Abstract
Understanding the mechanism of toxicity of nanoparticles (NPs) represents a major challenge for biomedical application. Since the cardiotoxicity of drugs is mainly due to blockade of the human ether-a-go-go related gene (hERG) protein, the inhibition of hERG channel is a first step in a non-clinical testing strategy. Superparamagnetic iron oxide nanoparticles (SPIONs) are composed of either a magnetite (Fe3O4) or maghemite (γ-Fe2O3) core coated with a biocompatible polymer. Both maghemite and magnetite are ferrimagnetic in nature, and when the size of the particles enters the nanometric scale (below ca. 80-120 nm) they assume a single domain magnetic structure and superparamagnetic feature. SPIONs are suitable for biological application for the following reasons: i) Fe is a naturally occurring metal in the human body; ii) they can be utilized by the body in subsequent metabolic processes; iii) their magnetic behavior allows them to be used in various biomedical applications, e.g. magnetic fluid hyperthermia.In this work we describe the interaction of SPIONs, coated with different ligands, with hERG channel. The NPs were synthesized by thermal decomposition and investigated by XRD, TEM and DLS analysis; the superparamagnetic behavior was confirmed by SQUID magnetometric analysis. We functionalized the NPs by a coating exchange reaction with several ligands and analyzed them by DLS and Z-Potential analysis. The interaction between SPIONs and hERG channel, expressed in HEK cells, was investigated by patch-clamp. We found that NPs coated with polyacrylic acid (PAA) or 2,3-dimercaptosuccinic acid (DMSA) blocked hERG channels. On the contrary, 3-aminopropyl phosphonic acid (APPA)-stabilized NPs or non-coated NPs had no effect on hERG channel, suggesting an important role of charge density of NPs in hERG binding interactions. A mode of action fitting the experimental evidence has been proposed for the observed hERG blocking activity.
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