Iron oxide nanoparticles (IONPs) have emerged as a promising alternative to conventional contrast agents (CAs) for magnetic resonance imaging (MRI). They have been extensively investigated as CAs due to their high biocompatibility and excellent magnetic properties. Furthermore, the ease of functionalization of their surfaces with different types of ligands (antibodies, peptides, sugars, etc.) opens up the possibility of carrying out molecular MRI. Thus, IONPs functionalized with epithelial growth factor receptor antibodies, short peptides, like RGD, or aptamers, among others, have been proposed for the diagnosis of various types of cancer, including breast, stomach, colon, kidney, liver or brain cancer. In addition to cancer diagnosis, different types of IONPs have been developed for other applications, such as the detection of brain inflammation or the early diagnosis of thrombosis. This review addresses key aspects in the development of IONPs for MRI applications, namely, synthesis of the inorganic core, functionalization processes to make IONPs biocompatible and also to target them to specific tissues or cells, and finally in vivo studies in animal models, with special emphasis on tumor models.

DualT₁andT₂MRI contrast agents based on PEGylated manganese ferrite nanoparticles with long circulation times.

Passive tumor targeting via the enhanced permeability and retention (EPR) effect has long been considered the most effective mechanism for the accumulation of nanoparticles inside solid tumors. However, several studies have demonstrated that the EPR effect is largely dependent on the tumor type and location. Particularly complex is the situation in brain tumors, where the presence of the blood–brain tumor barrier (BBTB) adds an extra limiting factor in reaching the tumor interstitium. However, it remains unclear whether these restraints imposed by the BBTB prevent the EPR effect from acting as an efficient tumor targeting mechanism for metallic nanoparticles. In this work, we have studied the EPR effect of metallic magnetic nanoparticles (MMNPs) in a glioblastoma (GBM) model by parametric MRI. Our results showed that only MMNPs ≤50 nm could reach the tumor interstitium, whereas larger MMNPs were unable to cross the BBTB. Furthermore, even for MMNPs around 30–50 nm, the amount of them found within the tumor was scarce and restricted to the vicinity of large tumor vessels, indicating that the BBTB strongly limits the passive accumulation of metallic nanoparticles in brain tumors. Therefore, active targeting becomes the most reasonable strategy to target metallic nanoparticles to GBMs.