Superparamagnetic Iron Oxide Nanoparticles: Cytotoxicity, Metabolism, and Cellular Behavior in Biomedicine Applications

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely investigated and applied in the field of biomedicine due to their excellent superparamagnetic properties and reliable traceability. However, with the optimization of core composition, shell types and transfection agents, the cytotoxicity and metabolism of different SPIONs have great differences, and the labeled cells also show different cellular behaviors. Therefore, a holistic review of the construction and application of SPIONs is desired. This review focuses the advances of SPIONs in the field of biomedicine in recent years. After summarizing the toxicity of different SPIONs, the uptake, distribution and metabolism of SPIONs in vitro were discussed. Then, the regulation of labeled-cells behavior is outlined. Furthermore, the major challenges in the optimization process of SPIONs and insights on its future developments are proposed.

Keywords: biological behavior; cytotoxicity; stem cells; superparamagnetic iron oxide nanoparticles.

Figure 1

The cytotoxicity effects of SPIONs on NSCs. (A) Cell viability measured by the CCK-8 assay. (B) Total GSH content measured by monochlorobimane assay. (C) Activities of glutathione peroxidase and SOD in neural stem cells after 4 hours of exposure. (D) Mitochondrial membrane potential measured in neural stem cells after 4 hours of exposure. *p<0.05. Reproduced with permission from Pongrac IM, Pavičić I, Milić M, et al. Oxidative stress response in neural stem cells exposed to different superparamagnetic iron oxide nanoparticles. Int J Nanomedicine. 2016;11:1701–1715. Copyright 2016, Dove Medical Press.

Figure 2

Cellular uptake of silica-coated SPIONs by hAMSCs. (A) The relative amount of non-heme iron inside the cells after incubating with 10, 50 and 100 μg/mL of SPIONs for different time. (B) Immunofluorescence images of untreated cells. (C) Treated with 50 μg/mL of silica-coated SPIONs for 48 h, nanoparticles (green), phalloidin (red) and Hoechst (blue). (D–F) Prussian blue staining of untreated cells (D), SPIONs labeled cells (E and F). Reproduced with permission from Ledda M, Fioretti D, Lolli MG, et al. Biocompatibility assessment of sub-5 nm silica-coated superparamagnetic iron oxide nanoparticles in human stem cells and in mice for potential application in nanomedicine. Nanoscale. 2020;12:1759–1778. Copyright 2020, Royal Society of Chemistry.

Figure 3

Fluorescence images of Cy5.5 (red)-labeled PCS localized within lysosomes (green) at different time points. (A) Control (a, e, i); PCS exposure for 24 h (b, f, j); PCS exposure for 48 h (c, g, k); PCS exposure for 60 h (d, h, l); (B) Merged fluorescence intensities PCS nanoparticle and lysosome. Reproduced with permission from Lee SH, Park DJ, Yun WS, et al. Endocytic trafficking of polymeric clustered superparamagnetic iron oxide nanoparticles in mesenchymal stem cells. J Control Release. 2020;326:408–418. Copyright 2020, Elsevier.

Figure 4

Immunohistology of grafts one-month post-transplantation. (A–D) SPIO-labeled NSCs with nestin (A), β-tubulin (B), MAP2 (C), GFAP (D). (E–H) SPIO-labeled NSCs with nestin (E), β-tubulin (F), MAP2 (G), GFAP (H) staining. Scale Bar=50 mm. Reproduced with permission from Egawa EY, Kitamura N, Nakai R, et al. A DNA hybridization system for labeling of neural stem cells with SPIO nanoparticles for MRI monitoring post-transplantation. Biomaterials. 2015;54:158–167. Copyright 2015, Elsevier.

Figure 5

Effect of RLX-SPION on hPSCs contractility and migration. (A) Representative images and quantification. (B) Representative microscopic images and quantification showing. Statistical differences are *p < 0.05, **p < 0.01, ***p < 0.001. Reproduced with permission from Mardhian DF, Storm G, Bansal R, et al. Nano-targeted relaxin impairs fibrosis and tumor growth in pancreatic cancer and improves the efficacy of gemcitabine in vivo. J Control Release. 2018;290:1–10. Copyright 2018, Elsevier.