The internalization pathway, metabolic fate and biological effect of superparamagnetic iron oxide nanoparticles in the macrophage-like RAW264.7 cell

Abstract

The potential applications of superparamagnetic iron oxide nanoparticles (SPIONs) in several nanomedical fields have attracted intense interest based on the cell-nano interaction. However, the mechanisms underlying cell uptake, the intracellular trail, final fate and the biological effects of SPIONs have not yet been clearly elucidated. Here, we showed that multiple endocytic pathways were involved in the internalization process of SPIONs in the RAW264.7 macrophage. The internalized SPIONs were biocompatible and used three different metabolic pathways: The SPIONs were distributed to daughter cells during mitosis; they were degraded in the lysosome and free iron was released into the intracellular iron metabolic pool; and, the intact SPIONs were potentially exocytosed out of the cells. The internalized SPIONs did not induce cell damage but affected iron metabolism, inducing the upregulation of ferritin light chain at both the mRNA and protein levels and ferroportin 1 at the mRNA level. These results may contribute to the development of nanobiology and to the safe use of SPIONs in medicine when administered as a contrast medium or a drug delivery tool.

Comparison of Contrast Agents for Atherosclerosis Imaging Using Cultured Macrophages: FDG Versus Ultrasmall Superparamagnetic Iron Oxide

“…5). Gu et al reported that internalized USPIO in mouse macrophages was degraded in lysosomes, and free iron was released into intracellular iron pools (23). Fpn1 is known to have an important role in the export of iron from cells (19).…”

Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers

“…These results confirmed that several endocytic uptake mechanisms worked cooperatively for uptake of SPIONs by macrophage-like RAW264.7 cells. 64 However, in another study by Yang et al, ferucarbotran, a clinically approved SPIO-coated carboxydextran with a mean diameter range of 45-60 nm, was found to be internalized in macrophage-like RAW264.7 cells via clathrin-dependent endocytosis. 65 It seems that there is a correlation between SPION factors (size, surface charge, and surface coating) and endocytotic pathways, that needs to be explored in more detail.…”

“…Thirdly, some of the internalized SPIONs may potentially be exocytosed out of RAW264.7 cells, although direct evidence for this proposed mechanism is lacking. 64 Levy et al conducted a long-term (3-month) in vivo biotransformation study of 8 nm SPIONs coated with hydrophilic glucose derivatives following intravenous administration in mice. Using ferromagnetic resonance and superconducting quantum interference device measurements, they supported the view of continuous biotransformation of injected magnetic nanoparticles into iron storage species within intracellular lyzosomes.…”

Long term biotransformation and toxicity of dimercaptosuccinic acid-coated magnetic nanoparticles support their use in biomedical applications

“…Several previous studies examined the effects of DMSA-MNP on different cell types, and showed little reduction in cell viability [11,16,40]. These studies used low MNP doses, however, or incubation times too short to permit analysis of all possible toxic effects of iron oxide nanoparticles.…”