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Cited by 1,112Nanoparticles: synthesis and applicationsCharacterization and Applications of Magnetic NanoparticlesNanoparticle-Based Drug Delivery

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Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION)

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Singh, Neenu, Jenkins, Gareth J.S., Asadi, Romisa, Doak, Shareen H.·2010·Nano Reviews
DOI 10.3402/nano.v1i0.5358PMC PMC3215220
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Abstract

Superparamagnetic iron oxide nanoparticles (SPION) are being widely used for various biomedical applications, for example, magnetic resonance imaging, targeted delivery of drugs or genes, and in hyperthermia. Although, the potential benefits of SPION are considerable, there is a distinct need to identify any potential cellular damage associated with these nanoparticles. Besides focussing on cytotoxicity, the most commonly used determinant of toxicity as a result of exposure to SPION, this review also mentions the importance of studying the subtle cellular alterations in the form of DNA damage and oxidative stress. We review current studies and discuss how SPION, with or without different surface coating, may cause cellular perturbations including modulation of actin cytoskeleton, alteration in gene expression profiles, disturbance in iron homeostasis and altered cellular responses such as activation of signalling pathways and impairment of cell cycle regulation. The importance of protein-SPION interaction and various safety considerations relating to SPION exposure are also addressed.

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Fig. 1 Cellular toxicity induced by SPION. Exposure to SPION could potentially lead to toxic side effects such as membrane leakage of lactate dehydrogenase, impaired mitochondrial function, inflammation, formation of apoptotic bodies, chromosome condensation, generation of reactive oxygen species (ROS) and DNA damage.
Fig. 1 Cellular toxicity induced by SPION. Exposure to SPION could potentially lead to toxic side effects such as membrane leakage of lactate dehydrogenase, impaired mitochondrial function, inflammation, formation of apoptotic bodies, chromosome condensation, generation of reactive oxygen species (ROS) and DNA damage.CC BY-NC · PubMed Central
Fig. 2 Methods of SPION synthesis. Various methods can be employed for the synthesis of SPION with the desired physico-chemical characteristics. These can be also coated with biocompatible molecules either in situ or via post-synthesis methods wherein the uncoated SPION are surface-coated subsequent to their synthesis.
Fig. 2 Methods of SPION synthesis. Various methods can be employed for the synthesis of SPION with the desired physico-chemical characteristics. These can be also coated with biocompatible molecules either in situ or via post-synthesis methods wherein the uncoated SPION are surface-coated subsequent to their synthesis.CC BY-NC · PubMed Central
Fig. 3 Schematic representation of different intracellular uptake pathways of SPION. Possible mechanisms of uptake include passive diffusion, receptor-mediated endocytosis, clathrin-mediated endocytosis, caveolin-mediated internalisation, and other calthrin and caveolin-independent endocytosis (105, 106). Upon internalisation, the SPION may presumably be degraded into iron ions in the lysosomes. This ‘free iron’ can potentially cross the nuclear or mitochondrial membrane and in the latter case the free iron in the form of ferrous ions (Fe2+) can react with hydrogen peroxide and oxygen produced by the mitochondria to produce highly reactive hydroxyl radicals and ferric ions (Fe3+) via the Fenton reaction. Hydoxyl radicals (·OH) generated could indirectly damage DNA, proteins and lipids (8-OH-dG=8 hydroxydeoxyguanosine, MDA=malondialdehyde, HNE=4-hydroxy-2-nonenal).
Fig. 3 Schematic representation of different intracellular uptake pathways of SPION. Possible mechanisms of uptake include passive diffusion, receptor-mediated endocytosis, clathrin-mediated endocytosis, caveolin-mediated internalisation, and other calthrin and caveolin-independent endocytosis (105, 106). Upon internalisation, the SPION may presumably be degraded into iron ions in the lysosomes. This ‘free iron’ can potentially cross the nuclear or mitochondrial membrane and in the latter case the free iron in the form of ferrous ions (Fe2+) can react with hydrogen peroxide and oxygen produced by the mitochondria to produce highly reactive hydroxyl radicals and ferric ions (Fe3+) via the Fenton reaction. Hydoxyl radicals (·OH) generated could indirectly damage DNA, proteins and lipids (8-OH-dG=8 hydroxydeoxyguanosine, MDA=malondialdehyde, HNE=4-hydroxy-2-nonenal).CC BY-NC · PubMed Central
Fig. 4 Preliminary data to demonstrate the effect of dextran-coated SPION on the expression of genes involved in iron homeostasis using real-time RT-PCR. (A) TfR1 and (B) hepcidin. The students’ paired t-test was used to determine if down-regulation proved to be significant change in expression (with error bars representing standard deviation (*P<0.05); as compared to the control where water was used in place of the nanoparticles.
Fig. 4 Preliminary data to demonstrate the effect of dextran-coated SPION on the expression of genes involved in iron homeostasis using real-time RT-PCR. (A) TfR1 and (B) hepcidin. The students’ paired t-test was used to determine if down-regulation proved to be significant change in expression (with error bars representing standard deviation (*P<0.05); as compared to the control where water was used in place of the nanoparticles.CC BY-NC · PubMed Central
Fig. 5 Schematic representation of SPION-induced toxicity at cellular level. SPION may cause direct DNA damage or result in the generation of oxidative radicals that in turn have the potential to cause DNA damage (indirect), have an impact on actin cytoskeleton by modulating the Akt signalling pathway, and also alter the expression of various genes such as those involved in cell cycle regulation, iron homeostasis and pancreatic functioning.
Fig. 5 Schematic representation of SPION-induced toxicity at cellular level. SPION may cause direct DNA damage or result in the generation of oxidative radicals that in turn have the potential to cause DNA damage (indirect), have an impact on actin cytoskeleton by modulating the Akt signalling pathway, and also alter the expression of various genes such as those involved in cell cycle regulation, iron homeostasis and pancreatic functioning.CC BY-NC · PubMed Central

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Cites

Research works printed but not linked: 3

  1. Gould P, 2006, Nano Today, 1, 34
  2. 10.1016/j.biomaterials.2004.10.012 · DOI
  3. Sodum RS, 1988, Cancer Res, 48, 320

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Metadata

Authors
Singh, N., Jenkins, G. J. S., Asadi, R., & Doak, S. H.
Affiliations
  • Swansea University (GB)
  • Cardiff University (GB)
Corresponding author
Singh, Neenu
ORCID
Venue
Nano Reviews
Publisher
Informa UK Limited
Published
2010-01-01
Volume
1
Issue
1
Pages
5358
ISSN
2000-5121 (ISSN-L)
DOI
10.3402/nano.v1i0.5358
PMC
PMC3215220
OpenAlex
W2045080998
Cited by
1,112
References
107
Citations by year
2026: 30 · 2025: 63 · 2024: 69 · 2023: 70 · 2022: 87 · 2021: 109 · 2020: 91 · 2019: 78 · 2018: 92 · 2017: 83 · 2016: 83 · 2015: 92 · 2014: 57 · 2013: 60 · 2012: 33
FWCI
16.82
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Nano Reviews (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Nanoparticles: synthesis and applications
  • Physical Sciences › Engineering › Biomedical Engineering › Characterization and Applications of Magnetic Nanoparticles
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
superparamagnetic iron oxide nanoparticles, nanoparticle toxicity, cytotoxicity, DNA damage, oxidative stress, actin cytoskeleton, gene expression profiling, iron homeostasis, signaling pathways, cell cycle regulation, nanoparticle-protein interactions, surface coating, MRI contrast agents, drug delivery, hyperthermia

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