**Iron Oxide Nanoparticles: An Alternative for Positive Contrast in Magnetic Resonance Imaging**

**Irene Fernández-Barahona 1,2,**†**, María Muñoz-Hernando 1,3,**†**, Jesus Ruiz-Cabello 2,4,5,6, Fernando Herranz 1,4 and Juan Pellico 4,7,\***


Received: 31 March 2020; Accepted: 8 April 2020; Published: 10 April 2020

**Abstract:** Iron oxide nanoparticles have been extensively utilised as negative (*T*2) contrast agents in magnetic resonance imaging. In the past few years, researchers have also exploited their application as positive (*T*1) contrast agents to overcome the limitation of traditional Gd3<sup>+</sup> contrast agents. To provide *T*<sup>1</sup> contrast, these particles must present certain physicochemical properties with control over the size, morphology and surface of the particles. In this review, we summarise the reported *T*<sup>1</sup> iron oxide nanoparticles and critically revise their properties, synthetic protocols and application, not only in MRI but also in multimodal imaging. In addition, we briefly summarise the most important nanoparticulate Gd and Mn agents to evaluate whether *T*<sup>1</sup> iron oxide nanoparticles can reach Gd/Mn contrast capabilities.

**Keywords:** iron oxide nanoparticles; magnetic resonance imaging; positive contrast agents

#### **1. Introduction**

Iron oxide nanoparticles (IONPs) are one of the most used nanomaterials in biomedicine. Among the reasons justifying this interest, their biocompatibility and magnetic properties are probably the most important. These properties have boosted their use in hyperthermia cancer treatment and, as imaging probes, in magnetic resonance imaging (MRI). When IONPs are prepared using "traditional" synthetic methods they show superparamagnetic properties. In other words, these nanoparticles show a very strong magnetic response when placed under the influence of a magnetic field, turning to zero when the magnetic field is off. Because of this, when placed inside MRI equipment, IONPs act as "small magnets", suppressing the signal and, therefore, appearing as a dark spot, the so-called negative contrast. Due to the strong magnetic response, the concentration needed for an in vivo application is often low. However, based on this, IONPs have been, for a long time, the never fulfilled eternal promise to change the current clinical scenario in MRI. Currently, Gd-based compounds are the standard probes when an MRI scan is performed. It is well-known that, under certain circumstances, Gd compounds

show important toxicity. This is particularly important for patients suffering from kidney problems. Besides the toxicity problems, Gd probes normally have a small molecular weight and are, after injection, rapidly extravasated, excluding them from many applications that require long circulating times. If Gd-based probes present these problems, why have IONPs not displaced them from clinical practice? Basically, because the signal provided by Gd compounds is much more useful for in vivo diagnosis than that provided by IONPs for many diseases. This is due to the dark, negative signal that traditional IONPs generate. Frequently, in many diseases, hypointense (dark) areas appear naturally in an MR image. If the image probe generates a dark signal over a dark background, diagnosis gets complicated. For this reason, in recent years, researchers have searched for an alternative that can join the good physicochemical properties of IONPs with the outstanding imaging properties of Gd compounds. This has led to numerous synthetic developments producing extremely small iron oxide nanoparticles that, being more paramagnetic than superpramagmetic, are capable of generating bright, positive contrast in MRI. Here, we will critically review these developments, highlighting achievements and considering what is left to accomplish to reach a point at which the use of IONPs in clinics is as frequent as the use of gadolinium compounds.
