Iron‐induced myocardial injury: an alarming side effect of superparamagnetic iron oxide nanoparticles

Superparamagnetic iron oxide nanoparticles (SPION), as magnetic resonance (MR) imaging contrast agents or magnetic targeting carriers, have potential applications in diagnostics, imaging, cell and drug/ gene delivery for cardiovascular diseases. SPION are highly magnetic particles that cause magnetic field perturbations, which can be identified on T2* weighted images [1]. Clinically, SPION allows noninvasive detection of the region of myocardial infarction and the periinfarct zone based on a multiparametric cardiovascular MR approach [2, 3], characterization of acute MI pathology by detecting infiltrating macrophages and altered perfusion kinetics [4] and non-invasive visualization of the aorta and aortic diseases [5]. Preclinically, a large number of animal studies have been performed with SPION and cardiac magnetic resonance imaging to deliver, track or determine the efficacy of stem cell therapy in the heart in the past 10 years [1]. More recently, magnetic targeting has emerged as a promising and novel strategy for ischaemic heart disease [6–10], in which SPION can direct drugs, genes or cells to the target site under a magnetic field gradient. Superparamagnetic iron oxide nanoparticles’ biocompatibility with the target organ is the first prerequisite for clinical translation, and iron oxide nanoparticles have long been believed to have low toxicity and are well-tolerated in the human body. However, with the expanding application of SPION, toxic effects, such as oxidative stress and inflammatory reaction, have increasingly attracted attention. Iron oxide nanoparticles accumulate in lysosomes (following cellular internalization), in which the low pH breaks the iron oxide core down into iron ions. It has been reported that iron oxide nanoparticle inhalation exposure may induce lung cytotoxicity via oxidative stress and biphasic inflammatory responses in Wistar rats [11]. In vitro studies have also suggested that iron oxide nanoparticles mediate activation of microglia in the brain [12] and differentiation of blood mononuclear cells into pro-inflammatory macrophages to secrete higher levels of pro-inflammatory cytokines [13]. In addition, iron oxide particles stabilized with coatings, such as dextran or citric acid, induced toxic effects on the behaviour and function of endothelial cells [14–16] and activated the expression of genes related to oxidative stress [17]. Moreover, the oxidative injury caused by SPION can be suppressed via antioxidant poly (trolox) nanoparticles binding to and internalizing in endothelial cells [16]. Thus, could the invasion of SPION produce similar side effects in the myocardium? Iron oxide nanoparticles with systemic administration were mainly cleared by the reticuloendothelial system and renal excretion, resulting in cytopathological effects on the lungs, liver and kidneys, while the heart and brain remain free from adverse effects because of limited iron deposits [18]. A recent clinical study also showed that a single dose of intravenous iron oxide administration has a beneficial effect on LV remodelling in patients with acute ST-elevation myocardial infarction [19], in which the underlying iron deficiency with a decline in iron circulating levels was reported [20]. However, this situation is quite different from local delivery of SPION-mediated therapeutic agents (stem cells, gene or drug) in the treatment of ischaemic heart disease. First, intramyocardial injection of SPION-mediated agents contains large amounts of iron oxide nanoparticles, and the local quantity of SPION deposition in the myocardium is higher than that reported in previous intravenous studies [21–23], in which SPION was administered systemically and proved to be a relatively safe and efficient MR contrast agent. Second, the heart is not a monocyte-macrophage organ, and iron clearance occurred more slowly in the heart than in the liver [24]. Thus, it is difficult for macrophages to migrate away from the massive SPION introduced by SPION-mediated agents. Moreover, SPION-mediated therapeutic agents target the ischaemic or injured lesion rather than the normal myocardium. Thus, the injected SPION easily accumulates in situ for a prolonged period of time due to the lack of blood flow and mechanical These authors contributed equally to this work. *Correspondence to: Junbo GE, M.D., FACC, FESC, FSCAI E-mail: junboge@126.com