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Review
. 2015 Oct 15;16(10):24417-50.
doi: 10.3390/ijms161024417.

In Vitro/In Vivo Toxicity Evaluation and Quantification of Iron Oxide Nanoparticles

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Free PMC article
Review

In Vitro/In Vivo Toxicity Evaluation and Quantification of Iron Oxide Nanoparticles

Ujwal S Patil et al. Int J Mol Sci. .
Free PMC article

Abstract

Increasing biomedical applications of iron oxide nanoparticles (IONPs) in academic and commercial settings have alarmed the scientific community about the safety and assessment of toxicity profiles of IONPs. The great amount of diversity found in the cytotoxic measurements of IONPs points toward the necessity of careful characterization and quantification of IONPs. The present document discusses the major developments related to in vitro and in vivo toxicity assessment of IONPs and its relationship with the physicochemical parameters of IONPs. Major discussion is included on the current spectrophotometric and imaging based techniques used for quantifying, and studying the clearance and biodistribution of IONPs. Several invasive and non-invasive quantification techniques along with the pitfalls are discussed in detail. Finally, critical guidelines are provided to optimize the design of IONPs to minimize the toxicity.

Keywords: iron oxide nanoparticles; physicochemical properties; quantification; toxicity.

Figures

Figure 1
Figure 1
Effect of bare and passivated Fe3O4/SiO2 nanoparticles (NPs) on the viability and membrane damage in two cell lines (A549 and HeLa). (A,B) (2-(2-Methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-8) proliferation assay and (C,D) Lactate dehydrogenase (LDH) assay on A549 and HeLa cells incubated with increasing concentrations (0.5, 1, 2.5, 5 nM) of bare and passivated Fe3O4/SiO2 NPs at different times (48 and 96 h). c identifies the negative control in the absence of NPs. Viability of NPs-treated cells is expressed relative to non-treated control cells. As positive control (P) cells were incubated with 5% dimethyl sulfoxide (DMSO) in WST-8 assay and 0.9% Triton X-100 in LDH assay (not shown). Data are reported as mean ± SD from three independent experiments; * p < 0.05 compared with control (n = 8). Reprinted with permission from Malvindi et al. [40]. Copyright 2015 PLoS One-Public library of science.
Figure 2
Figure 2
Major spectrophotometric and imaging based quantification techniques for IONPs.
Figure 3
Figure 3
Distribution and quantification of Prussian blue stained superparamagnetic iron oxide nanoparticles (SPIONs) on day 13 post-antigen-induced arthritis (AIA) induction. Photomicrographs of Prussian-blue-stained sections showing an example of the distribution of SPIONs (red arrows) in the synovium of untreated animal (A) versus a Dexa-treated animal (B) on day 13 post-AIA induction at 1.5 times magnification. Quantification of the area (C) and number (D) of Prussian-blue-stained SPIONs on day 13 post-AIA induction. Photomicrographs of Prussian-blue-stained sections were scanned, and the images were analyzed for the area (C) and the number (D) of SPIONs using Tissue Studio® software. Four sections were quantified and averaged per animal. Data points are mean ± standard error of the mean and n = 5 per group. * p = 0.005 (A) and 0.016 (B) compared to the untreated control group. Reprinted with permission from Gramoun et al. [141] Copyright 2014 Biomed Central Ltd.
Figure 4
Figure 4
Bright-field microscopy (A,C) and photoacoustic (PA) (B,D) images of unstained tumor slices with (A,B) and without (C,D) NPs. An overlay of the optical and PA image of the tumor with NPs from (A) and (B) are shown in (E). R2 map of the area in the white box in (E) is shown in (F); Quantitative PA image using R2 > 0.97 with unquantifiable areas in white is shown in (H); (G) Quantitative comparison of the unstained and Prussian blue stained bright-field images and the qPA images. The values for the graphs were generated from a line shown in (A). Reprinted with permission from Cook et al. [171] Copyright 2015 American Chemical Society.

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