Self-consumption: The interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell. Biol. 2014, 15, 81–94.
DOI Google Scholar
42

Booth, L. A.; Tavallai, S.; Hamed, H. A.; Cruickshanks, N.; Dent, P. The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell. Signal. 2014, 26, 549–555.
DOI Google Scholar
43

Chen, Y.; McMillan-Ward, E.; Kong, J.; Israels, S. J.; Gibson, S. B. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 2008, 15, 171–182.
DOI Google Scholar
44

Khan, M. I.; Mohammad, A.; Patil, G.; Naqvi, S. A. H.; Chauhan, L. K. S.; Ahmad, I. Induction of ros, mitochondrial damage and autophagy in lung epithelial cancer cells by iron oxide nanoparticles. Biomaterials 2012, 33, 1477–1488.
DOI Google Scholar
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Publication history
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Acknowledgements

Publication history

Received: 18 September 2017
Revised: 27 October 2017
Accepted: 01 November 2017
Published: 12 May 2018
Issue date: May 2018

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany 2017

Acknowledgements

Acknowledgements

We would like to dedicate this article to Professor Qing Huang. This work was supported by National Natural Science Foundation of China (Nos. 31771102, 31371015, 21675167, U1532119, 31470970, 31371493, and 31571498), the National Basic Research Program of China (Nos. 2013CB932803, 2013CB933802, 2016YFA0400900, and 2016YFA0201200), the Youth Innovation Promotion Association from Chinese Academy of Sciences (No. 2015211), Key Research Program of Frontier Sciences, CAS (Nos. QYZDJ-SSW-SLH019 and QYZDJ-SSW-SLH031).

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