ReviewRecent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics
Graphical abstract
Introduction
Cancer is one of the most dreadful diseases among all human diseases. According to World Health Organization (WHO) statistics, close to 8.2 million cancer related deaths had happened till 2012 and more than 14 million people are newly diagnosed with cancer (www.who.int/en/). All over the world, cancer related research is ongoing to control cancer as well as to kill cancer cells completely. Nanotechnology has garnered a great deal of attention in medical research and has created a vast impact on the economy (www.nano.gov) in recent days. A commission for regulating the usage of nanotechnology in biological applications is expected by approximately 43% of people, in a poll recently taken from more than 18,000 people via social media throughout the world (Sechi et al., 2014). Nanomedicines are significantly involved in cancer research because of their ability to provide an improvised therapeutic and diagnostic (theranostic) approach by overcoming multi-drug resistance of cancer cells and drawbacks of conventional cancer treatments such as poor solubility of hydrophobic anti-cancer drugs, biocompatibility, usage of harmful radiations, etc. In cancer nanomedicine, different nanoparticles, anticancer drugs and imaging agents are encapsulated and/or embedded within the biocompatible organic/inorganic shell structures to form a multifunctional system for combined therapy and imaging.
Among various nanoparticles, superparamagnetic iron oxide nanoparticles (SPIONs) particularly magnetite (Fe3O4) and meghamite (γ-Fe2O3) nanoparticles are used primarily in cancer theranostic applications such as magnetic resonance imaging (MRI) and magnetic hyperthermia due to their significant magnetic properties and biodegradability. Yet, toxicity of SPIONs towards normal cells has been pointed out by scientific communities, when SPIONs are involved in in vivo cancer treatments. SPIONs exhibit superparamagnetic behavior at size below 30 nm at room temperature. Superparamagnetism can be defined as the ability of magnetic nanoparticles to show robust paramagnetic nature with high susceptibility and saturation magnetization under the influence of a magnetic field and the tendency of losing the same nature completely once the magnetic field is removed, resulting in zero magnetic remanence and zero coercivity. The surfaces of SPIONs at reduced sizes are so reactive due to the increased surface area-to-volume ratio. So, the surfaces of SPIONs are usually coated with surfactants/capping agents/polymers to prevent agglomeration in colloidal solution, and to maintain the size and shape of SPIONs. Otherwise, SPIONs tend to aggregate to form bulk structures and settle down in colloidal solutions. However, these surface coatings affect the inherent magnetic properties of SPIONs depending upon the nature, amount/length, composition and thickness of the surface coatings.
The SPIONs are conjoined with other contrast agents, fluorescence tags/dyes, quantum dots, etc. for effective imaging of cancer cells/tissues through fluorescence imaging, near infra-red (NIR) imaging, computed tomography (CT), ultrasound imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), etc. The SPIONs are also combined with chemotherapeutic drugs (such as anthracyclines, antimetabolites, platinum-based-drugs, taxanes, vinca alkaloids and so on), nucleic acids (deoxyribonucleic acids and ribonucleic acids), unconjugated monoclonal antibodies (for instance, rituximab, trastuzumab), targeting agents (peptides, proteins, and small biological), photodynamic, photothermal and sonodynamic agents/nanoparticles to form combinatorial nanopackages for effective cancer treatment. However, the magnetic properties of SPIONs are deteriorated by the conjugation of these drugs/antibodies/other nanoparticles with SPIONs.
Many review articles have already discussed about various synthesis procedures, surface coatings, encapsulations and biomedical applications of the SPIONs. However, there is a serious lack of studies on the magnetic properties of the SPIONs at the fundamental level. Moreover, there is a lack of comprehensive studies on the recently developed SPIONs and their in vitro and in vivo applications for cancer theranostics. Therefore, we have discussed here the effects of physicochemical parameters such as size, shape and surface coatings on the magnetic properties of the SPIONs. Furthermore, we have discussed the mechanism of different predominant chemical synthesis of SPIONs and their encapsulation using silica and polymers. Finally, we have discussed the recent progress made in the usage of SPIONs independently and also in combination with other therapeutic and imaging agents for advanced in vitro and in vivo cancer theranostic applications.
Section snippets
Magnetic properties of SPIONs
The transformation from multi-domain phase to single-domain phase in a material begins at the nanometer scale. When the magnetostatic energy equalizes the domain-wall energy in magnetic nanomaterials, the single-domain phase dominates at specific dimensions. The critical diameter for a spherical Fe3O4 nanoparticle to possess a single-domain is believed to be 128 nm. At single-domain phase, SPIONs possess one huge magnetic moment and exhibit superparamagnetism above the blocking temperature (TB)
Synthesis methods of SPIONs
The basic strategies involved in the formation of SPIONs are physical, wet chemical, and microbial methods. Each method has its own advantages and disadvantages, and impacts over various properties of SPIONs. In this section, the predominant chemical procedures used for synthesizing SPIONs have been reviewed with typical examples.
Encapsulation of SPIONs
Both organic polymers and inorganic materials are extensively used for encapsulating the bare and surfactants/capping agents modified SPIONs (which are prepared using different chemical synthesis procedures) for improving the biocompatibility, increasing the cellular uptake, enhancing the circulation of SPIONs and preventing protein corona adsorption. The encapsulated SPIONs should be in definite sizes to prevent them from clearing through kidneys and from reticulo-endothelial system (RES) (i.e.
Magnetic resonance imaging (MRI)
In general, MRI is a biomedical imaging technique used to image soft tissues of human body in very thin slices in two dimensional as well as three dimensional spaces. The water present in our body plays an important role in obtaining MRI images. The hydrogen nucleus in water tends to align them in a direction parallel to applied external magnetic field. Then a radiofrequency (RF) signal is applied to change the direction of alignment of protons in the hydrogen nucleus, where the frequency of
Conclusion and perspectives
Much advancement has been achieved in preparing high quality SPIONs as compared to other nanoparticles/nanostructures for cancer theranostic applications. The SPIONs with different sizes, shapes and surface coatings have been engineered for achieving high crystallinity, very narrow size distribution, and improved magnetic properties for their better performance in biomedical applications. However, the usage of SPIONs is only limited to in vitro level except few in vivo studies and clinical
References (203)
- et al.
Key synthesis of magnetic Janus nanoparticles using a modified facile method
Particuology
(2014) - et al.
Carboxyl decorated Fe3O4 nanoparticles for MRI diagnosis and localized hyperthermia
J. Colloid Interface Sci.
(2014) - et al.
Rapid synthesis of water-dispersible superparamagnetic iron oxide nanoparticles by a microwave-assisted route for safe labeling of endothelial progenitor cells
Acta Biomater.
(2014) - et al.
Characterization of aqueous dispersions of Fe3O4 nanoparticles and their biomedical applications
Biomaterials
(2005) - et al.
Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration
Biomaterials
(2010) - et al.
Synthesis and characterization of magnetic iron oxide nanoparticles via w/o microemulsion and Massart's procedure
J. Mater. Process. Technol.
(2007) - et al.
Recent advances in iron oxide nanocrystal technology for medical imaging
Adv. Drug Deliv. Rev.
(2006) - et al.
Sonochemical synthesis of iron oxide nanoparticles loaded with folate and cisplatin: effect of ultrasonic frequency
Ultrason. Sonochem.
(2015) - et al.
Magnetic nanoparticle-induced hyperthermia treatment under magnetic resonance imaging
Magn. Reson. Imaging
(2011) - et al.
Gelatin-coated magnetic iron oxide nanoparticles as carrier system: drug loading and in vitro drug release study
Int. J. Pharm.
(2009)
Size-dependant heating rates of iron oxide nanoparticles for magnetic fluid hyperthermia
J. Magn. Magn. Mater.
Fe3O4/MnO hybrid nanocrystals as a dual contrast agent for both T1- and T2-weighted liver MRI
Biomaterials
Complete regression of mouse mammary carcinoma with a size greater than 15 mm by frequent repeated hyperthermia using magnetite nanoparticles
J. Biosci. Bioeng.
Synthesis of oleic acid functionalized Fe3O4 magnetic nanoparticles and studying their interaction with tumor cells for potential hyperthermia applications
Colloids Surf. B: Biointerfaces
Folic acid-conjugated Fe3O4 magnetic nanoparticles for hyperthermia and MRI in vitro and in vivo
Appl. Surf. Sci.
Dual MRI T1 and T2(*) contrast with size-controlled iron oxide nanoparticles
Nanomedicine
Synthesis and characterization of CREKA-conjugated iron oxide nanoparticles for hyperthermia applications
Acta Biomater.
Heparin-coated superparamagnetic iron oxide for in vivo MR imaging of human MSCs
Biomaterials
PEG-functionalized iron oxide nanoclusters loaded with chlorin e6 for targeted NIR light induced, photodynamic therapy
Biomaterials
Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells
Biomaterials
Folic acid-Pluronic F127 magnetic nanoparticle clusters for combined targeting, diagnosis, and therapy applications
Biomaterials
Magnetic iron oxide nanoparticles: reproducible tuning of the size and nanosized-dependent composition, defects, and spin canting
J. Phys. Chem. C
Toward design of magnetic nanoparticle clusters stabilized by biocompatible diblock copolymers for T2-weighted MRI contrast
Langmuir
A/C magnetic hyperthermia of melanoma mediated by iron(0)/iron oxide core/shell magnetic nanoparticles: a mouse study
BMC Cancer
Cell-delivered magnetic nanoparticles caused hyperthermia-mediated increased survival in a murine pancreatic cancer model
Int. J. Nanomed.
Properties and suspension stability of dendronized iron oxide nanoparticles for MRI applications
Contrast Media Mol. Imaging
Effect of the nanoparticle synthesis method on dendronized iron oxides as MRI contrast agents
Dalton Trans.
Facile synthesis and shape control of Fe3O4 nanocrystals with good dispersion and stabilization
CrystEngComm
Finite-size effects in fine particles: magnetic and transport properties
J. Phys. D: Appl. Phys.
Ultra magnetic liposomes for MR imaging, targeting, and hyperthermia
Langmuir
Tumor lysing genetically engineered T cells loaded with multi-modal imaging agents
Sci. Rep.
Magnetite nanoparticles can be coupled to microbubbles to support multimodal imaging
Biomacromolecules
Quasi-cubic magnetite/silica core–shell nanoparticles as enhanced MRI contrast agents for cancer imaging
PLoS ONE
Intracellular delivery of siRNA by polycationic superparamagnetic nanoparticles
J. Drug Deliv.
Synthesis of multifunctional magnetic nanoflakes for magnetic resonance imaging, hyperthermia, and targeting
ACS Appl. Mater. Interfaces
Design maps for the hyperthermic treatment of tumors with superparamagnetic nanoparticles
PLOS ONE
Multidentate block-copolymer-stabilized ultrasmall superparamagnetic iron oxide nanoparticles with enhanced colloidal stability for magnetic resonance imaging
Biomacromolecules
Highly crystallized iron oxide nanoparticles as effective and biodegradable mediators for photothermal cancer therapy
J. Mater. Chem. B
Composites of aminodextran-coated Fe3O4 nanoparticles and graphene oxide for cellular magnetic resonance imaging
ACS Appl. Mater. Interfaces
Core/shell structured hollow mesoporous nanocapsules: a potential platform for simultaneous cell imaging and anticancer drug delivery
ACS Nano
Hybrid nanotrimers for dual T1 and T2-weighted magnetic resonance imaging
ACS Nano
Photon activated therapy (PAT) using monochromatic synchrotron X-rays and iron oxide nanoparticles in a mouse tumor model: feasibility study of PAT for the treatment of superficial malignancy
Radiat. Oncol.
Synthesis of various magnetite nanoparticles through simple phase transformation and their shape-dependent magnetic properties
RSC Adv.
Nanoscale size effect on surface spin canting in iron oxide nanoparticles synthesized by the microemulsion method
J. Phys. D: Appl. Phys.
Assessment of DNA complexation onto polyelectrolyte-coated magnetic silica nanoparticles
Nanoscale
Study of heating efficiency as a function of concentration size, and applied field in γ-Fe2O3 nanoparticles
J. Phys. Chem. C
SiO2 versus chelating agent@ iron oxide nanoparticles: interactions effect in nanoparticles assemblies at low magnetic field
J. Sol–Gel Sci. Technol.
99mTc-bisphosphonate-iron oxide nanoparticle conjugates for dual-modality biomedical imaging
Bioconjug. Chem.
Green synthesis of Fe3O4 nanoparticles by one-pot saccharide-assisted hydrothermal method
Turk. J. Chem.
Physicochemical characterization of ultrasmall superparamagnetic iron oxide particles (USPIO) for biomedical application as MRI contrast agents
Int. J. Nanomed.
Cited by (328)
Amino-modified IONPs potentiates ferroptotic cell death due to the release of Fe ion in the lysosome
2025, Journal of Environmental Sciences (China)From 0D to 2D: Synthesis and bio-application of anisotropic magnetic iron oxide nanomaterials
2024, Progress in Materials ScienceNanomaterials in theranostics
2024, Handbook of Nanomaterials, Volume 2: Biomedicine, Environment, Food, and AgricultureMagnetic properties of Al<sup>3+</sup> doped Fe<inf>3</inf>O<inf>4</inf> by solid-solid reaction and biological applications of GQDs grafted MNPs
2023, Journal of Magnetism and Magnetic Materials