Elsevier

Advanced Drug Delivery Reviews

Volume 138, 1 January 2019, Pages 302-325
Advanced Drug Delivery Reviews

Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications

https://doi.org/10.1016/j.addr.2019.01.005Get rights and content

Abstract

Many different iron oxide nanoparticles have been evaluated over the years, for a wide variety of biomedical applications. We here summarize the synthesis, surface functionalization and characterization of iron oxide nanoparticles, as well as their (pre-) clinical use in diagnostic, therapeutic and theranostic settings. Diagnostic applications include liver, lymph node, inflammation and vascular imaging, employing mostly magnetic resonance imaging but recently also magnetic particle imaging. Therapeutic applications encompass iron supplementation in anemia and advanced cancer treatments, such as modulation of macrophage polarization, magnetic fluid hyperthermia and magnetic drug targeting. Because of their properties, iron oxide nanoparticles are particularly useful for theranostic purposes. Examples of such setups, in which diagnosis and therapy are intimately combined and in which iron oxide nanoparticles are used, are image-guided drug delivery, image-guided and microbubble-mediated opening of the blood-brain barrier, and theranostic tissue engineering. Together, these directions highlight the versatility and the broad applicability of iron oxide nanoparticles, and indicate the integration in future medical practice of multiple iron oxide nanoparticle-based materials.

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).

References (266)

  • Z. Hedayatnasab et al.

    Review on magnetic nanoparticles for magnetic nanofluid hyperthermia application

    Mater. Des.

    (2017)
  • C. Xu et al.

    New forms of superparamagnetic nanoparticles for biomedical applications

    Adv. Drug Deliv. Rev.

    (2013)
  • B.K. Sodipo et al.

    Recent advances in synthesis and surface modification of superparamagnetic iron oxide nanoparticles with silica

    J. Magn. Magn. Mater.

    (2016)
  • N. Remya et al.

    Toxicity, toxicokinetics and biodistribution of dextran stabilized Iron oxide Nanoparticles for biomedical applications

    Int. J. Pharm.

    (2016)
  • A.K. Gupta et al.

    Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications

    Biomaterials

    (2005)
  • K. Petcharoen et al.

    Synthesis and characterization of magnetite nanoparticles via the chemical co-precipitation method

    Mater. Sci. Eng. B

    (2012)
  • Y. Liu et al.

    Studies of Fe 3 O 4-chitosan nanoparticles prepared by co-precipitation under the magnetic field for lipase immobilization

    Catal. Commun.

    (2011)
  • S. Wu et al.

    Fe 3 O 4 magnetic nanoparticles synthesis from tailings by ultrasonic chemical co-precipitation

    Mater. Lett.

    (2011)
  • E. Roy et al.

    Stimuli-responsive poly(N-isopropyl acrylamide)-co-tyrosine@gadolinium: iron oxide nanoparticle-based nanotheranostic for cancer diagnosis and treatment

    Colloids Surf. B: Biointerfaces

    (2016)
  • I. Sharifi et al.

    Ferrite-based magnetic nanofluids used in hyperthermia applications

    J. Magn. Magn. Mater.

    (2012)
  • M.T.C. Fernandes et al.

    The competing effect of ammonia in the synthesis of iron oxide/silica nanoparticles in microemulsion/sol–gel system

    Colloids Surf. A Physicochem. Eng. Asp.

    (2013)
  • B.K. Sodipo et al.

    One minute synthesis of amino-silane functionalized superparamagnetic iron oxide nanoparticles by sonochemical method

    Ultrason. Sonochem.

    (2018)
  • E.H. Kim et al.

    Biomedical applications of superparamagnetic iron oxide nanoparticles encapsulated within chitosan

    J. Alloys Compd.

    (2007)
  • D. Ramimoghadam et al.

    Progress in electrochemical synthesis of magnetic iron oxide nanoparticles

    J. Magn. Magn. Mater.

    (2014)
  • J.K. Oh et al.

    Iron oxide-based superparamagnetic polymeric nanomaterials: design, preparation, and biomedical application

    Prog. Polym. Sci.

    (2011)
  • L. Li et al.

    Effect of synthesis conditions on the properties of citric-acid coated iron oxide nanoparticles

    Microelectron. Eng.

    (2013)
  • L. Zhang et al.

    Oleic acid coating on the monodisperse magnetite nanoparticles

    Appl. Surf. Sci.

    (2006)
  • J. Mamani et al.

    Synthesis and characterization of magnetite nanoparticles coated with lauric acid

    Mater. Charact.

    (2013)
  • B. Gaihre et al.

    Gelatin-coated magnetic iron oxide nanoparticles as carrier system: drug loading and in vitro drug release study

    Int. J. Pharm.

    (2009)
  • H.-l. Ma et al.

    Preparation and characterization of superparamagnetic iron oxide nanoparticles stabilized by alginate

    Int. J. Pharm.

    (2007)
  • J. Castelló et al.

    Chitosan (or alginate)-coated iron oxide nanoparticles: a comparative study

    Colloids Surf. A Physicochem. Eng. Asp.

    (2015)
  • A.J. Cole et al.

    Polyethylene glycol modified, cross-linked starch-coated iron oxide nanoparticles for enhanced magnetic tumor targeting

    Biomaterials

    (2011)
  • S. García-Jimeno et al.

    Ferrofluid based on polyethylene glycol-coated iron oxide nanoparticles: characterization and properties

    Colloids Surf. A Physicochem. Eng. Asp.

    (2013)
  • W. Brullot et al.

    Versatile ferrofluids based on polyethylene glycol coated iron oxide nanoparticles

    J. Magn. Magn. Mater.

    (2012)
  • S. Kayal et al.

    Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery

    Mater. Sci. Eng. C

    (2010)
  • N. Schleich et al.

    Dual anticancer drug/superparamagnetic iron oxide-loaded PLGA-based nanoparticles for cancer therapy and magnetic resonance imaging

    Int. J. Pharm.

    (2013)
  • W. Sun et al.

    Dendrimer-based magnetic iron oxide nanoparticles: their synthesis and biomedical applications

    Drug Discov. Today

    (2016)
  • Y.-X.J. Wang

    Superparamagnetic iron oxide based MRI contrast agents: current status of clinical application

    Quant. Imaging Med. Surg.

    (2011)
  • J. Vega-Chacón et al.

    pH-responsive poly (aspartic acid) hydrogel-coated magnetite nanoparticles for biomedical applications

    Mater. Sci. Eng. C

    (2017)
  • R. Cheng et al.

    Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery

    Biomaterials

    (2013)
  • H.-M. Yang et al.

    Multifunctional poly (aspartic acid) nanoparticles containing iron oxide nanocrystals and doxorubicin for simultaneous cancer diagnosis and therapy

    Colloids Surf. A Physicochem. Eng. Asp.

    (2011)
  • W. Wei et al.

    Synthesis and characterization of a novel pH-thermo dual responsive hydrogel based on salecan and poly (N, N-diethylacrylamide-co-methacrylic acid)

    Colloids Surf. B

    (2015)
  • E.A. Kamoun et al.

    Thermo-and pH-sensitive hydrogel membranes composed of poly (N-isopropylacrylamide)-hyaluronan for biomedical applications: influence of hyaluronan incorporation on the membrane properties

    Int. J. Biol. Macromol.

    (2018)
  • W. Wu et al.

    Recent progress on magnetic iron oxide nanoparticles: synthesis, surface functional strategies and biomedical applications

    Sci. Technol. Adv. Mater.

    (2015)
  • N. Lee et al.

    Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents

    Chem. Soc. Rev.

    (2012)
  • Y. Du et al.

    Design of superparamagnetic nanoparticles for magnetic particle imaging (MPI)

    Int. J. Mol. Sci.

    (2013)
  • R.M. Ferguson et al.

    Magnetic particle imaging with tailored iron oxide nanoparticle tracers

    IEEE Trans. Med. Imaging

    (2015)
  • J. Weizenecker et al.

    Three-dimensional real-time in vivo magnetic particle imaging

    Phys. Med. Biol.

    (2009)
  • E.A. Perigo et al.

    Fundamentals and advances in magnetic hyperthermia

    Appl. Phys. Rev.

    (2015)
  • J.B. Haun et al.

    Magnetic nanoparticle biosensors, Wiley

    Interdiscip. Rev. Nanomed. Nanobiotechnol.

    (2010)
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    These authors contributed equally to this work.

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