Ahmad, 2017

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Review
Pitfalls and Challenges in Nanotoxicology: A case
of Cobalt Ferrite (CoFe2O4) Nano-composites
Farooq Ahmad, and Ying Zhou
Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.6b00377 • Publication Date (Web): 24 Jan 2017
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Page 1 of 48 Chemical Research in Toxicology
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4 Pitfalls and Challenges in Nanotoxicology: A case of Cobalt Ferrite (CoFe2O4)
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Nano-composites
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12 Farooq Ahmad †, ǁ*, Ying Zhou †, ‡ *
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15 College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032,
16 China
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19 State Key Laboratory of Metal Matrix Composites, School of Material Science and Engineering,
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21 Shanghai Jiao Tong University, Shanghai, China
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Research Center of Analysis and Measurement, Zhejiang University of Technology, Hangzhou,
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25 China
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28 *Co-Corresponding and co- first author:
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32 Farooq Ahmad and Ying Zhou contributed equally in this Manuscript and will be considered as
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34 co-first author and co-corresponding author as well.
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38 *Farooq Ahmad
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41 College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032,
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43 Zhejiang, China
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45 State Key Laboratory of Metal Matrix Composites, School of Material Science and Engineering,
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47 Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
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50 Tel.: +86 57188320666
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Email: [email protected]
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58 *Ying Zhou
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ACS Paragon Plus Environment
Chemical Research in Toxicology Page 2 of 48
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Research Center of Analysis and Measurement, Zhejiang University of Technology, 18
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5 Chaowang Road, Hangzhou 310032, Zhejiang Province, China.
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8 Tel.: +86 571 88320568
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E-mail: [email protected]
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Abstract
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7 Nanotechnology is developing at a rapid pace with promises of the brilliant socio-economic
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9 future. The apprehensions of vivid future involvement with nanotechnology make the nano
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11 objects ubiquitous in the macroscopic world of humans. Nanotechnology helps us to visualize
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14 the new mysterious horizons in engineering, sophisticated electronics, environmental
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16 remediation, bio-sensing and nanomedicine. In all these hotspots, cobalt ferrite (CoFe)
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nanoparticles (NPs) are the outstanding contestant because of its astonishing controllable
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21 physicochemical and magnetic properties with easiness of synthesis method. The extensive use
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23 of CoFe NPs may easily penetrate into the human body unintentionally by ingestion, inhalation,
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26 adsorption etc. and intentionally instilled into the human body during the biomedical diagnostics
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28 and treatment. After being housed into the human body, it might induce oxidative stress,
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30 cytotoxicity, genotoxicity, inflammation, apoptosis and developmental, metabolic and hormonal
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33 abnormalities. In this review, we compiled the toxicity knowledge of CoFe NPs aimed to provide
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35 the safety usage of this breed of nanomaterials.
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38 Key words: Nano cobalt ferrite, Oxidative stress, Genotoxicity, Apoptosis, Malformation,
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41 Toxicity
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Introduction In the new millennium, innovations in technology boost the modernized human
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6 society with improved health and sanitation conditions. Modern technological innovations are
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8 also closely allied with encroachment in nanotechnology, which are transforming the current and
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future with improved attributes of nano-technological products. Although, the spacious use
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13 because of endless benefits, the nanotechnology is also packed with negative side effects for
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15 human society and health. 1-3
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Among nanomaterials (NMs), magnetic nanoparticles (MNPs) are one of the very vital and
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21 extensively exploited sub category of NMs. MNMs are usually multi-component,
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23 characteristically enclosed with nano-scale magnetic constituents to trigger the response to an
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26 external magnetic field. Thus far, with the rapid development in nanotechnology, novel magnetic
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28 nanomaterials with combination of diverse range of materials such as liquid crystals, gels, self
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30 4-11
healing polymers and silica, carbon or organo-metallic frameworks have emerged. This
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33 enables the utilization of magnetic force for the control of properties and flow of the liquids,
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35 corresponds to plentiful practical applications. 12
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38 Recently, MNPs are overwhelmingly used in sophisticated nano-based medicine, electronics,
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41 environmental remediation, biosensing, medical imaging, improved drug and gene delivery,
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43 nanoprobes, catalyst and optical devices. Above all, in nanomedicine, MNPs are used in
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45 cellular therapy, tissue repair, biosensors, drug delivery, magnetic resonance imaging, magnetic
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47 25-31
48 fluid hyperthermia and solar cells. All these applications oblige elevated magnetization
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50 values of NPs, size of less than 100 nm with homogeneous physical and chemical properties.
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Furthermore, it is indispensible to comprehend the biological as well as environmental fate and
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4 Magnetic Nanoparticles
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Magnetic
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7 NPs
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15 Iron oxide
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17 CoFe NPs
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21 Cobalt ferrite Nanoparticles
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24 Synthesis
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26 Catalyst
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36 Fig.1 Scientific papers published concerning the synthesis and toxicity studies of magnetic and
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39 cobalt ferrite nanoparticles (data from ISI web of science as searched on October. 08, 2016)
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42 prospective toxicity of MNPs for their rumbling appliances in nano-tech based rapid point of
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44 care like in diabetics, pregnancy testing, electrolyte and blood analysis, cardiac marker, cancer,
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46 16, 27, 28, 33
47 drug abuse and infectious disease diagnostics and lot more. For example, magnetic
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49 nanofluids effectively reduce tumor progression in the cat mammary glands. 34 In the last decade,
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51 magnetite (Fe3O4) was the most investigated MNPs because of easier to synthesis and having
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54 much control over their physicochemical properties. 26
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Cobalt-ferrite (CoFe) NPs belongs to the crystal family of spinal ferrites (MFe2O4) and are the
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6 most prevalently exploited NPs in nanomedicine. These NPs are considered superlative to be
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8 exploit in nanotech, because of comparatively larger coercivity (~5 kOe), permeability,
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reasonable magnetic saturation (~80emu), chemical stability, mechanical hardness, high
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13 electromagnetic and magneto-optic performance and tunable magnetic properties at the
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atomic level. Therefore, CoFe is a talented contestant material for high-density magnetic
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18 recordings, ferrofluids, drug delivery,39 magnetic resonance imaging (MRI), cancer treatment
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20 and in magneto-optical devices. 14, 25, 36, 40
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23 Up to October 08, 2016, more than 19800 studies on iron oxide NPs, which the number of papers
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26 published on cobalt ferrite NPs were more than 1700 and only 37 papers had discussed the
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28 biological effects of CoFe NPs had been published (Fig.1). This number is far more less as their
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30 main area of application is in the medicine as illustrated above. Since, all above mentioned
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33 features make CoFe NPs outstanding and remarkable candidates for biomedical applications, but
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35 the release of higher amounts of cobalt and iron, agglomeration/aggregation and reduced surface
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37 functionality by diverse collection of coating materials (bio-macromolecules) and higher toxicity
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40 limits their use in biomedical applications. The good news is that these hitches can be conquered
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42 by surface fashioning of CoFe NPs with attuned, non-hazardous, and water-stable/dispersing
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material.38 Coating of Oleylamine over the CoFe NPs significantly reduces their toxicity in
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47 healthy cells (MRC5 and dental MSCS) as compared to the cancerous cells (HeLa and A549). 41
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50 Broad spectrum applications of CoFe NPs ranges from cancer therapy, drug delivery, magnetic
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recording material and in transducers necessitate the fabrication of mono-dispersed and
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55 homogenous physicochemical properties. 39, 42
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Fig. 2 Shows physicochemical properties, synthesis method and possible applications of Cobalt
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40 ferrite nano-composites.
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43 Synthesis methods play very important role in undermining the toxicity of NPs as it controls the
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cation distribution, physicochemical properties and presence of residual reagents. CoFe NPs can
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48 (Fig.3) be manufactured by four different ways, i-e.; co-precipitation method, conventional
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50 hydrothermal, micro emulsion and sol-gel method. But the most used method is co-precipitation
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53 method, because of its simplicity, use of less hazardous chemicals with stable mono-dispersed
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55 suspension, uniform size distribution and better magnetic properties for safe use in
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57 nanomedicine.43 The details of the different synthesis routes and their respective advantages and
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disadvantages are out of the scope of the review, but the readers may find different methods of
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6 synthesis in elsewhere. 44-57
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9 Doping of CoFe NPs with some other metal oxides (e.g., Zn, Ni, Cu, Mn or Cr) significantly
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11 enhance the magnetic, chemical, hyperthermia and antibacterial characteristics.25, 43 The reason
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14 for improved antibacterial property lies in the fact that doping results in the CoFe NPs with
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16 irregular shape with sharp edges are more lethal than the round shaped counterparts. Doping with
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copper yields the most lethal CoFe NPs composites, but again it also depends on the specie of
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21 test model. 25 Folic acid (FA) fabrications of CoFe NPs generate mono-dispersed with enhanced
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23 peroxidase activity of NPs. Such FA fabricated CoFe NPs can be exploited in tagging HeLa cells
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26 (folate receptors) from NIH-3T3 cells (without foliate receptors).35 The FA fabrication also
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28 enhances the targeted drug delivery potential of CoFe NPs. Alcantara et al (2011) reported the
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30 attachment of methotrexate and doxorubicin (anti-cancer drugs) with FA conjugated CoFe NPs
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29 Fig. 3 Characterization of Co-Fe NPs by TEM images prepared by co-precipitation method. (A)
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Bright field image, (B) dark field image, (C-D) high resolution images, inset- magnification of
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34 single particle. Reprinted from Limor Horev-Azaria, Giovanni Baldi, Delila Beno, Daniel
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36 Bonacchi, Ute Golla-Schindler, James C. Kirkpatrick, Susanne Kolle, Robert Landsiedel, Oded
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39 Maimon, Patrice N. Marche, Jessica Ponti, Roni Romano, François Rossi, Dieter Sommer,
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41 Chiara Uboldi, Ronald E. Unger, and, C. V., and Korenstein, R. (2013) Predictive Toxicology of
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43 cobalt ferrite nanoparticles: comparative in-vitro study of different cellular models using
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46 methods of knowledge discovery from data. Part. Fibre. Toxicol. 10, 1-17.
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48 (https://particleandfibretoxicology.biomedcentral.com/articles/10.1186/1743-8977-10-32).32
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51 Toxicity of nano-CoFe
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55 Toxicity of nano-CoFe on respiratory system
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During the course of fabrication, circulation, exploitation and recycling, nano-CoFe is easy to
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6 spread into the air. Therefore, industrial or commercial CoFe NPs might be fall into one of
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most familiar route of CoFe NPs to enter human body, there was also a possibility that nano-
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13 CoFe did impairment to respiratory system. Respiratory tract and intravenous system became the
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18 there were a lot of studies that paid attention to this significant problem. Mechanographic
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20 investigation of guinea pig airways evidenced that powdered nano-CoFe with size of 5-20 nm
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22 (0.5mg/ml) meticulously compromised the functionality of normal contractile job of trachea and
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25 major bronchi, measured by Musson-1M ultrasonic nebulizer (OJS Altay Instrumental Factory
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27 Rotor) at the rate of 30-min per day for 4 days. Mechanical function disability of the respiratory
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system advocated the both in vitro and in vivo inhalation of powdered nano-CoFe abruptly
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32 augment the contractile amplitude of the air passage ways which put an immense force on the
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34 delicate respiratory membranes terrorizing the bursting of them. This results in dwindled surface
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37 area and abridged body oxygen leading to hypoxia condition. This hypoxia condition if sustains
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39 longer than norm escorts to cell death in different parts of the body. In addition, presence of
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nano-CoFe elicits the disproportionate discharge of histamine and adrenergic salbutamol. But
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44 this study did not provide any information regarding the coating material and zeta-potential of
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46 used CoFe NPs. Moreover, the exposure concentration (0.5mg/ml) used in this study was even
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48 higher than to be used for MRI imaging,61, 62 which make results ambiguous and redundant. In in
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51 vitro respiratory toxicity after exposure for 24-72 hours of pristine CoFe NPs (10 nm) at 23.5-
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53 282.5 µg/ml dosage, was measured by the Alamar blue, MTT and neutral red assays. These
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assays clearly presents that CoFe NPs cause severe oxidative stress to the respiratory system in
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the order; lung slices from rat>NCIH441 cells>A549 lung cells. 45The results also confirmed that
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6 sensitivity to different NPs also varies among different types of cell lines. 32, 63 This indicates that
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8 nano-CoFe not only disrupt the normal functionality of respiratory system by compromising the
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alveolar membranes mediated by oxidative stress and inflammation but can also reach into the
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13 different vital parts of the body e.g., liver by circulatory system.
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16 Toxicity of nano-CoFe on Skin
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19 The route of exposure is very important in predicting the possible toxicity of NPs and skin is one
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22 of the major portals of entry for NPs into the human and animal bodies. Disease states such as
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24 atopic and contact dermatitis, acne, seborrheic dermatitis, inflamed skin and psoriasis can make
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the skin more permeable. In addition, simple acts such as shaving or injuries such as sunburns,
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29 cuts, or scrapes can increase cutaneous permeability. NPs in undergarments or skin care
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31 products may enter into the female reproductive tract and incite alterations of the reproductive
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lining. Thereafter, they may circulate to the entire body through the circulatory system of the
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36 animals or humans. 64 Well there are also evidences that NPs may not give harm to the skin but
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38 may penetrate and accumulate into the stratum corneum by photohydrolysis, which in turn
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41 increases the risk of higher circulatory metal ions (M+n) in the blood and other system organs
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43 such as kidney and liver. A recent in vitro study contradicted the above report and revealed
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45 that bare CoFe NPs with size of ~27nm when exposed to human keratinocytes cells (HaCaT) at
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48 0.5,1, 2 and 4 mg/mL concentration caused the toxicity in a dose dependent way. Prussian blue,
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50 MTT and apoptosis assays showed very moderate toxicity at 2mg/mL, while the metabolic
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analysis showed that even at the moderate toxic concentration of 2mg/mL; CoFe NPs induces the
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55 oxidative stress by elevation in cellular alanine, taurine, ethanol and succinate levels and
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4 decrease in isoleucine in human keratinocytes cells (HaCaT). The elevation in the alanine level is
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7 connected with apoptosis.68 While the decrease in isoleucine indicates the cellular energy
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perturbations incited by CoFe NPs exposure. The leucine and isoleucine are branched-chained
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12 and most abundant essential amino acids. Among essential amino acids, leucine is involved in
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14 protein synthesis and degradation, leptin secretion, energy-balance regulation, and so on. Valine,
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17 leucine, and isoleucine biosynthesis pathway can supply the TCA cycle with various anaplerotic
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19 substrates including α-ketoisocaproate, which can be further metabolized to acetyl coenzyme A
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21 and acetoacetate. 68, 69 Fe3O4 NPs with size of 65nm induce toxicity in human dermal fibroblasts
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24 (HDF) and cells of the squamous tumor cell line (SCL-1) , oxidative stress was build up inside
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26 the cells by the excessive generation of reactive oxygen species (ROS) leading to the instigation
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28 of lipid peroxidation process. 70
In another study, polygonal smooth surfaced Fe3O4 NPs with
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31 size of 25nm at concentrations of 25-100µg/mL induces dose dependent cytotoxicity and
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33 apoptosis in skin epithelium A431 cells after 24 hours of exposure. Dose dependent oxidative
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stress was evident by the depletion of glutathione and elevation of ROS and lipid peroxidation. 71
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38 Interaction of nano-CoFe with U87MG cells evidenced by synchrotron radiation X-ray
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40 fluorescence illustrated the significant reduction in the viability of these cells. In fact, these NPs
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43 were also accumulated into the cytoplasm near the perinuclear region and compromised the
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45 nuclear membrane. 72
Red-allotrope selenium NPs (rSeNPs) with size of 123.5±33.6 nm
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49 exposed to head and neck squamous cell carcinoma (HNSCC) and human dermal fibroblast
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51 (HDF) cells at concentrations ranging from 0.01 to 100 µg rSeNP/mL media, decrease the
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53 viability of HNSCC and HDF cells with severe inculcation of apoptosis. These rSeNPs also have
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56 higher tendency to accumulate near the lysosomal and mitochondrial region of HNSCC and HDF
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cell lines and believed to persuade the possible energy perturbations leading to the apoptosis.73
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6 Exposure of HaCaT cells to 10µg/ml of tannic acid modified 13 and 33 nm AgNPs led to a
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8 significant rise in the production of ROS in comparison to control and the activation of
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phosphorylated ERK pathway.74 This is the very good indicator of not only the cellular stress
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13 but also perturbed the cellular viability and proliferation (decrease in Ki-67 percentage).74, 75
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15 Therefore, NPs not only use the skin as a transport route to enter into the body but also provoke
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18 oxidative stress (by excessive ROS generation), apoptosis and isoleucine based energy
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20 imbalances. This also leads to the imbalance of Ca+2 transports, alteration in metabolism and
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22 excretory function of normal skin. These all dreadful things may also (1) leads to the increased
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25 chances of skin damage with and without photocatalysis, (2) makes the skin pores wide open
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27 providing the gateway of entry for the various ambient pathogens and contaminants into the body,
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from where they may transport to the different parts of the body and foster the cultivation of
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32 complex diseases.
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35 Toxicity of nano-CoFe on liver and kidney
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38 Once the NPs housed into the animal body either intentionally or unintentionally, they would be
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41 distributed into the whole body through the circulatory system. Liver is the vital organ of the
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43 body involved in the detoxification and production of digestive biochemicals, which will be the
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45 core distribution site for CoFe NPs. In addition, nano-CoFe can reside for longer duration inside
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48 the liver and cause inflammation leading to disturbances in liver functionality. In vivo (whole
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50 animal, mice) after intravenous injection and in vitro (Hep3B cells) study reported that
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rhodamine B isothiocyanate coated with silica shell nano-CoFe exhibit substantial liver
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55 accumulation. In mice, the CoFe NPs were accumulated 50 times more than the normal one and
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57 the target site is the vesicle like spaces in cytoplasm.76 MTT assay confirmed, nano-CoFe
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divulged ruthless cytotoxic effects mediated by oxidative and metabolic perturbations directly
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6 dependent on dosages and treatment times in liver. In addition to oxidative and metabolic stress,
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8 carcinogenesis and inflammation and growth arrest in liver cells were very prominent
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phenomena's observed after nano-CoFe exposure. As the liver is the focal clearing house of the
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13 animal body, so the compromised functionality of the liver results in perturbed metabolic activity
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15 and body become the waste house for harmful metabolites. Furthermore, the hemotoxylin and
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18 eosin staining revealed that CoFe NPs causes deformation of nuclei in the viable cells. CoFe
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20 NPs also induce extraordinary cytotoxicity and oxidative stress in HepG2 cell-line (liver),
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22 MDCK cell-line (kidney) and Caco-2/ TC7 cell-line (intestine). Caco-2/ TC7 and MDCK cell-
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25 lines are more vulnerable to CoFe NPs as compare to HepG2 cell-line (liver), indicating the
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27 compromised major cleaning route of toxicants out of body. 32 In in vitro accumulation of nano-
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CoFe in cancer cells (MiaPaCa2) of human liver illustrates moderate toxicity on the basis of their
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32 viability and proliferation index, however disparity in response to nano-CoFe were incredibly
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34 diverse from cell to cell lines of same and different organisms belongs to diverse intricate system
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37 organization.78 The fate of liver accumulated CoFe NPs was further assessed in invertebrate
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39 terrestrial isopod (Porcellio scaber) model, the results showed those gastric juices of Porcellio
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41 scaber biodegrade the CoFe NPs into Co+2 and Fe+3 ions. In addition Co+2 ions accumulated in
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44 comparatively high concentration inside the hepato-pancreas compromising the structure and
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46 normal functionality, also released Co+2 ions are substantially more toxic than Fe+3 and CoFe
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48 NPs. What is more, the accumulation of Co+2 ions are also the main precursor of genotoxicity.79
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51 Another study revealed that in vivo investigation of polyol coated zinc doped cobalt ferrite
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53 (Zn0.8Co0.2Fe2O4) NPs with size of 8nm in New Zealand rabbit showed excessive accumulation
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in liver and kidney leads to inflammation with 50% increase in WBCs, granuloma and multiple
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congestions. These toxic effects comes from the NPs itself and not from the release of metal
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6 ions,80 which is clear contradiction with the study of Novak et al.79 But the drawback of this
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8 study is, they did not observe the dissolution behavior of (Zn0.8Co0.2Fe2O4) NPs inside the
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specific cells that is why we do not know the actual reason of contradiction with the previous
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13 study. Zirconia nanoparticles (ZrO2NPs) with 20nm size at dosage of 0.1 mg/ml leads to
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15 increase in creatinine content, congestion and destruction of the glomerular capsule space in
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18 wistar rats.81 From what we have listed above, nano-CoFe not only accumulate into the vital
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20 detoxifying organs of the body but also cause oxidative stress, cancer and complete destruction
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22 of the internal structure of liver as well as kidney. This may also leads to inhibit the excretion of
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25 harmful toxins and metabolites from the body and accumulates in higher concentrations among
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27 various organs and sites of the body at dangerously excessive levels causing cell deaths, joints
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degeneration and impairment etc..
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33 Toxicity of nano-CoFe on reproductive system and embryo development
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36 The adsorption leading to internalization of CoFe NPs into cells or organs results in the
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38 biodistribution and biodegradation through circulatory system and biological enzymes
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41 respectively. Internalization and accumulation of CoFe NPs inside the cells induces
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43 physicomechanical destruction of sub-cellular organelles and to delicate biological membranes.
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45 In vitro acute toxicity (5 day) profiling of nano-CoFe to embryonic stem cells (ES-D3) illustrates
46
47
48 pristine nano-CoFe were relatively more toxic compared to Gold (Au) or silane coated CoFe NPs
49
50 and cause cytotoxicity leading to abnormal cellular differentiation process. 82 The mechanism of
51
52
endocytosis of nano-CoFe in Chinese hamster ovary was corresponded by macropinocytosis
53
54
55 (membrane ruffle) and clathrin mediated routes in a time dependent way. CoFe NPs occupied
56
57 almost all the intracellular space of Chinese hamster ovary cells within 24 hours of exposure. In
58 15
59
60
1
2
3
addition, no excretion of nano-CoFe was observed even after 24 hours of accumulation. This
4
5
6 illustrates accumulation of nano-CoFe leads to the impairment of excretory role of hamster ovary
7
8 cells either by blocked or destructive excretory system.83 Accumulation of nano-CoFe into
9
10
11
human ovary cancer cell lines (A2780) exhibited severe cytotoxicity leading to death of cells. In
12
13 addition, exposure of nano-CoFe at higher concentration illustrates the decreased clonogenicity
14
15 and epithelial cell adhesion,78 with most probable cytotoxicity driving forces involved were
16
17
18 disturbed cellular iron balance, perturbations in multiple cellular signaling pathways, DNA
19
20 damage, oxidative stress, mechanical destruction of cytoskeleton with accompanying changes in
21
22 gene expression.84 Recently it is also reported that polyol coated zinc doped cobalt ferrite
23
24
25 (Zn0.8Co0.2Fe2O4) NPs also reduces the viability of Human Umbilical Vein Endothelial Cells
26
80
27 (HUVECs) and hence leads to premature abortion. Spermine coated cobalt ferrite NPs also
28
29
proved effective in curing the human breast cancer MCF-7 cell line compared to the Fe3O4 NPs,
30
31
32 it is because of the higher hyperthermia and coercivity induced by the combining the magnetic
33
34 constituent (Co) with Fe3O4.85 Meanwhile, recent studies revealed that in vivo exposure of CoFe-
35
36
37 NPs induce developmental malformations like arrested development, absence of head and late
38
39 eyes spot development, finfold abnormality and tail flexure with absence of tail extension,
40
41 cardiac malformation/ pericardial edema, yolk sac edema and spinal cord abnormality in
42
43
44 developing Zebrafish embryos in a time (96 and 168 hpf) and concentration dependent way.
45
46 CoFe NPs also put mechanical pressures by adhering to the external chorion, blocking the air
47
48 passage ways posing sever hypoxia condition. In addition, CoFe NPs cause serious oxidative
49
50
51 stress by excessive ROS generation compromising the antioxidant defense systems and
52
53 aggravation of apoptosis. These developmental malformations and oxidative stressors were
54
55
56
further corresponds to thyroid endocrine disruptions and sever DNA damage.13, 86 Moreover,
57
58 16
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3
nano-CoFe potential of inducing oxidative stress, accumulation, alter the cell signaling, DNA
4
5
6 damage in the reproductive system leads to abnormal development of fetus, premature abortions,
7
8 genetic mutations with a possible transfer to the next generations leads to the impairment of the
9
10
11
organ systems and improper development, and poses the more serious threats to the life of
12
13 mother during pregnancy.
14
15
16 Toxicity of nano-CoFe on central nervous system
17
18
19 The significance of studying the harmful effects of NPs on nervous system can be understood by
20
21
22 the fact that brain is the most crucial organ of the body involved in regulation, communication
23
24 and homeostasis in response to internal and external changes, neuron and glial cells, organized in
25
26 30
specialized structures, cooperate to allow the articulated functions provided by the brain.
27
28
29 Recently, the CoFe NPs are extensively utilized in in vivo use, so there is a pressing need to
30
31 know about the long and short term exposure effects of these NPs on the nervous system, but
32
33
34
unfortunately this information is still lacking. The NPs may also enter the animal neural network
35
36 through skin (commercial exposure of CoFe NPs) and most probably by circulatory system
37
38 (intravenous injection) trans-synaptic transport and by crossing the blood brain barrier (BBB).87
39
40
41 However, the neural toxicological effects can be predicted from analogous studies of particulate
42
88
43 matter (PM) for long and short term exposure. For example, the well studied oxidative stress
44
45 paradigm is the root of various diseases like hyperglycemia, cardio vascular disease, cancer,
46
47
48 neuro-degeneration and pulmonary disorder etc.88-91 It is also well known that metal ions (Fe+3,
49
50 Co+2, Zn+2, Mn+2 etc.) accumulation leads to multiple neurodegenerative diseases including
51
52
Parkinson and Alzheimer disease.91-93 The deregulation of metals in the body leads to the
53
54
55 overloading of metal ions in the brain or other body parts consequently results in impairment of
56
57 nervous system.94 Iron has traditionally thought to cross the blood-brain barrier (BBB) by
58 17
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60
1
2
3
multiple routes like transferrin-mediated route through the capillary endothelium,
4
5
6 circumventricular or olfactory nerves. Additionally, ferrtin is also act as an auxiliary protein for
7
8 95
iron transport. It has also reported that iron and cobalt could generate the ROS within brain
9
10
11
synapses and interfere with transduction of neurotransmitters96-98 as well as compromised the
12
13 normal functioning of neuron protection proteins e.g., prions and melatonin, causing the sever
14
15 91, 93
hypoxia in hippocampus. It is also reported that nano-CoFe can cross the sensitive neural
16
17
18 membrane and accumulate inside the SH-SY5Y neural cells instigating the necrosis process.99
19
20 Even though nano-CoFe have the potential to induce the damage to the CNS but still there are
21
22 lake of studies explaining the mechanisms of toxicity induced by this breed of NPs.
23
24
25
26 There is a natural fact that brain is highly vulnerable to oxidative stress and requires metal ions
27
28 (Fe+3, Co+2) in a balanced amount for its high respiratory activity, as well as generation of
29
30 numerous neurotransmitters and myelin development. All these activities make the brain highly
31
32
33 vulnerable to the slight imbalances in oxidation equilibrium and lead to the neurodegeneration
34
35 and associated disorders. 88
36
37
38 Toxicity of CoFe NPs on Immune system
39
40
41
42
Peripheral blood system is also very important for healthy animal body as it protects the body
43
44 from foreign pathogens. If the peripheral blood system stopped working or damaged by any
45
46 means directly shortens the life span of that animal. Nano-CoFe (~5.6 nm) showed significant
47
48
49 (p<0.05) down and up regulation of cytokinesis blocked proliferation index (CBPI) and micro
50
51 nucleated binucleated lymphocytes (BNMN) indices, respectively. While nano-CoFe with sizes
52
53 of 10 and 120nm significantly (p<0.05) up regulate the micro nucleated binucleated lymphocytes
54
55
56 (BNMN) index in the size dependent way. It is further investigated that up regulation of micro
57
58 18
59
60
1
2
3
nucleated binucleated lymphocytes (BNMN) is associated with greater release of Co+2 ions. 100
4
5
6 CoFe NPs also induce oxidative stress and cytotoxicity in TK6 (lymphoblasts) and primary
7
8 mouse dendritic-cells. While TK6 (lymphoblasts) are more susceptible to lost their functionality
9
10
11
by cytotoxicity and oxidative stress compared to primary mouse dendritic-cells.32 These results
12
13 also indicate the higher vulnerability of humans immune system towards CoFe NPs compared to
14
15 other animals.
16
17
18
19
The metallic NPs upon interaction with cellular components generate excessively high levels of
20
21 reactive oxygen species (ROS) leads to the pro-inflammatory responses.101 ROS perturbations
22
23 are the main contributing factor in modulating the immune responses.102 Comparative
24
25
26 immunotoxic responses of Ag, ZnO and TiO2 NPs induce respiratory immunity through
27
102, 103
28 oxidative stress, elevated cytokine secretion and dysregulation of cytokines network.
29
30
31 Aluminum oxide (Al203) NPs of higher aspect ratio (long-type: 6.2 ± 0.6) and low aspect ratio
32
33
34 (short-type: 2.1 ± 0.4) with same size and charge after single intravenous injection (i.v) rapidly
35
36
37
38
bioaccumulated in liver and spleen after 14 days of injection in wistar rats and induces severe
39
40 oxidative stress. In addition, long and short type Al2O3 NPs both enhanced the levels of IL-1β,
41
42 IL-8 and MCP-1 in the blood of mice. Furthermore, after injection of long shaped Al2O3 NPs
43
44
45 (5mg/kg) leads to the increase in the percentages of neutrophils and monocytes among the WBCs.
46
104
47 CdSe/ZnS quantum dots (QDs) with concentration of 1.25 and 2.5 nM notably decreases the
48
49 cell viability, elevated the ROS production, increased apoptotic events and perturbations in
50
51
52 phagocytic ability with limiting release on TNF- and IL-6 in macrophages leading to overall
53
54 suppression of immune responses. In addition, these QDs were accumulated in the major
55
56 immune organs for more than 42 days.105 In addition to the physicochemical properties of
57
58 19
59
60
1
2
3
NPs/NMs such as size, charge, surface chemistry and crystal structure etc.106, impurities during
4
5
6 chemical synthesis and protein corona formation are some of the factors which control and
7
8 impact the immunotoxicity of NPs/NMs107 and should be discussed in detail especially for
9
10
11
immunotoxicological studies.
12
13
14 It is also very important to note that NPs/NMs may induce both phenomena of suppression and
15
16 activation of specific immune cells i-e., immunoregulatory and immunosuppressive cells. As
17
18
19
mentioned above, the most prominent mechanism is ROS generation but still need further
20
21 elaborations to unveil the other additional mechanisms of immunotoxicity and possible link with
22
23 physicochemical properties of NPs/NMs.
24
25
26
Toxicity of nano-CoFe on biomembranes and biomolecules
27
28
29
30 When NPs come in contact with membranes they may attach to the membranes and induce
31
32 notable mechanical damage to the membranes. The damage to membranes depends on the type,
33
34 coating and agglomerated state of the NPs. Guglielmo et al. reported that citric acid coated nano-
35
36
37 CoFe are comparatively less damaging towards artificial and biological membranes than pristine
38
39 46, 82
by oxidation. Also the CA-coated CoFe NPs severely compromised the shape of red blood
40
41
42
cells and hence the oxygen carrying ability of that RBCs. Due to paramagnetic property of nano-
43
44 CoFe, they rapidly undergo agglomeration/aggregation and induce hefty mechanical effects.
45
46 Larger agglomerates of NPs were confirmed to be reactive against lipid membranes and thus not
47
48
49 acceptable for use with red blood cells. This finding is significant with respect to the efficient
50
82
51 and safe application of NPs as medicinal agents. Animal body is the house of lot of
52
53 biological(macro)molecules, whose functionality largely confined into the specific structure of
54
55
56 biomolecules. It is reported that NPs undergoes into the direct interaction with biological
57
58 20
59
60
1
2
3
macromolecules i-e.; carbohydrates, lipids and proteins, poison them by blocking the active sites
4
5
6 and induce transformations in their functional conformation.108-110 Fluorescence quenching study
7
8 of bovine serum albumin (BSA) by citric acid (CA) coated CoFe NPs (16nm) illustrated,
9
10
11
CA@CoFe NPs make complex with tryptophan residues results in reducing its ability to direct
12
111, 112
13 exposure to substrate. It is also confirmed by the latest study that nano-CoFe severely
14
15 disrupt the normal functionality of serum albumins by making strong hydrogen bonding and
16
17
18 protein corona formation with notable decrease in its esterase activity. Furthermore, this protein
19
20 corona formation also introduces unbearable physicochemical modifications in the nano-CoFe.
21
22 113
But again these studies were conducted in a far less complex biological environment as
23
24
25 compared to the actual environment of cells or within organism, where NPs experiences more
26
27 diverse range of interactions. Another study conducted by our group shed light on the fact that
28
29
nano-CoFe have a great potential to disturb the kinetics of one of the most important enzyme in
30
31
32 living systems called Acid phosphatase (ACP). Increased value of Michaelis constant (Km),
33
34 reversed direction of enzymatic Velocity (Vm) and boost in activation energy of ACP (extracted
35
36
37 from Chlorella vulgaris and used without further purification) further illustrates the danger
38
39 associated with utilization of nano-CoFe medicine. 114
40
41
42 CoFe nanocrystals (NCs) also undergo electrostatic interactions with the most important and
43
44
45
abundant oxygen carrying protein i-e.; hemoglobin. This uninvited interaction with hemoglobin
46
47 severely hitches the oxygen carrying ability by transformation in the structure. In addition to
48
49 electrostatic attractions, adsorption of hemoglobin@CoFe NCs also played very crucial role in
50
51
52 biomolecule conformation transformation.112 Furthermore, nano-CoFe induce ROS mediated
53
54 oxidative stress and leads directly to alterations in biomembranes and biomolecules. If this
55
56
57
58 21
59
60
1
2
3
situation persists for a longer period of time, may leads to cell death and introduce various blood
4
5
6 diseases e.g., hemophilia or sickle cell anemia etc.
7
8
9
10 Dermal Inhalation
11
12 Exposure
13 Route
14
Injection Ingestion
15
16
17 Nano-
CoFe2O4
18
19
20
21
22 Brain
23
24
Skin
25
26
Lungs
27
28
Liver Kidney
29
30
Spleen
31
32
Blood
33
oxidative stress
34 Bio-
molecule
35 Genotoxicity
36
37 Apoptosis
38
39
40
41
42
43 Fig. 4 An overview of nano-CoFe2O4 mediated toxicity in different organ and organ systems.
44
45
46 Genotoxicity of nano-CoFe
47
48
49 The fate and genotoxicity of nano-CoFe at single cell level was examined in Balb/3T3 cells. At
50
51 nominal concentrations of nano-CoFe, CoFe NPs set aside in the perinuclear moiety retaining
52
53
54 their initial chemical content. While at higher concentrations of nano-CoFe, change in cellular
55
56 morphology due to destruction of cytoskeleton, metabolism and membrane damage. In addition,
57
58 22
59
60
1
2
3
magnetic NMs also severely degrade the metabolic and oxidative defense machinery of aquatic
4
5
6 animals.115 Cellular nuclear materials also biodegrade the native chemical structure of nano-
7
8 CoFe into its constituent ions and tends to high accumulation of Co ions in the nuclear region. 116
9
10
11
Recently, it is reported that CoFe NPs elevates the mutagenic glutathione-s-transferase (mu-GST)
12
13
13 level in developing Zebrafish and Chlorella vulgaris,37 indicating the mutagenic
14
15 transformation of the major antioxidant defense system. It is also reported that CoFe NPs also
16
17
18 severely affect the spatial orientation of double stranded DNA in in vitro, including the complete
19
117
20 lose of optical activity with the complete destruction of three dimensional structure. CoFe
21
22 NPs develop strong interactions with the phosphate groups and oxygen atoms of heterogeneous
23
24
25 bases (thymine and guanine) of DNA with coordinate covalent bond. 118, 119 In the result of nano-
26
27 biocomposite formation leads to the adsorption of DNA on the surface of the CoFe NPs, reduces
28
29
it content in the solution. The limited free availability of DNA significantly reduces the
30
31
32 efficiency of endonuclease (DNase I) from enzymatic cleavage of DNA.120 Another possible
33
34 reason for this alteration in functionality by adsorption is the transformation of spatial structural
35
36
37 orientation of the DNA due to which endonucleases did not recognized their target. The intricate
38
39 cleavage pattern point towards that several local as well as global helix parameters influence the
40
41 121
cutting ability and frequency of DNase I at a given bond. A variety of gene (52 genes)
42
43
44 expression profiles, after intravenous and tail injection of magnetic-core NPs in mice were
45
46 elucidated by Real-time polymerase chain reaction (RT-PCR). RT-PCR array demonstrated that
47
48 17 genes were significantly affected, mostly in relation to DNA damage or repair (Atm, Rad23a,
49
50
51 and Rad50), apoptosis (Anxa5 and Fasl), carcinogenesis (Ccnc, Ccnd1, and Ccng1),
52
53 inflammation (Cxcl10 and Il18), oxidative stress (Gpx2, Gsr, Mt2, Cyp4a10, Cyp4a14, and Por),
54
55
56
or growth arrest (Igfbp6).77 A recent study also confirmed the genotoxic potential of nano-CoFe
57
58 23
59
60
1
2
3
in various mammalian cell lines, liver (HepG2), colon (Caco-2), lung (A549), and neuron
4
5 99
6 (SHSY5Y) cells and this genotoxicity effect comes from the NPs itself. So, these all studies
7
8 gives a red signal by using of Cobalt ferrite NPs can transfer the mutated genetic material to the
9
10
11
next generations with significant amount of deformations of various kinds.
12
13
14 Toxicity of doped CoFe NPs
15
16
17 With the passage of time and keeping in mind the extraordinary sophistication and complexity of
18
19 human body we need to develop the nano-platforms with attributes of multiplexing i-e.,
20
21
22 simultaneous drug/gene delivery with improved diagnostic imaging strategies. To fulfill such
23
24 sophisticated aims we need to fabricate the NPs with different kinds of simple or complex
25
26
inorganic (heavy metals , non metals or rare earth metals) and organic materials with increased
27
28
29 biocompatibility, stability and with reduced health risks.122 The magnetic properties vary with
30
31 the addition or substitution with rare earth content reaching maximum values for coercivity and
32
33
34
saturation magnetization below 0.1 RE content with excellent heat generating ability and
35
36 promise to be used in hyperthermia treatment. The specific adsorption rate varies similar to
37
38 coercivity and saturation magnetization for Dy and Gd doped samples and opposite for Yb doped
39
40 123
41 samples, most likely due to average crystallite size exceeding 20 nm. CoFe NPs doped with
42
43 Zirconium (Zr) show improved magnetic characteristics,124 gold decoration of CoFe NPs gives
44
45 better catalytic properties,125 Zn substitution gives improved magnetic, in vitro and in vivo
46
47
48 imaging and hyperthermia properties,61,126,127 with coating of exfoliated graphene oxide gives
49
128
50 better amperiometric sensing of NADH and H2O2 and improved antibacterial activity in
51
52
multidrug resistant bacteria. 129 But at the same time these fabrications with inorganic or organic
53
54
55 constituents also may confined with specific kind of toxicity along with them. So, we have to
56
57 carefully investigate and evaluate such abnormal behaviors and outcomes with great care. The
58 24
59
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1
2
3
antibacterial activities of the transition metal-substituted cobalt ferrite NPs against E. coli and S.
4
5
6 aureus have shown in Fig. 5. Copper NPs after incubation with E.Coli compromise the cell
7
8 membrane integrity by adhering and degrading the bacterial cell wall and penetrate through the
9
10
11
cell membrane130 into the bacteria, induces degradation and lysis of cytoplasm followed by
12
13 death.131-132 For the zinc NPs system, zinc binds to the membranes of
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32 Fig. 5. Antibacterial activities against E. coli and S. aureus of synthesized transition metal-substituted
33
34 cobalt ferrite nanoparticles: (a) without cobalt ferrite nanoparticles, (b) CoFe2O4, (c) Co0.5Cu0.5Fe2O4, (d)
35
36
37
Co0.5Zn0.5Fe2O4, (e) Co0.5Mn0.5Fe2O4 and (f) Co0.5Ni0.5Fe2O4. Reprinted from Acta Biomater., Vol. 9,
38
39 Sanpo, N., Berndt, C. C., Wen, C., and Wang, J., Transition metal-substituted cobalt ferrite nanoparticles
40
41 for biomedical applications, Pages 5830-5837, Copyright 2013, with permission from Elsevier. 25
42
43
44
45
46
47 microorganisms, similar to mammalian cells, prolonging the lag phase of the growth cycle and
48
49 133
50 increasing the generation time of the organisms. Another proposition maintained, the main
51
52 chemical species contributing to the occurrence of the antibacterial activity is reactive oxygen
53
54 species (H2O2, O2-), generated from the surface of the zinc doped ferrites. 134 These active oxides
55
56
57 played very important role in killing the microorganisms by readily penetrating the cell wall of
58 25
59
60
1
2
3
bacteria and cause cell destruction. 135 Moreover, the orientation and spatial arrangements of Zn
4
5
6 and O also leads to the specie specific toxicity. Zinc atoms at outermost layer (ZnO−Zn) showed
7
8 a more pronounced antibacterial effect towards gram-negative E. coli (Escherichia coli), whereas
9
10
11
oxygen atoms (ZnO−O) at outmost layer showed a stronger antibacterial activity against gram-
12
13 positive S. aureus.136 This is also due to the possible strong interactions of specific element with
14
15 the constituents of specific type of cell wall. The E. coli cell wall consists of lipid A,
16
17
18 lipopolysaccharide and peptidoglycan, whereas that of S. aureus consists mainly of
19
20 peptidoglycan. The results indicate that active oxides generated from transition metal-substituted
21
22 cobalt ferrite have more capability to penetrate the cell wall and decrease the cell division of E.
23
24
25 coli rather than S. aureus. However, the actual mechanism of interaction between bacteria (E.
26
27 coli and S. aureus) and transition metal substituted CoFe NPs still needs to be examined further.
28
29
The another factor is a dose matrix as cobalt zinc ferrite NPs (Co0.5Zn0.5Fe2O4+γ[CZF-NPs])
30
31
32 encapsulated by amorphous silica in Rat mesenchymal stem cells (rMSCs) cause cytotoxicity
33
34 only at higher dose (0.55 mM) comparative to low dose (0.05mM) exposure with the enhanced
35
36 137
37 magnetic resonance imaging. Even though some studies suggest this doping of other
38
39 transition metal ions in CoFe NPs also reduces the risk of their lethality. 138
40
41
42 Toxicity of Cobalt substitution with other metal Ferrites
43
44
45 The physicochemical properties of spinel ferrites (MFe2O4, M=Fe, Mn, Co, Zn, or Ni) changed
46
47
48 significantly with the substitution of transition metal (M), hence the toxicity. Zhao et al. reported
49
50 that with change in substituted transition metals such as Fe3O4, MnFe2O4 and CoFe2O4 spinel
51
52
ferrites with an average size of 3nm at concentrations of 100, 500, 1000 mg/mL significantly
53
54
55 change the toxicity of NPs in human epithelial lung A549 cells after 48 hours of exposure. On
56
57 the basis of cellular morphology, mitochondrial function (MTT assay), reactive oxygen species
58 26
59
60
1
2
3
(ROS), superoxide dismutase (SOD), membrane lipid peroxidation (LPO) and glutathione (GSH)
4
5
6 end points, ascribed that Fe substitution was the least toxic as compared to Mn and Co
7
8 139
substitution ( Fe3O4<MnFe2O4<CoFe2O4 NPs). Contrary to the above study, polygonal
9
10
11
smooth surface Fe3O4 NPs with size of 25nm at concentration of 25-100µg/mL induces dose
12
13 dependent cytotoxicity and apoptosis in skin epithelium A549 cells after 24 hours of exposure
14
15 duration. Dose dependent oxidative stress was evident by the depletion of glutathione, ROS
16
17
18 species and LDH and lipid peroxidation. 71 The former study conducted by Zhao et al. 139 did not
19
20 study the toxicity of Fe3O4, MnFe2O4, and CoFe2O4 NPs at concentrations lower than the
21
22 100µg/mL as well as the non-toxic effect concentrations of NPs in A549 cells; this makes the
23
24
25 results non-comparable and nanotoxicology data just pilling up without any considerable
26
27 advancement. While it is also reported that Fe3O4 NPs induces oxidative stress, elevated
28
29
metabolism leading to cirrhosis in liver 140 and promote thrombosis, cardiac oxidative stress and
30
31
32 DNA damage in mice. 141
33
34
35 NiFe2O4 NPs with size of 26nm also induces cytotoxicity by ROS mediated oxidative stress and
36
37 apoptosis after 24 hours of exposure in A549 cells even at concentration of 25µg/mL and non-
38
39 142
40 toxic at 10 µg/mL. Nickel Ferrite (NiFe2O4) NPs also cause size and coating dependent
41
42 toxicity in Neuro-2A cells. MTT assay shows the larger (150nm) NiFe2O4 NPs with oleic acid
43
44
45
coating are more cytotoxic as compared to the smaller (10nm) and without oleic acid coating. 143
46
47 Spherical smooth shaped NiFe2O4 NPs with size of 21nm at the concentration of 5-25µg/mL
48
49 induces the cytotoxicity measured by MTT, neutral red uptake (NRU) and LDH assays after 24
50
51
52 hours of exposure duration in liver HepG2 and breast MCF-7 cell lines. MCF-7 cells are more
53
54 susceptible as compared to HepG2 cell line and the toxicity is believed to come from reactive
55
56 oxygen species (ROS). 144
Furthermore, NiFe2O4 NPs incubation with various kinds of cells
57
58 27
59
60
1
2
3
corroborate that the level of mRNA for the tumor suppressor gene p53 and the apoptotic genes
4
5
6 bax, CASP3 and CASP9 were up regulated and anti-apoptotic gene bcl-2 was down regulated as
7
8 well as the activities of apoptotic enzymes caspase-3 and caspase-9 were also higher in all types
9
10
11
of cells.142-144 MTT assay shows that CuFe2O4 (56nm) and ZnFe2O4 (68nm) NPs induces higher
12
145
13 cytotoxicity at concentration >125µg/mL in MCF cells after 72 hour exposure. ZnFe2O4 NPs
14
15 with size of 44nm at the concentration of 10-40 µg/mL induces the dose dependent cytotoxicity
16
17
18 (MTT and LDH) and oxidative stress (ROS and GSH) in A549, skin epithelial A431 and liver
19
20 HepG2 cell lines. Transcriptome sequencing illustrates the level of tumor suppressor gene p53
21
22 and apoptotic genes (bax, caspase-3 and caspase-9) were up-regulated while the anti-apoptotic
23
24
25 gene bcl-2 was down-regulated in cells after ZnFe2O4 NPs exposure. In addition, the cytotoxicity
26
27 of ZnFe2O4 NPs in different cells were in the following order; A549>HepG2>A431. 146 Spherical
28
29
smooth surface CuFe2O4 NPs with size of 15nm at the concentration of 10-100 µg/mL induces
30
31
32 the ROS mediated cytotoxicity and apoptosis in human breast cancer cells (MCF-7) in a dose
33
34 147
and time dependent way. CuFe2O4 NPs with size of almost 35nm at the concentration of 10-
35
36
37 100 µg/mL induces cytotoxicity and apoptosis mediated by excessive ROS generation in a dose
38
39 dependent way in A549 and HepG2 cell lines after 24 hours of exposure.148 After summarizing,
40
41 the current knowledge of toxicity of transition substituted spinel ferrites showed the same mode
42
43
44 of toxicity among various kinds of cell lines. Which strengthens the idea that major part of
45
46 toxicity induced by spinel ferrites mostly comes from the ferrite part and not from the transition
47
48 metals. While the substitution with various transition metals only may intensify the toxic
49
50
51 response with some change in physicochemical properties of NPs such as shape or magnetic
52
53 characteristics etc.
54
55
56 in vitro and in vivo toxicity of cobalt ferrite nano-composites
57
58 28
59
60
1
2
3
The combination of in vivo and in vitro toxicity testing would be extremely advantageous in
4
5
6 terms of reliability and reproducibility of nanotoxicology data, if they were conducted in an
7
8 appropriate analytical way. For example cell culture/animal rearing/growing, administration of
9
10 149
11
dosages and sample preparation assay procedures. In fact, in vitro-in vivo toxicity testing of
12
13 NMs not only makes the nanotoxicology test results more reliable and reproducible but also can
14
15 provide a framework of guidance for the environmental regulatory and legal authorities as well
16
17
18 as FDA for the prior approval of nanomedicine and products coming into the market.
19
20
21 L.F Cotica et al. also reported that spherical CoFe NPs with size of 20-100nm showed no in vivo
22
23 and in vitro toxicity in human blood cells (RBCs and polymorphonuclear (PMN) leukocytes) as
24
25
26 well as in Swiss male mice (8 weeks old). In in vitro toxicity tests at concentration range of 0.02,
27
28 0.01, 0.005 and 0.0025 mg/mL for RBCs and PMN leukocytes for the period of 24 and 6 hours
29
30 showed no significant toxicity. Whereas the renal function analysis of Swiss male mice after oral
31
32
33 gavage, once (1mg/kg and 5mg/kg) a day for 7 day exposure showed an increase in the
34
35 concentration of blood urea nitrogen (UREA), but the normal level of creatinine (Cre)
36
37 concentration. 150
The most probable reason for the increase in blood UREA is the possible
38
39
40 breakdown of the CoFe NPs and release of the Co+2 ions which in turn activate the defense
41
42 system and initiate the cell death process.150, 151
in vivo investigation of CoFe NPs
43
44
45
(1.2×1011particles/mL) in Swiss female mice after endovenous administration with different
46
47 coatings viz. (1) a water-based, citrate-coated, cobalt ferrite MF (CiCoMF); (2) CiCoMF
48
49 encapsulated in conventional (without PEG) liposomes (ConvML) and (3) CiCoMF encapsulated
50
51
52 in stealth liposomes (PEGML) showed no significant toxicity in liver spleen, kidney, lung ,
53
54 pancreas, brain and bone marrow. But they showed clear difference in blood clearance,
55
56 phagocytosis susceptibility, and MNP cluster size and amount. Results showed that CoFe were
57
58 29
59
60
1
2
3
heavily aggregated in the parenchyma or vessels of each investigated organ. While CoFe from
4
5
6 PEGML were found in the blood stream even after 24 hours of exposure while the CoFe with
7
8 ConvML and CiCoMF are found in the phagocytic cells in the organ parenchyma, and the
9
10
11
residence time of PEGML is longer than the CiCoNF composition. 152 So the coating material is
12
13 also a very important contributing factor in the elimination of the NPs from the animal body and
14
15 hence the toxicity. In in vitro investigation of polyacrylic acide coated CoFe NPs induced the
16
17
18 heavy production of reactive oxygen species (ROS) even after 24 and 48 hours of exposure in
19
20 Chinese Hamster Ovary (CHO), mouse melanoma (B16) cell line, and primary human myoblasts
21
22 (MYO) cell types. These NPs readily enter and accumulate inside the cells by macropinocytosis
23
24
25 mostly and by clathrin mediated endocytosis partially. MYO cells showed the lowest viability
26
27 due to higher accumulation of internalized NPs. 83 Our studies also strengthen the idea that CoFe
28
29
NPs with size of 40nm could initiate the apoptosis in developing Zebrafish due to the excessive
30
31
32 production of ROS even after 96 hours of exposure with endocrine disruption, leading to the
33
34 developmental abnormalities after 168 hours of exposure. 13, 153 Comparative ex vivo and in vivo
35
36
37 study showed, MnFe2O4 NPs with three different coatings (Citrate coated, tripolyphosphated
38
39 coated and bare) are more cardio toxic in ex vivo (isolated perfused rat hearts) experiment and
40
41 showed different cardiotoxic end points as well. Citrate coated MnFe2O4 NPs induces a transient
42
43
44 decrease in the left ventricular end de-systolic pressure. While the bare and tripolyphosphate
45
46 coating induce an increase in left ventricular end-diastolic pressure resulting in a decreased left
47
48 ventricular pressure. In addition, the latter two kinds of NPs also caused the decrease in the
49
50
51 maximal rate of left ventricular pressure rise (+dP/dt) and maximal rate of left ventricular
52
53 pressure decline (-dP/dt). Moreover, all the three kinds of NPs induce an increase in the
54
55
56
perfusion pressure of isolated hearts. Also the bare NPs induce a light vasorelaxant effect in the
57
58 30
59
60
1
2
3 154
isolated aortic rings. A recent study showed that Zn0.8Co0.2Fe2O4 exhibit both in vivo and in
4
5
6 vitro toxicity at the concentration of 100µg/mL. The results of in vitro toxicity showed a
7
8 significantly reduced viability of human umbilical vein endothelial cells (HUVECs) after 4hours
9
10
11
of exposure duration. In addition, in vivo investigation in New-Zealand rabbits revealed that
12
13 they cause severe toxicity in lungs, liver and kidneys. 80 Therefore, CoFe NPs have the potential
14
15 to induce both in vivo and in vitro toxicity by the generation of ROS species. In addition the site
16
17
18 of toxicity may vary with the change in model animal or cells and specifically the
19
20 physicochemical properties of the CoFe nano-composites. It is also a fact that in vivo NPs
21
22 experience very complex biological conditions as compared to the in vitro toxicity testing, which
23
24
25 leads to variation in in vivo and in vitro toxicity outcomes and it is suggested that both methods
26
27 should be used together for deep understanding of the actual mechanism of nanotoxicity.
28
29
30 Conclusion and outlook
31
32
33
34
The broad spectrum applications of CoFe NPs make them the essential and ubiquitous part of our
35
36 life. No doubt there are lots of studies focused on their toxicity to improve the health care issues
37
38 but their number is still very small as compared to the studies explaining synthesis and
39
40
41 fabrication techniques.
42
43
44 1. Most of the in vitro and in vivo studies indicate that CoFe NPs induce cytotoxicity,
45
46 oxidative stress, apoptosis, developmental malformation, endocrine disruption,
47
48
49 genotoxicity by DNA rupture/mutation, circulatory and respiratory system dysfunction,
50
51 liver and kidney damages. These NPs also have the ability to change the biochemistry of
52
53 most important enzymes and proteins (i-e., serum protein and hemoglobin) by altering
54
55
56 their functional conformation. These all stressors are believed to come from severe
57
58 31
59
60
1
2
3
oxidative stress manipulated by CoFe NPs. We can predict that long term exposure and
4
5
6 residence of these NPs into the animal body have more detrimental effects. Furthermore,
7
8 there is also a need to study the mechanism of Nanotoxicity by molecular, system biology
9
10
11
or -omics approaches.
12
13 2. It is also concluded that toxicity of CoFe NPs varies a lot from cell to cell and organ to
14
15 organ, so for better comparison among different studies, research groups should provide
16
17
18 the complete details of used concentrations in terms of their exposure and entrance route
19
20 and units of concentration. We should also device a new unified system of measuring
21
22 concentration of NPs on the basis of their basic unit constituents. What is more, there is
23
24
25 also a great need to promote and encourage to conduct the nanotoxicity studies at or close
26
27 to the concentrations of real human exposure. This will provide us the clear perspective
28
29
of actual Environmental health and safety (EHS) threat posed by these NPs or other NMs/
30
31
32 NPs as well.
33
34 3. One very important development is that most of the studies included the physicochemical
35
36
37 characterization prior to study their toxicological effect but they have not provided any
38
39 information of their fate and transformations inside the specific biological media. This
40
41 also raises concerns over the toxicity data provided in such publications.
42
43
44 4. Meantime, all these studies also lacks some important information which can advance
45
46 and understand the gaps in nanotoxicology and provide a measure of healthy limit of
47
48 using such breed of NPs, is that not more than two or three studies accommodate the
49
50
51 "no-effect study" . It means we don't know the safe used concentration limit of CoFe NPs
52
53 among different cell lines or even in different organisms. Such kind of studies just pilling
54
55
56
up the nano-toxicological data with lack of vital significant information.
57
58 32
59
60
1
2
3
5. Another very important point which is lacking in these studies, they all ignore the
4
5
6 possibility of interaction of CoFe NPs with the reagent components, which might give
7
8 false positive and false negative results. It is a well known fact that magnetic NPs do
9
10
11
interfere with assay components. 155, 156 Only just two studies13, 37 provide the information
12
13 about the possible interference of CoFe NPs with the assay components. So, such
14
15 consistent lack of knowledge makes these studies very redundant consistently.
16
17
18 6. In addition, Cell line ID, model animal, NP dispersion, and choice of dosing intervals can
19
20 significantly influence the assay results and possible interferences coming from NPs. In
21
22 combination of above mentioned factors specific laboratory environment and handling
23
24
25 also directly affect the nanotoxicity results even among the same kind of nanomaterials
26
27 toxicity. 157 There is an absolute need for developing a unified consensus on nanotoxicity
28
29
testing among the scientific world, in addition to detailed physicochemical
30
31
32 characterization of NPs in medium as well as in vivo and in vivo fate of NPs and possible
33
34 interference studies, we should also promote inter laboratory testing protocols for
35
36
37 nanotoxicity assays of various cell lines, laboratory animals and models for
38
39 environmental health and safety regulation of nanoparticles. This will help us to eliminate
40
41 misconceptions and variations in the results of nanotoxicity testing.
42
43
44 7. As most of the applications (other than nanomedicine) of CoFe NPs are in daily
45
46 consumer products, so it's very crucial to extend the studies on their release, fate and
47
48 transportation into the environment and their subsequent effect on plants. There is also a
49
50
51 need to determine the real environmental concentration of CoFe NPs. Only one study
52
53 elaborates the possible growth and developmental toxicity of CoFe NPs in Lycopersicum
54
55
56
esclantum (tomato). 158 A recent editorial in Frontiers of Plant Science also highlights the
57
58 33
59
60
1
2
3
importance of nanotoxicological studies should be conducted in plants especially which
4
5 159
6 are the basic part of the human nutrition and which can ultimately affects the food
7
8 chain.
9
10
11
8. There is also a need to include the sophisticated computational approaches such as nano-
12
13 QSAR/QSPR etc. for developing the predicting model of the possible toxicity of large
14
15 range of nanomaterials. This not only reduces the excessive consumption of time and
16
17
18 money as well as the misery of laboratory animals. But the problem with these studies is
19
20 that composite Nano-structures require more sophisticated operating systems and much
21
22 trained professionals which can handle such heavy and time consuming calculations.
23
24
25
26 In summary, this review concludes the current in vivo and in vitro studies about toxicological
27
28 harmful effects of CoFe NPs on diverse organs and systems is mostly caused by the enormous
29
30 uncontrolled inculcation of ROS, which in turn leads to different abnormalities and perturbations
31
32
33 among various kinds of cells, organs and organ systems. This review also highlights the gaps of
34
35 high significance should be filled in the upcoming studies and would facilitate us to comprehend
36
37
the menace of NPs in everyday life and formulate the application of CoFe NPs safety usage.
38
39
40
41 Author Information
42
43 Corresponding Authors
44
45 *Email: [email protected] (Farooq Ahmad)
46
47
48 *Email: [email protected] (Ying Zhou)
49
50 Funding Sources
51
52
This work was supported by grants from the Project of Science and Technology Zhejiang Food
53
54
55 and Drug Administration (SP201717) and the Key Innovation Team of Science and Technology
56
57 in Zhejiang Province (2010R50018).
58 34
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6
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11
Abbreviations
12
13 A549, Adenocarcinomic human alveolar basal epithelial cells; ACP, Acid Phosphatase; Ag,
14
15 Silver; Anxa5, Annexin A5; Atm, Ataxia telangiectasia mutated; BBB, Blood brain barrier;
16
17
18 BNMN, Micro nucleated binucleated lymphocytes; BSA, Bovine serum Albumin; CA, Citric
19
20 acid; Caco-2 cell-line, Adenocarcinoma of the colon; CBPI, Cytokinesis blocked proliferation
21
22 index; CNS, Central nervous system; CoFe, Cobalt ferrite (CoFe2O4); Cre, Creatinine; Cyp4a10,
23
24
25 Cytochrome P450 4A10; Cyp4a14, Cytochrome P450 4A14; DNA, Deoxyribonucleic acid; Dy,
26
27 Dysprosium; E. coli, Escherichia coli; emu, Magnetic moment; ERK , Extracellular signal-
28
29
regulated kinases; FA, Folic acid; Gd, Gadolinium; Gpx2 , Glutathione peroxidase 2; GSH,
30
31
32 Glutathione; Gsr, Glutathione-disulfide reductase; H2O2, Hydrogen peroxide; HaCaT, Human
33
34 keratinocytes cells; HDF, Human dermal fibroblasts; HeLa, Henrietta Lacks cells; HNSCC,
35
36
37 Head and neck squamous cell carcinoma; i.v, Intravenous injection; Igfbp6, Insulin-like growth
38
39 factor-binding protein 6; IL-1β, Interleukin-1β; IL-6, Interleukin 6; IL-8, Interleukin 8; Km,
40
41 Michaelis constant; kOe, Kilo oersted; LPO, Lipid peroxidation; MCF-7 , Michigan Cancer
42
43
44 Foundation-7; MCP-1, Monocyte chemoattractant protein 1; MDCK , Madin-Darby canine
45
46 kidney; MNPs, Magnetic nanoparticles; MRC5, Medical research council cell 5; MSCS,
47
48 Mesenchymal stem cells; Mt2, Metallothionein 2; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-
49
50
51 diphenyltetrazolium bromide; mu-GST, mutagenic glutathione-s-transferase; MYO, Myoblasts;
52
53 NADH, Nicotinamide adenine dinucleotide; NCs, Nanocrystals; NMs, Nanomaterials; NPs,
54
55
56
Nanoparticles; PMN, Polymorphonuclear; Por, Cytochrome P450 oxidoreductase; QSAR,
57
58 35
59
60
1
2
3
Quantitative structure activity relationship; QSPR, Quantitative structure property relationship;
4
5
6 Rad23a, Restriction site associated DNA 23A; Rad50, Restriction site associated DNA 50;
7
8 RBCs., Red blood cells; rMSCs, Rat mesenchymal stem cells; ROS, Reactive oxygen species;
9
10
11
RT-PCR, Real-time polymerase chain reaction; S. aureus, Staphylococcus aureus; SCL-1,
12
13 Squamous tumor cell line; SOD, Superoxide dismutase; SPIONs, Superparamagnetic iron oxide
14
15 nanoparticle; TK6 , Thymidine kinase 6; TNF, Tumor necrosis factor; U87MG cells, Uppsala 87
16
17
18 Malignant Glioma cells; UVB, Ultraviolet spectrum with 280-320nm range; Vm, Enzymatic
19
20 Velocity; WBCs, White blood cells; Yb, Ytterbium;
21
22
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Author Bibliography
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42 Farooq Ahmad recieved his M.Sc chemistry (2009) from University of Gujrat, Pakistan.
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45 He received his PhD degree in Chemical Engineering and Technology (2016) from
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47 Zhejiang University of Technology, China, under the supervision of Professor Ying
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49 Zhou. He got the Chinese Government scholarship for his PhD study from 2012 to 2016.
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52 He is currently a Postdoctor in State Key Laboratory of Metal Matrix Composites, School
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54 of Material Sciences and Engineering, Shanghai Jiao Tong University, Shanghai, China.
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His current research interests are synthesis, design and farbrication of theranositic smart
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6 nanomaterials for non-invasive diagnosis and cancer therapies.
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39 Dr. Ying Zhou is a professor at College of Chemical Engineering, Zhejiang University of
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42 Technology (ZJUT), China. She is responsible for ICP-MS facility and other spectroscopy
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44 instruments housed in the Research Center of Analysis and Measurement at ZJUT, China. Her
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current research interests include (1) environmental health and safety behavior of chemical
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49 contaminants as well as sophisticated (mirco/nano)materials and their complex interplay, (2)
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51 analytical method development and applications.
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