Skip to main content
SpringerLink
Log in

Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    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.

    Article  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.

    Article  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.

    Article  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.

    Article  Google Scholar 

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

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  Google Scholar 

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

    Article  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.

    Article  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.

    Article  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.

    Article  Google Scholar 

  32. Lewinski, N.; Colvin, V.; Drezek, R. Cytotoxicity of nanoparticles. Small 2008, 4, 26–49.

    Article  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.

    Article  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 signalingassociated metabolic effects of dietary gold nanoparticles in drosophila. Sci. Rep. 2012, 2, 563.

    Article  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 nanocarriermediated generation of highly toxic reactive oxygen species. Nano Lett. 2017, 17, 928–937.

    Article  Google Scholar 

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

    Article  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.

    Article  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.

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  Google Scholar 

Download references

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).

Author information

Author notes

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

Authors and Affiliations

  1. Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201800, China

    Lu Wang, Zejun Wang, Yi Zhang, Min Yin, Jiang Li, Jiye Shi, Lihua Wang, Nan Chen & Chunhai Fan

  2. School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China

    Xiaoming Li & Chunhai Fan

  3. Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Haiyun Song

  4. UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK

    Jiye Shi

  5. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Daishun Ling

Authors
  1. Lu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zejun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haiyun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiye Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daishun Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lihua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chunhai Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nan Chen or Chunhai Fan.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Wang, Z., Li, X. et al. Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism. Nano Res. 11, 2746–2755 (2018). https://doi.org/10.1007/s12274-017-1905-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-017-1905-8

Keywords

Search

Navigation