Ferucarbotran, a carboxydextran-coated superparamagnetic iron oxide nanoparticle, induces endosomal recycling, contributing to cellular and exosomal EGFR overexpression for cancer therapy

Abstract

Superparamagnetic iron oxide (SPIO) nanoparticles have shown many impacts on stem cell attributes when they are used as labels for cellular magnetic resonance imaging (MRI) in the application of stem cell-based therapy. Although it is plausible that iron ions from the lysosomal degradation of SPIO nanoparticles are one of the possible candidates, the mechanisms underlying SPIO-induced cellular responses remain unclear. Herein, the mechanism of ferucarbotran, an ionic SPIO, for the regulation of epidermal growth factor receptor (EGFR) expression in human mesenchymal stem cells (hMSCs) is explored. Ferucarbotran can be internalized into EGFR-localized endosomes, and the endosomal EGFRs in ferucarbotran-labeled hMSCs, compared to unlabeled cells, are mainly localized on the early endosomes and recycling endosomes, but not on late endosomes/lysosomes, and thus escape from lysosomal degradation. Afterward, the recycling endosomal EGFRs are transferred to the cellular membrane and extracellular exosomal vesicles (exosomes) through back fusion and a secretory pathway, respectively, resulting in EGFR-overexpressed hMSCs and EGFR-overexpressed exosomes. Moreover, as EGFR-overexpressed hMSCs, EGFR-overexpressed exosomes can more effectively capture tumorous EGF than native exosomes, which may contribute to the inhibition of tumor growth. This is the first report to find that the SPIO nanoparticles have an impact on stem cell attributes through inducing endosomal recycling instead of them undergoing lysosomal degradation.