Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications
Graphical abstract
Introduction
Iron oxide nanoparticles, which belong to the ferrimagnetic class of magnetic materials, are used for many different biomedical and bioengineering applications [1,2]. Among the different types of iron oxide-based nanoparticles are magnetite (Fe3O4), maghemite (γ-Fe2O3) and mixed ferrites (MFe2O4 where M = Co, Mn, Ni or Zn) [3]. Upon surface-modification, the resulting superparamagnetic iron oxide nanoparticles (SPION) can be employed for magnetic resonance imaging (MRI) [[4], [5], [6], [7], [8]], magnetic particle imaging (MPI) [[9], [10], [11], [12]], targeted delivery of drugs, proteins, antibodies, and nucleic acids [6,7,13,14], hyperthermia [[15], [16], [17]], biosensing [18], tissue repair [19], and separation of biomolecules [20]. This widespread list of applications not only results from the magnetic properties of SPION, but also from the fact that they can be synthesized in different sizes and shapes. SPION have high magnetic moments when exposed to an external magnetic field, and no remaining magnetic moment when the magnetic field is turned off [21]. Many iron oxide nanoparticles have been evaluated in preclinical and clinical trials, and several of them have reached the market (Table 1) [4,[22], [23], [24], [25], [26]]. However, some of the approved SPION have later on been withdrawn, because of the availability of alternative diagnostic probes and protocols [27].
In this manuscript, we summarize synthetic protocols and characterization methods to obtain iron oxide nanoparticles with desired features, and we outline their most prominent (pre-) clinical applications. In the first part, the most frequently used preparation techniques are summarized. We focus on those synthesis routes which cover about 90% of all synthesis techniques and which have advantages such as simplicity, low cost and high reproducibility. We also discuss the most common surface modification strategies, which are necessary to optimally exploit their specific properties and causes usefulness for biomedical applications [28]. The second part of our review provides an overview of SPION formulations currently used in the clinic for diagnostic, therapeutic and theranostic purposes. We summarize selected preclinical and clinical studies conducted in these areas of research, and we discuss strategies to expand the use and the usefulness of iron oxide nanoparticles in future biomedical settings.
Section snippets
Synthesis methods
The magnetic properties of iron oxide nanoparticles depend on their composition and morphology. Thus, the synthetic method needs to be carefully selected, ensuring control over shape, size, size distribution and crystallinity of the particles. SPION can be produced in several different ways, encompassing chemical, physical and biosynthetic methodologies [3,25,28,29]. Chemical approaches are employed in the vast majority of cases. Physical methods, which include powder ball milling, electron
Diagnostic application of iron oxide nanoparticles
SPION have been extensively used for diagnostic purposes, for visualizing tumors and metastases in liver, spleen and lymph nodes [137,138], for angiography as a blood pool agent [139] and for visualizing inflammatory lesions like atherosclerotic plaques [140]. Due to their superparamagnetic behavior, SPION shorten the relaxation time of surrounding protons. On the basis of this, they can be employed as contrast media in MRI. MR contrast agents can be divided into two major types: positive
Anemia
Besides for diagnostic purposes, iron oxide nanoparticles have also been used for therapeutic application, for instance to supplement iron in individuals with iron deficiency. Ferumoxytol is clinically used to treat anemia in patients with chronic kidney disease (CKD). This SPION formulation was initially developed for sentinel lymph node and atherosclerotic plaque imaging, but did not manage to outperform alternative diagnostic probes and protocols. In 2009, it received FDA approval for the
Theranostic applications of iron oxide nanoparticles
The term theranostics refers to the combination of diagnosis and therapy. From a clinical and translational point of view, it relates to an intimate combination of diagnostic and therapeutic interventions, as e.g. for staging and treatment of patients with thyroid cancer with radioactive iodine, or to perform patient selection and treatment of somatostatin receptor-expressing neuroendocrine neoplasias with DOTATOC/TATE-based theranostic pairs (e.g. gallium and yttrium). In the nanomedicine
Conclusions
Iron oxide nanoparticles possess many unique and attractive properties, explaining their extensive use in biomedical research. In this review, we summarize recent advances in the development of iron oxide nanoparticles for in vitro and in vivo biomedical applications, focusing primarily on diagnosis, therapy and theranostics. An overview of the key studies applying SPION in the field of biomedicine is given in Table 3.
Iron oxide nanoparticles can be synthesized by multiple different techniques,
Acknowledgments
The authors gratefully acknowledge financial support by the European Research Council (ERC: Starting Grant 309495 (NeoNaNo) and Proof-of-Concept Grants 680882 (CONQUEST) and 813086 (PIcelles)), by the European Union (ERA-Net EuroNanoMedicine-III: NSC4DIPG), by the German Research Foundation (DFG: La2937/1-2, SFB/TRR57, SFB1066 and GRK2375 (grant 331065168)) and by the Interdisciplinary Center for Clinical Research at RWTH Aachen University Hospital (IZKF).
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These authors contributed equally to this work.