iron oxide-based polymeric magnetic nanoparticles for drug ... · and unique properties of iron...

Iron Oxide-Based Polymeric MagneticNanoparticles for Drug and Gene Delivery:In Vitro and In Vivo Applications in Cancer

Serap Yalcin and Ufuk Gündüz

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Iron Oxide-Based Magnetic Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Surface Coating of Magnetic Iron Oxide Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Characterization of Magnetic Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Biomedical Applications of Iron Oxide-Based Magnetic Nanoparticles in Cancer Diagnosis andTherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Gene Therapy with Magnetic Nanoparticles in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

AbstractIn the war against cancer, nanotechnology has important role by improving theefficacy of traditional therapies. Nanoparticle-based drug delivery system hasmany advantages including imaging, drug delivery, extended circulation time,and controlled release. In recent years, iron oxide-based polymeric magneticnanoparticles have gained significance in biomedical applications due to theirsuperparamagnetism, high surface area, low toxicity, and easy separation in thepresence of magnetic fields. Numerous methods have been developed for theproduction of iron oxide-based polymeric magnetic nanoparticles of differentshapes and sizes, including hydrothermal, coprecipitation, thermal decompositionelectrochemical, biological synthesis, etc. The nanoscale size, large surface area,

S. Yalcin (*)Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Kırsehir Ahi EvranUniversity, Kırsehir, Turkeye-mail: [email protected]; [email protected]

U. GündüzDepartment of Biology, Faculty of Arts and Sciences, Middle East Technical University,Ankara, Turkeye-mail: [email protected]

© Springer Nature Switzerland AG 2019C. M. Hussain, S. Thomas (eds.), Handbook of Polymer and Ceramic Nanotechnology,https://doi.org/10.1007/978-3-030-10614-0_38-1

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https://doi.org/10.1007/978-3-030-10614-0_38-1

and unique properties of iron oxide-based polymeric magnetic nanoparticlesmake them highly efficient in the diagnosis and treatment of such ailments ascancer, neurodegenerative disorders, and cardiovascular disease. This chapterinvestigates the design, synthesis, characterization, and in vivo/in vitro applica-tion of iron oxide-based polymeric magnetic nanoparticles in the treatment ofcancer, as well as recent progress and perspectives in the field.

KeywordsMagnetic polymeric nanoparticles · Synthesis · Characterization · Drug · Gene ·Cancer

Introduction

Recently, significant advances have been made in the use of nano-therapeutics forthe diagnosis and treatment of cancer. Magnetic iron oxide nanoparticles (MNPs) areone of the most important parts of nanomaterials, having gained popularity for use invarious pharmaceutical and biomedical applications, such as MRI, hyperthermia,targeted drug delivery disease therapy, diagnostic sensing, 3D cell culturing, cellseparating, etc. (Fig. 1; Bakhtiary et al. 2016).

The different synthesis methods for iron oxide-based magnetic nanoparticles havebeen developed for various application areas. They have low toxicity, shape, stabilityand dispersibility, and unique structural size-dependent properties (Soni et al. 2014),and these properties support the use of new drug delivery systems in the diagnosisand treatment of cancer. Magnetic nanoparticles, however, are chemically highlyactive and can easily become oxidized in air, and this can lead to a loss of magnetismand dispersibility of magnetic nanoparticles (Lu et al. 2007). Accordingly, thesurface modification of magnetic nanoparticles with different functional groups isimportant in the application of targeted drug delivery systems (Dilnawaz et al. 2010).Chemo-drug agent-loaded iron oxide-based magnetic nanoparticles offer advantageswhen targeting cancer cells (Chomoucka et al. 2010). Drug-loaded magnetic nano-particles can be used in the treatment of cancer to increase the drug accumulation inthe targeted tumor cells, providing for the reversal of drug resistance and ensuringhealthy cells are not damaged (Oh et al. 2017). In this chapter, we focus on recentstudies into the synthesis and properties of surface-coated iron oxide nanoparticlesystems designed for theranostic applications.

Iron Oxide-Based Magnetic Nanoparticles

Iron oxide nanoparticles are most often used for cancer therapy and for diagnosis andimaging applications. Metals like cobalt and nickel, as strong magnetic materials, aresensitive to oxidation and are toxic, and so there has been little interest in them(Hussain 2017). Nanoparticles smaller than 100 nm offer some clear advantages interms of greater surface areas, lower sedimentation rates, and developed tissular

2 S. Yalcin and U. Gündüz

diffusion (Park et al. 2005). Another advantage of these nanoparticles is theirmagnetic dipole-dipole interactions (Lee et al. 2004) that allow them to be targetedto pathologic tissue (Thorek et al. 2006).

The naturally occurring iron oxides are hematite (α-Fe2O3), magnetite (Fe3O4),and maghemite (γ-Fe2O3), and all are important in biomedical applications (Fig. 2).Hematite (α-Fe2O3) plays an n-type semiconductor role and has long-term stabilityunder ambient conditions. It is commonly used in catalysts, pigments, and gassensors due to its low cost, stability, and high resistance to corrosion, leading to itbeing widely investigated over the past decade. Magnetite, with the chemicalformula Fe3O4, is known also as lodestone and is a common ferrimagnetic that hasa cubic inverse spinel structure with an oxygen forming face-centered cubic (fcc)close packing structure (Wu et al. 2016).

Several methods have been developed for the synthesis of iron oxide (Fe3O4,MNPs) nanoparticles, containing coprecipitation of hydroxides, hydrothermal syn-thesis, solgel transformation (Kandpal et al. 2015; Table 1). Coprecipitation synthe-sis is one of the easiest and the most effective methods (Fig. 3; Peternele et al. 2014).In general, MNPs are prepared through the use of ferrous and ferric ions(FeCl2�4H2O and FeCl3�6H2O) and such precipitants as sodium hydroxide andammonia. The obtained MNPs have monodisperse and uniform properties as thequality of size and shape (Fig. 4; Shen et al. 2014). Magnetic particles are coatedwith a biocompatible polymer that includes dextran, chitosan, dendrimer, poly-

HandlingCell C

apture

Cellular

Proteomics

Diagnosis

Tracing

Sensing

Imag

ing

Therapy

Cell fate control

Hyperthermia

Drug delivery

Bio

sepa

ratio

n

Fig. 1 Schematic diagram of potential applications of iron oxide nanoparticles in medicine

Iron Oxide-Based Polymeric Magnetic Nanoparticles for Drug and Gene Delivery. . . 3

lactic-co-glycolic acid (PLGA), poly(vinyl alcohol) (PVA), and poly-hydroxybutyrate (PHB). The coating of MNPs with a polymer is important for invivo applications, allowing for the avoidance of the formation of large aggregates,changes to the original structure, and biodegradation when exposed to the biologicalsystem. Furthermore, the binding of therapeutic agents to the surface of polymer-coated MNPs have the potential to deliver drug-laden nano-formulations directlyinto the targeted cells in various disease therapies. The thermal decompositionmethod provides perfect control over the size and morphology of the nanoparticles.Monodispersed MNPs with various morphologies may also be synthesized viamicroemulsion, although one disadvantage of this method is that the excess solventis used during synthesis. The hydrothermal synthesis method is rarely used, althoughit leads to the production of high-quality magnetic nanoparticles (Lu et al. 2007;Table 1).

Surface Coating of Magnetic Iron Oxide Nanoparticles

Magnetic nanoparticles must endure long blood circulation times against aggrega-tion or precipitation in any treatment, although they have an easy aggregationbehavior, and surface protection of MNPs is obligatory (Pazos-Perez et al. 2007).There are two leading approaches to the surface coating of MNPs: one approach is tocoat the synthesized MNPs with organic shells (e.g., polymers, etc.) or inorganicsubstances (e.g., silica, carbon, etc.) (Zhu et al. 2012), while the other involves the insitu coating of MNPs in polymer/silica composites during the synthesis process(Corr et al. 2008). The most commonly used coatings materials are dextran andderivatives, chitosan, arabinogalactan, polyethylene glycol (PEG), polyvinylalcohol (PVA), poloxamers and polyoxamines, etc. (Table 2; Laurent et al. 2008).These polymers can be linked either chemically or physically using chemical

Fig. 2 Schematic illustrationof magnetic nanoparticles


reagents/cross-linkers on the surface of MNPs (Fig. 5). After being applied with apolymer coating, MNPs gain good water dispersibility and good physical andchemical stability (Laurent et al. 2004). The polymer coating on the surface ofmagnetic nanoparticles is important for biomedical applications, as functionalgroups of polymer-coated magnetic nanoparticles allow for the binding of anticancerdrugs to their surface (Sosnovik et al. 2007).

Table 1 Some of methods used for the synthesis of magnetic nanoparticles

Methods Synthesis procedure Properties of MNPs References

Coprecipitationsynthesismethod

Coprecipitation synthesisoccurs as a result of mixing oftwo or more metal salts andprecipitating medium (Laurentet al. 2008)

The quasi-sphericalshape, 13.5 � 3.2 nm inaverage diameter

Wang et al.(2012)

Thermaldecompositionsynthesismethod

The thermal decompositionprocessing produces ultrasmallmagnetic nanoparticles in thepresence of high temperature(Park et al. 2004)

Spherical shape and moreuniform size distribution,<3 nm in averagediameter

Erdem et al.(2017)

Solvothermal orhydrothermalsynthesismethod

The solvothermal synthesiscan be defined as chemicalreactions in a closed systems,higher temperature, andpressure (Byrappa andYoshimura 2001; Li et al.2015). During synthesis, ifwater is used as solvent,process is defined as“hydrothermal synthesis”

Sphere shape, �5 nm inaverage diameter

Cui et al.(2014)

Microemulsionsynthesismethod

The preparation procedure ofmicroemulsion involves achemical reaction, within theusually water and oil phase(Langevin 1992, Richard et al.2017)

�4.5 nm in averagediameter

Lopez et al.(2013)

Sonochemicalsynthesismethod

In sonochemical method,nanoparticles are preparedusing ultrasonic vibration bydissolving metal salts insolutions (Stankic et al. 2016)

~5.3 nm in averagediameter

Stephen et al.(2016)

Microwave-assistedsynthesismethod

Nanoparticles are producedunder microwave irradiation(Baghbanzadeh et al. 2011)

spherical shape, ~5–8 nmin average diameter

Liang et al.(2016),Wang andRuan (2007)

Biologicalsynthesismethod

The metal oxide nanoparticlesoccur under environmentalconditions such as plant andmicroorganism. This methodhas been accepted as a greenand efficient way (Deravi et al.2010)

Spherical shape,~60–80 nm in averagediameter

Sundaram etal. (2012)


Fig. 3 An illustration of magnetic nanoparticle synthesis via the coprecipitation method

Fig. 4 Magnetic separation of iron oxide nanoparticles via external magnetic fields (Yalcin andGunduz, unpublished data)


In cancer chemotherapy, the anticancer-agent-loaded nanoparticles permit themore efficient and preferential delivery of drugs to tumors due to the increasedpermeability and retention (EPR) effect (Feng and Tong 2016; Fig. 6). The EPReffect allows for the passive targeting of nanoparticles to the cancerous region owingto structural changes in the tumor blood vessels (Maeda 2001). Nanoparticles carrytherapeutic agents by improving the therapeutic index of agents through targeting,stretching the circulation half-life of drugs, and providing for the controlled releaseof the drug in the tumor microenvironment (Sanna et al. 2014).

Table 2 Different polymers/molecules that can be used for iron oxide core coating in cancer-targeted therapy

Polymer References

Dextran Unterweger et al. (2017)

Polyethylene glycol (PEG) Xiong et al. (2017)

Polyvinylpyrrolidone (PVP) Yang et al. (2016)

Polyvinyl alcohol (PVA) Nadeem et al. (2016)

Chitosan Parsian et al. (2016)

Poly-hydroxybutyrate (PHB) Yalcin et al. (2014)

Cyclodextrin Rastegari et al. (2017)

Sodium alginate Sood et al. (2017)

Polyethyleneimine Strojan et al. (2017)

Silica Rascol et al. (2017)

Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) Vazhnichaya et al. (2015)

Fig. 5 Same important linkers used in the conjugation of therapeutic agents to magneticnanoparticles


Anticancer agents such as palbociclib, paclitaxel, zoledronic acid, docetaxel,doxorubicin, gemcitabine, irinotecan, siRNA, miRNA, etc. can be conjugated/loaded onto surface-coated nanoparticles (Fig. 7), and in addition, therapeutic agentscan be encapsulated into various nanoparticles (Feng and Tong 2016). In Table 3 hasbeen shown that several magnetic nanoparticle-based therapeutics.

Characterization of Magnetic Nanoparticles

Characterization techniques are used to determine the properties of magnetic nano-particles (including surface morphology, chemical composition, and spatial distri-bution of the functional groups) (Hyeon 2003). The primary techniques used toinvestigate MNPs include X-ray diffraction analysis (XRD), dynamic light scatter-ing (DLS), Fourier-transform infrared spectroscopy (FTIR), transmission electronmicroscope (TEM), scanning electron microscope (SEM), atomic force microscopy(AFM), X-ray photoelectron spectroscopy (XPS), vibrating sample magnetometry(VSM), and thermal gravimetric analysis (TGA), nanoparticle tracking analysis,tilted laser microscopy, zeta-potential measurements, and hydrophobic interactionchromatography (Ali et al. 2016). The properties of the fundamental characterizationtechniques are summarized in Table 4.

The particle size and size distribution of magnetic nanoparticles are employedwith DLS (Goldburg 1999), TEM (Chatterjee et al. 2003), thermomagnetic mea-surement (DiPietro et al. 2010), dark-field microscopy (Lim et al. 2011), and AFM(Silva et al. 2004). TEM is one of the most efficient and popular analytical tools for

Fig. 6 Schematic illustration of the tumor targeting of therapeutic molecule-loaded magneticnanoparticles for cancer therapy


the determination of the direct structural and size information of the MNP (Lim et al.2013). Raman spectroscopy and infrared absorption spectroscopy are similar com-plementary methods, in that both use IR wavelength radiation and describe thechemical bonds of MNPs. The IR spectrum provides information on the functionalgroups on the surface of MNPs (Wan et al. 2007). X-ray diffraction (XRD) analyzesthe diffraction spectroscopy of materials stimulated via X-ray. Generally, a wide-angle XRD pattern exudes the presence of compounds magnetic solids, and the low-angle XRD pattern reveals the pore structure of the magnetic material (Ke et al.2012). X-ray photoelectron spectroscopy (XPS) is the most commonly used analysismethod in the investigation of the element components of magnetic materials (He etal. 2012).

Biomedical Applications of Iron Oxide-Based MagneticNanoparticles in Cancer Diagnosis and Therapy

Cancer is one of the most deadly diseases around the world (Boyle and Levin 2008).Effective early diagnosis can reduce the mortality associated with cancer. Chemo-therapy has many uses in the treatment of cancer, but at the same time, chemo-drugscome with many side effects such as nausea and vomiting, etc. Nanotechnologies are

Fig. 7 Anticancer agents and dendrimeric magnetic nanoparticles


Table 3 Presents selected published about anticancer drug/molecules loaded magnetic nano-particles in drug resistance/sensitive breast cancer cell lines

References Cell line Topics

Yalcin et al.(2015)

Doxorubicin-resistant MCF-7(MCF-7/1 μM) breast cancercells

Doxorubicin-loaded PHB-magneticnanoparticles

Wang et al.(2016b)

MCF-7/ADR breast cancer PTX/MNPs/QDs@Biotin-PEG-PCDAnanoparticles

Gunduz et al.(2014)

MCF-7 breast cancer Idarubicin-loaded folic acid conjugatedmagnetic nanoparticles

Zavareh etal. (2016)

Breast adenocarcinoma modelof BALB/c mice

DOX-imprinted polydopamine (DOX-IP)magnetic nanoparticles

Parsian et al.(2016)

SKBR and MCF-7 breastcancer cells

Gemcitabine-loaded chitosan magneticnanoparticles

Rose et al.(2013)

MCF-7 breast cancer cells Epirubicin hydrochloride FA-PVP-coated ironoxide nanoparticles

Tarvirdipouret al. (2016)

SKBR-3 (HER2-positivehuman breast cancer cell line)

Doxorubicin (DOX)-loaded magneticdextran-spermine (DEX-SP) nanocarriers(DEX-SP-DOX)

Peng et al.(2015)

MCF-7 cells Etoposide-β-cyclodextrin-modifiedFe3O4@ZnO:Er(3+),Yb(3+) nanocarrier

Arami et al.(2017)

MCF-7 cells Survivin-siRNA-loaded-Fe3O4-PEG-LAC-chitosan-PEI nanoparticles

Zolata et al.(2016)

SKBR3 cells Indium-111-labeled, trastuzumab- anddoxorubicin (DOX)-conjugated APTES-PEG-coated SPIONs

Table 4 The various techniques for the characterization of magnetic nanoparticles in cancertherapy and diagnosis

Analyses technique Defined properties

Literaturesamples foranalysestechnique

Thermogravimetric analysis(TGA)

The quantitative determination of thecoatings on nanoparticles

Rana et al. (2016)

Dynamic light scattering (DLS) The hydrodynamic mean diameter Rastegari et al.(2017)

Transmission electron microscopy(TEM), scanning electronmicroscopy(SEM)

The quantitative measures of particle,particle size, size distribution, andmorphology

Danafar et al.(2017)

Fourier-transform infraredspectroscopy (FTIR)

The surface chemistry Monteiro et al.(2017)

X-ray diffraction (XRD) The size determination, crystalstructure

Sulaiman et al.(2017)

Atomic force microscopy (AFM) The surface morphology, sizedetermination

Prabha and Raj(2017)

Small angle X-ray scattering(SAXS)

The size distributions, aggregatestructure

Guibert et al.(2015)


an emerging field in the detection and treatment of cancer (Weissleder 2006).Currently, the most effective means of cancer treatment is through the use ofnanotechnology-based therapeutic systems, which have exhibited clear benefitswhen compared to chemo-drugs, including nano-drug stability, increased half-life,targeted delivery, controlled drug release, and cost-efficiency. Nanotechnology-based therapeutics, as novel and highly effective agents, can allow the rapid andsensitive diagnosis and treatment of cancer (Wang et al. 2007). Furthermore, systemsinvolving new nanotechnology applications can detect cancer disease-specific bio-markers, can aid in the imaging of tumors and their metastases, can provide for thefunctional delivery of therapeutic agents to target cells, can overcome drug resis-tance, and can permit the real-time monitoring of treatment in progression(Parvanian et al. 2017).

MNPs are used in biomedical applications due to their nontoxic, magneticbehavior, as well as their small size (Berry and Curtis 2003). MNPs have beenapplied in magnetic resonance imaging (MRI), hyperthermia, and controlled drugdelivery/release for theranostic purposes (Zhu et al. 2017).

Nuclear MRI (magnetic resonance imaging) has been used to distinguish betweentissue types and so can be used with contrast agents to increase noninvasive clinicaldiagnosis. The size of paramagnetic, ferromagnetic, or superparamagnetic nano-particles are usually in the 1–100 nm range and have been used as MR contrastagents in medicine (Shabestari Khiabani et al. 2017).

High temperatures and hyperthermia (heat stress in the temperature range of41–47 �C) can actually destroy cancer cells, although they can also harm normalcells and tissue. In magnetic/targeting hyperthermia, when MNPs are given to thecancer patient, they can easily be delivered to the location of the cancer through theuse of a magnetic field. In the tumor region, MNPs lose their permanent magneticenergy, and this energy transforms into heat (Banobre-Lopez et al. 2013). Themagnetic energy loss of magnetic nanoparticles increases the temperature in thecancerous region, causing the cancer cells to heat up and die (Gkanas 2013). Thisheating therapy involving the use of MNPs has been studied extensively for itspotential in cancer therapy (Hajba and Guttman 2016; Hauser et al. 2015; Table 5).

Magnetic targeting refers to the ability to simultaneously carry drug-, molecule-,or gene-loaded MNPs to the targeted region. When anticancer agent-loaded MNPsenter the body, they can be accumulated in the targeted region in presence of anexternal magnetic field (Figs. 8 and 9; Mody et al. 2013). In the targeted region, theanticancer agents separate from the MNPs by simple diffusion or by mechanismsthat involve enzymatic activity or changes in physiological conditions, such as pH orosmolarity or temperature, and can exert a local effect on the cancer cells (Arruebo etal. 2007).

Gene Therapy with Magnetic Nanoparticles in Cancer

Gene therapy refers to the delivery of therapeutic nucleic acid (DNA, miRNA,siRNA oligonucleotides, etc.) into cells as a drug for the treatment of variousdiseases, including genetic disorders, cancer, and AIDS (Jiang et al. 2017).


In recent years, gene delivery systems have found use as therapeutic targets, inthat free genes are rapidly degraded by humoral substances and enzymes in cells.Over the past decade, there have been many studies in which magnetic nanoparticlesare used for the transfer of genes to tumor sites (Wang et al. 2016). Gene-loaded/

Table 5 The table presents selected published researches into iron oxide-based nanoparticles inbiomedical applications

Iron oxide nanoparticlesBiomedicalapplication In vitro/in vivo study References

Magnetic iron oxide/alginatecore-shell nanoparticles(Fe3O4@Alg-GA nanoparticles)

Targetinghyperthermia

Human hepatocellularcarcinoma cell line

Liao et al.(2015)

CREKA-conjugated iron oxidenanoparticles

Hyperthermia Lung cancer Kruse et al.(2014)

Doxorubicin (DOX) loaded-phospholipid-polyethyleneglycol (PEG) coating iron oxidenanoparticles

Hyperthermia Cervix cancer Quinto et al.(2015)

Fe/Fe3O4 core/shellnanoparticles

Hyperthermia Mouse model Balivada etal. (2010)

BSA-conjugated iron oxidenanoparticles

Hyperthermia Baby hamster kidney(BHK) cells

Kalidasan etal. (2016)

Heparin-coated iron oxidenanoparticles

MRI Mice Groult et al.(2017)

Iron oxide/gold ion nanoprobes MRI andhyperthermia

NIH-3 T3 fibroblast cellsand 4 T1 cancer cells

Fazal et al.(2017)

Folic acid-functionalizedpolyethyleniminesuperparamagnetic iron oxidenanoparticles

MRI Folate receptor-overexpressing gastriccancer cell line SGC-7901

Luo et al.(2017)

Dextran-coatedsuperparamagnetic iron oxidenanoparticles

MRI Pig model Unterwegeret al. (2017)

Paclitaxel-loaded polymer: PEG-PCCL-modified magnetic ironoxide nanoparticles

Targeteddelivery

HepG2 and HEK293 cells,Male BALB/c mice andNew Zealand rabbit

Li et al.(2017)

Survivin-siRNA loading Fe3O4-PEG-LAC-chitosan-PEInanoparticle

Targeteddelivery

Breast cancer MCF-7 andleukemia K562 cells

Arami et al.(2017)

Gemcitabine (Gem)-loadedPLGA � PEG magneticnanoparticles

Targeteddelivery

Human breast cancer cellline (MCF-7)

Hamzian etal. (2017)

Daunomycin-loadedsuperparamagnetic iron oxidenanoparticles

Targeteddelivery

Human cervixadenocarcinoma cell line(HeLa)

Liu et al.(2016)

PSMA targeted docetaxel-loadedsuperparamagnetic iron oxidenanoparticles

Targeteddelivery

prostate cancer C4–2(PSMA(+)) cells and PC-3(PSMA(�)) cells

Nagesh etal. (2016)


Fig. 8 Schematic representation of targeted drug delivery in cancerous tissue

Fig. 9 Magnetic nanoparticles as targeted theranostic agents for MRI


gene-attached nanoparticles are able to increase cellular internalization and thetargeted release of the genes, improving the treatment effect. Iron oxide-basednanoparticles as gene carriers can be coated with chitosan, PLGA, PEG, PAMAMdendrimer, etc. (Stephen et al. 2016), after which genes can be loaded/attached to thenanoparticle for the treatment of the disease.

siRNAs and miRNAs are noncoding RNAs with critical roles in gene regulationthat can be easily degraded by nuclei and have a negative charge that is similar to thatof cell membranes (Lawrence and Ceccoli 2017). Consequently, they lack thepotential to be internalized from the cell membrane. The delivery of therapeuticnoncoding RNAs into target cells is extremely important for successful therapy(Wang et al. 2018). Moreover, viral vector linked noncoding RNAs have immuno-logical and toxicological side effects (Gardlik et al. 2005). Specific noncoding RNA-linked nanoparticle systems cause efficient gene silencing (Lam et al. 2015), andsuch systems have been widely investigated as a novel anticancer approach(Zuckerman and Davis 2015). Some siRNA- and miRNA-linked magnetic nano-particles are shown in Fig. 10.

The development of nanoparticle systems for the delivery of miRNAs has beenreported for prostate cancer therapy (Khatri et al. 2012). Different cationic polymersand formulations have been studied with the goal of increasing delivery efficiencywith siRNA/miRNA for successful therapeutic applications (Fig. 11; Huang et al.2013; Nagesh et al. 2018).

Fig. 10 DNA/RNA-Loaded Magnetic Nanoparticle


Dendrimers, as a new class of polymers, have a large number of cavities andfunctional groups on the surface and are positively charged due to the presence ofamine groups on the surface that help the merging of negatively charged siRNAmolecules through electrostatic interactions. For this purpose, there are severalsiRNA-dendrimer delivery systems used for targeted delivery (Ahmadzada et al.2018). Iron oxide-based nanoparticles have magnetic resonance imaging propertiesthat allow them to deliver siRNAwithout degradation to tumor site/cells (Nagesh etal. 2018; Table 6).

Conclusion

Conventional cancer chemotherapies come with significant handicaps related to thevarious associated side effects and systemic toxicity against healthy cells/tissue.Over the last decades, various targeted drug delivery systems have been developed toovercome these deficiencies of chemotherapeutics. Iron oxide-based magnetic nano-particles have significant potential in magnetic field-guided drug delivery and

MagnetEndocytosis

Cytosol

Gene loadedmagneticnanoparticle

Gene release frommagnetic nanoparticles

Target genesilence

Nucleus

Fig. 11 Gene Therapy with Noncoding RNA-Linked Magnetic Nanoparticles


hyperthermia MRI due to their nanoscale size and specific biological properties. Theopportunities and current successes of iron oxide-based magnetic nanoparticles havealso shown excellent progress in cancer diagnosis and treatment. Furthermore, thesemagnetic nanoparticles offer great opportunities for young scientists in the investi-gation of further applications and studies.

Table 6 Iron oxide-based magnetic nanoparticles for targeted gene delivery in cancer

Nanoparticles Loaded gene In vitro/in vivo References

Polyethylenimine-coatedmagnetic nanoparticles

siRNA targetinghuman telomerasereverse transcriptase(hTERT) gene

MCF-7, HepG-2 Li et al.(2014)

PAMAM dendrimer-coated magneticnanoparticles

CpGoligodeoxynucleotide

MDA-MB231, SKBR3 Pourianazarand Gunduz(2016)

Fe3O4@SiO2nanoparticles

EGFP-encodingplasmid DNA

HepG2, C6, HEK293 Wang et al.(2016)

Galactose (Gal) andpolyethylenimine (PEI)-modified magneticnanoparticles(Gal-PEI-SPIO)

siRNA duplexestargeting c-Met

Hepa1–6 cells, hepatictumor model in C57BL/6mice

Yang et al.(2018)

Magnetic chitosannanoparticles

Ang2-smallinterfering (si)RNA

A-375 cells Zhao-Lianget al. (2016)

Lipidoid-coated ironoxide nanoparticles

DNA and siRNA HeLa cells Jiang et al.(2013)

Magnetic zinc-doped ironoxide (ZnFe2O4) corenanoparticle and abiocompatiblemesoporous silica shell(mSi)

let-7a microRNA anddoxorubicin

MDA-MB-231, MCF-7,MDAMB-231xenografted nude mice

Yin et al.(2018)

miRNA-145-basedmagnetic nanoparticleformulation (miR-145-MNPF)

miRNA-145 HPAF-II and AsPC-1 Setua et al.(2017)

PEG-coated Fe3O4nanoparticles

miRNA-16 SGC7901/ADR,SGC7901/ADRfluctumor-bearing nude mice

Sun et al.(2014)

PEI-coated magneticnanoparticles

let-7a microRNA U87-EGFRvIII, U87-WTand U87-EGFR cells,SUM159 breast cancercells tumor-bearing nu/numice

Yin et al.(2014)

MPEI-PEG-magneticnanoparticles

miR-205 C4–2 and PC-3 cells Nageshet al. (2018)


References

Ahmadzada T, Reid G, McKenzie DR (2018) Fundamentals of siRNA and miRNA therapeutics anda review of targeted nanoparticle delivery systems in breast cancer. Biophys Rev 10(1):69–86

Ali A, Zafar H, Zia M, Haq I, Phull AR, Ali JS, Hussain A (2016) Synthesis, characterization,applications, and challenges of iron oxide nanoparticles. Nanotechnol Sci Appl 9:49–67

Arami S, Rashidi MR, Mahdavi M, Fathi M, Entezami AA (2017) Synthesis and characterization ofFe3O4 -PEG-LAC-chitosan-PEI nanoparticle as a survivin siRNA delivery system. Hum ExpToxicol 36(3):227–237

Arruebo M, Fernández-Pacheco R, Ibarra M, Santamaría J (2007) Magnetic nanoparticles for drugdelivery. NanoToday 2:22–32

Baghbanzadeh M, Carbone L, Cozzoli PD, Kappe CO (2011) Microwave-assisted synthesis ofcolloidal inorganic nanocrystals. Angew Chem 50:11312–11359

Bakhtiary Z, Saei AA, Hajipour MJ, Raoufi M, Vermesh O, Mahmoudi M (2016) Targetedsuperparamagnetic iron oxide nanoparticles for early detection of cancer: possibilities andchallenges. Nanomed Nanotechnol Biol Med 12:287–307

Balivada S, Rachakatla RS, Wang H, Samarakoon TN, Dani RK, Pyle M, Kroh FO, Walker B,Leaym X, Koper OB, Tamura M, Chikan V, Bossmann SH, Troyer DL (2010) A/C magnetichyperthermia of melanoma mediated by iron(0)/iron oxide core/shell magnetic nanoparticles: amouse study. BMC Cancer 10:119

Banobre-Lopez M, Teijeiro A, Rivas J (2013) Magnetic nanoparticle-based hyperthermia for cancertreatment. Rep Pract Oncol Radiother 18(6):397–400

Berry C, Curtis A (2003) Functionalisation of magnetic nanoparticles for applications in biomed-icine. J Phys D Appl Phys 36:198

Boyle P, Levin B (2008) World cancer report. World Health Organization Press, GenevaByrappa K, Yoshimura M (2001) In: AndrewW (ed) Handbook of hydrothermal technology. Noyes

Publications, NorwichChatterjee J, Haik Y, Chen CJ (2003) Size dependent magnetic properties of iron oxide nano-

particles. J Magn Magn Mater 8:113–118Chomoucka J, Drbohlavova J, Huska D, Adam V, Kizek R, Hubalek J (2010) Magnetic nano-

particles and targeted drug delivering. Pharmacol Res 62:144–149Corr SA, Gun’ko YK, Douvalis AP, Venkatesan M, Gunning RD, Nellist PD (2008) From

nanocrystals to nanorods: new iron oxide-silica nanocomposites from metallorganic precursors.J Phys Chem C 112:1008–1018

Cui HJ, Cai JK, Zhao H, Yuan B, Ai C, Fu ML (2014) One step solvothermal synthesis of functionalhybrid γ-Fe2O3/carbon hollow spheres with superior capacities for heavy metal removal.J Colloid Interface Sci 425:131–135

Danafar H, Sharafi A, Askarlou S, Manjili HK (2017) Preparation and characterization of pegylatediron oxide- gold nanoparticles for delivery of sulforaphane and curcumin. Drug Res (Stuttg)67:698–704

Deravi LF, Swartz JD, Wright DW (2010) The biomimetic synthesis of metal oxide nanomaterials.Wiley, New York

Dilnawaz F, Singh A, Mohanty C, Sahoo SK (2010) Dual drug loaded superparamagnetic ironoxide nanoparticles for targeted cancer therapy. Biomaterials 31:3694–3706

DiPietro RS, Johnson HG, Bennett SP, Nummy TJ, Lewis LH (2010) Determining magneticnanoparticle size distributions from thermomagnetic measurements. Appl Phys Lett 8:222506

Erdem M, Yalcin S, Gunduz U (2017) Folic acid-conjugated polyethylene glycol-coated magneticnanoparticles for doxorubicin delivery in cancer chemotherapy: Preparation, characterizationand cytotoxicity on HeLa cell line. Hum Exp Toxicol 36(8):833–845

Fazal S, Paul-Prasanth B, Nair SV, Menon D (2017) Theranostic iron oxide/gold ion nanoprobes forMR imaging and noninvasive RF hyperthermia. ACS Appl Mater Interfaces 9(34):28260–28272


Feng Q, Tong R (2016) Anticancer nanoparticulate polymer-drug conjugate. Bioeng Transl Med1:277–296

Gardlik R, Palffy R, Hodosy J, Lukacs J, Turna J, Celec P (2005) Vectors and delivery systems ingene therapy. Med Sci Monit 11:110–121

Gkanas EI (2013) In vitro magnetic hyperthermia response of iron oxide MNP’s incorporated inDA3, MCF-7 and HeLa cancer cell lines. Cent Eur J Chem 17:1042–1054

Goldburg WI (1999) Dynamic light scattering. Am J Phys 8:1152–1160Groult H, Poupard N, Herranz F, Conforto E, Bridiau N, Sannier F, Bordenave S, Piot JM,

Ruiz-Cabello J, Fruitier-Arnaudin I, Maugard T (2017) Family of bioactive heparins-coatediron oxide nanoparticles with positive contrast in magnetic resonance imaging for specificbiomedical applications. Biomacromolecules 18(10):3156–3167

Guibert C, Dupuis V, Peyre V, Fresnais J (2015) Hyperthermia of magnetic nanoparticles: exper-imental study of the role of aggregation. J Phys Chem C 119(50):28148–28154

Gunduz U, Keskin T, Tansık G, Mutlu P, Yalcin S, Unsoy G, Yakar A, Khodadust R, Gunduz G(2014) Idarubicin-loaded folic acid conjugated magnetic nanoparticles as a targetable drugdelivery system for breast cancer. Biomed Pharmacother 68(6):729–736

Hajba L, Guttman A (2016) The use of magnetic nanoparticles in cancer theranostics: towardhandheld diagnostic devices. Biotechnol Adv 34(4):354–361

Hamzian N, Hashemi M, Ghorbani M, Bahreyni Toosi MH, Ramezani M (2017) Preparation,optimization and toxicity evaluation of (SPION-PLGA) �PEG nanoparticles loaded withgemcitabine as a multifunctional nanoparticle for therapeutic and diagnostic applications. IranJ Pharm Res 16(1):8–21

Hauser AK, Wydra RJ, Stocke NA, Anderson KW, Hilt JZ (2015) Magnetic nanoparticles andnanocomposites for remote controlled therapies. J Control Release 10(219):76–94

He Q, Yuan T, Wei S, Haldolaarachchige N, Luo Z, Young DP, Khasanov A, Guo Z (2012)Morphology- and phase-controlled iron oxide nanoparticles stabilized with maleicanhydridegrafted polypropylene. Angew Chem Int Ed Engl 51(35):8842–8845

Huang X, Schwind S, Yu B, Santhanam R, Wang H, Hoellerbauer P, Mims A, Klisovic R, WalkerAR, Chan KK et al (2013) Targeted delivery of microRNA-29b by transferrin-conjugatedanionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia.Clin Cancer Res 19:2355–2367

Hussain CM (2017) Magnetic nanomaterials for environmental analysis. In: Hussain CM,Kharisov B (eds) Advanced environmental analysis-application of nanomaterials. The RoyalSociety of Chemistry, Cambridge

Hyeon T (2003) Chemical synthesis of magnetic nanoparticles. Chem Commun 8:927–934Jiang S, Eltoukhy AA, Love KT, Langer R, Anderson DG (2013) Lipidoid-coated iron oxide

nanoparticles for efficient DNA and siRNA delivery. Nano Lett 13(3):1059–1064Jiang L, Vader P, Schiffelers RM (2017) Extracellular vesicles for nucleic acid delivery: progress

and prospects for safe RNA-based gene therapy. Gene Ther 24:157–166. https://doi.org/10.1038/gt.2017.8

Kalidasan V, Liu XL, Herng TS, Yang Y, Ding J (2016) Bovine serum albumin-conjugatedferrimagnetic iron oxide nanoparticles to enhance the biocompatibility and magnetic hyperther-mia performance. Nanomicro Lett 8:80–93

Kandpal ND, Sah N, Loshali R, Joshi R, Prasad J (2015) Co-precipitation method of synthesis andcharacterization of iron oxide nanoparticles. J Sci Ind Res 73(2):87–90

Ke F, Qiu LG, Yuan YP, Jiang X, Zhu JF (2012) Fe3O4@MOF core–shell magnetic microsphereswith a designable metal-organic framework shell. J Mater Chem 22:9497–9500

Khatri N, Rathi M, Baradia D, Trehan S, Misra A (2012) In vivo delivery aspects of miRNA, shrnaand siRNA. Crit Rev Ther Drug Carrier Syst 29:487–527

Kruse AM, Meenach SA, Anderson KW, Hilt JZ (2014) Synthesis and characterization of CREKA-conjugated iron oxide nanoparticles for hyperthermia applications. Acta Biomater 10(6):2622–2629

Lam JK, Chow MY, Zhang Y, Leung SW (2015) siRNA versus miRNA as therapeutics for genesilencing. Mol Ther Nucleic Acids 4:e252

Langevin D (1992) Micelles and microemulsions. Annu Rev Phys Chem 43:341–369


https://doi.org/10.1038/gt.2017.8

https://doi.org/10.1038/gt.2017.8

Laurent S, Vander Elst L, Fu Y, Muller RN (2004) Synthesis and physicochemical characterizationof Gd-DTPA-B(sLex)A, a new MRI contrast agent targeted to inflammation. Bioconjug Chem15(1):99–103

Laurent S, Forge D, Port M, Roch A, Robic C, Vander Elst L, Muller RN (2008) Magnetic ironoxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizationsand biological applications. Chem Rev 108:2064–2110

Lawrence P, Ceccoli J (2017) Advances in the application and impact of MicroRNAs as therapiesfor skin disease. BioDrugs 31(5):423–438

Lee SJ, Jeong JR, Shin SC, Kim JC, Chang YH et al (2004) Nanoparticles of magnetic ferric oxidesencapsulated with poly (D,L latide-co-glycolide) and their applications to magnetic resonanceimaging contrast agent. J Magn Magn Mater 272–276:2432–2433

Li D, Tang X, Pulli B, Lin C, Zhao P, Cheng J, Lv Z, Yuan X, Luo Q, Cai H, Ye M (2014)Theranostic nanoparticles based on bioreducible polyethylenimine-coated iron oxide for reduc-tion-responsive gene delivery and magnetic resonance imaging. Int J Nanomedicine9:3347–3361

Li J, Wub Q, Wu J (2015) Synthesis of nanoparticles via solvothermal and hydrothermal methods.In: Handbook of nanoparticles. Springer, Cham, pp 295–328

Li X, Yang Y, Jia Y, Pu X, Yang T, Wang Y, Ma X, Chen Q, Sun M, Wei D, Kuang Y, Li Y, Liu Y(2017) Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG-PCCL-modified magnetic iron oxide nanoparticles. Drug Deliv 24(1):1284–1294

Liang YJ, Zhang Y, Guo Z, Xie J, Bai T, Zou J, Gu N (2016) Ultrafast preparation of monodisperseFe3 O4 nanoparticles by microwave-assisted thermal decomposition. Chemistry 22(33):11807–11815

Liao SH, Liu CH, Bastakoti BP, Suzuki N, Chang Y, Yamauchi Y, Lin FH, Wu KCW (2015)Functionalized magnetic iron oxide/alginate core-shell nanoparticles for targeting hyperthermia.Int J Nanomedicine 10:3315–3328

Lim JK, Lanni C, Evarts ER, Lanni F, Tilton RD, Majetich SA (2011) Magnetophoresis ofnanoparticles. ACS Nano 8:217–226

Lim JK, Yeap SP, Che HX, Low SC (2013) Characterization of magnetic nanoparticle by dynamiclight scattering. Nanoscale Res Lett 8(1):381

Liu MC, Jin SF, Zheng M, Wang Y, Zhao PL, Tang DT, Chen J, Lin JQ, Wang XH, Zhao P (2016)Daunomycin-loaded superparamagnetic iron oxide nanoparticles: preparation, magnetictargeting, cell cytotoxicity, and protein delivery research. J Biomater Appl 31(2):261–272

Lopez RG, Pineda MG, Hurtado G, Díaz de León R, Fernández S, Saade H, Bueno D (2013)Chitosan-coated magnetic nanoparticles prepared in one step by reverse microemulsion precip-itation. Int J Mol Sci 14(10):19636–19650

Lu A, Salabas EL, Sch F (2007) Magnetic Nanoparticles: synthesis, Protection, Functionalization,and Application. Angew Chem Int Ed 46:1222–1244

Luo X, Peng X, Hou J, Wu S, Shen J, Wang L (2017) Folic acid-functionalized polyethyleniminesuperparamagnetic iron oxide nanoparticles as theranostic agents for magnetic resonanceimaging and PD-L1 siRNA delivery for gastric cancer. Int J Nanomedicine 12:5331–5343

Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: thekey role of tumor-selective macromolecular drug targeting. Adv Enzym Regul 41:189–2077

Mody VV, Cox A, Shah S, Singh A, Bevins W, Parihar H (2013) Magnetic nanoparticle drugdelivery systems for targeting tumor. Appl Nanosci 4:385–392

Monteiro AP, Caminhas LD, Ardisson JD, Paniago R, Cortés ME, Sinisterra RD (2017) Magneticnanoparticles coated with cyclodextrins and citrate for irinotecan delivery. Carbohydr Polym1(163):1–9

Nadeem M, Ahmad M, Akhtar MS, Shaari A, Riaz S, Naseem S, Masood M, Saeed MA (2016)Magnetic properties of polyvinyl alcohol and doxorubicine loaded iron oxide nanoparticles foranticancer drug delivery applications. PLoS One 11(6):e0158084

Nagesh PKB, Johnson NR, Boya VKN, Chowdhury P, Othman SF, Khalilzad-Sharghi V, HafeezBB, Ganju A, Khan S, Behrman SW, Zafar N, Chauhan SC, Jaggi M, Yallapu MM (2016)PSMA targeted docetaxel-loaded superparamagnetic iron oxide nanoparticles for prostatecancer. Colloids Surf B Biointerfaces 144:8–20


Nagesh PKB, Chowdhury P, Hatami E, Boya VKN, Kashyap VK, Khan S, Hafeez BB, ChauhanSC, Jaggi M, Yallapu MM (2018) miRNA-205 nanoformulation sensitizes prostate cancer cellsto chemotherapy. Cancers (Basel) 10(9):pii: E289

Oh Y, Moorthy MS, Manivasagan P, Bharathiraja S, Oh J (2017) Magnetic hyperthermia and pH-responsive effective drug delivery to the sub-cellular level of human breast cancer cells bymodified CoFe2O4 nanoparticles. Biochimie 133:7–19

Park J, An K, Hwang Y, Park JG, Noh HJ, Kim JY, Park JH, Hwang NM, Hyeon T (2004) Ultra-large-scale syntheses of monodisperse nanocrystals. Nat Mater 3(12):891–895

Park J, Lee E, Hwang NM, Kang MS, Kim SC et al (2005) One-nanometer-scale size-controlledsynthesis of monodisperse magnetic iron oxide nanoparticles. Angew Chem Int Ed 44(19):2872–2877

Parsian M, Unsoy G, Mutlu P, Yalcin S, Tezcaner A, Gunduz U (2016) Loading of Gemcitabine onchitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug. Eur J Pharmacol5(784):121–128

Parvanian S, Mostafavi SM, Aghashiri M (2017) Multifunctional nanoparticle developments incancer diagnosis and treatment. Sens Biosensing Res 13:81–87

Pazos-Perez N, Gao Y, Hilgendorff M, Irsen S, Pérez-Juste J, Spasova M, Farle M, Liz-Marzán LM,Giersig M (2007) Magnetic-noble metal nanocomposites with morphology-dependent opticalresponse. Chem Mater 19:4415–4422

Peng H, Cui B, Li G, Wang Y, Li N, Chang Z, Wang Y (2015) A multifunctional β-CD-modifiedFe3O4@ZnO:Er(3+),Yb(3+) nanocarrier for antitumor drug delivery and microwave-triggereddrug release. Mater Sci Eng C Mater Biol Appl 46:253–263

Peternele WS, Fuentes VM, Fascineli ML, Silva JR, Silva RC, Lucci CM, Azevedo RB (2014)Experimental investigation of the coprecipitation method: an approach to obtain magnetite andmaghemite nanoparticles with improved properties. J Nanomater 10:682985

Pourianazar NT, Gunduz U (2016) CpG oligodeoxynucleotide-loaded PAMAM dendrimer-coatedmagnetic nanoparticles promote apoptosis in breast cancer cells. Biomed Pharmacother78:81–91

Prabha G, Raj V (2017) Sodium alginate-polyvinyl alcohol-bovin serum albumin coated Fe3O4

nanoparticles as anticancer drug delivery vehicle: doxorubicin loading and in vitro release studyand cytotoxicity to HepG2 and L02 cells. Mater Sci Eng C Mater Biol Appl 79:410–422

Quinto CA, Mohindra P, Tong S, Bao G (2015) Multifunctional superparamagnetic ironoxide nanoparticles for combined chemotherapy and hyperthermia cancer treatment. Nanoscale7(29):12728–12736

Rana S, Shetake NG, Barick KC, Pandey BN, Salunke HG, Hassan PA (2016) Folic acid conjugatedFe3O4 magnetic nanoparticles for targeted delivery of doxorubicin. Dalton Trans 45(43):17401–17408

Rascol E, Daurat M, Da Silva A, Maynadier M, Dorandeu C, Charnay C, Garcia M, Lai-Kee-Him J,Bron P, Auffan M, Liu W, Angeletti B, Devoisselle JM, Guari Y, Gary-Bobo M, Chopineau J(2017) Biological fate of Fe3O4 core-shell mesoporous silica nanoparticles depending onparticle surface chemistry. Nanomaterials (Basel) 7(7):pii: E162

Rastegari B, Karbalaei-Heidari HR, Zeinali S, Sheardown H (2017) The enzyme-sensitive releaseof prodigiosin grafted β-cyclodextrin and chitosan magneticnanoparticles as an anticancer drugdelivery system: synthesis, characterization and cytotoxicity studies. Colloids Surf BBiointerfaces 18(158):589–601

Richard B, Lemyre JL, Ritcey AM (2017) Nanoparticle size control in microemulsion synthesis.Langmuir 33(19):4748–4757

Rose PA, Praseetha PK, Bhagat M, Alexander P, Abdeen S, Chavali M (2013) Drug embedded PVPcoated magnetic nanoparticles for targeted killing of breast cancer cells. Technol Cancer ResTreat 12(5):463–472

Sanna V, Pala N, Sechi M (2014) Targeted therapy using nanotechnology: focus on cancer.Int J Nanomedicine 9:467–483

Setua S, Khan S, Yallapu MM, Behrman SW, Sikander M, Khan SS, Jaggi M, Chauhan SC (2017)Restitution of tumor suppressor MicroRNA-145 using magnetic nanoformulation for pancreaticcancer therapy. J Gastrointest Surg 21(1):94–105


Shabestari Khiabani S, Farshbaf M, Akbarzadeh A, Davaran S (2017) Magnetic nanoparticles:preparation methods, applications in cancer diagnosis and cancer therapy. Artif Cells NanomedBiotechnol 45(1):6–17

Shen L, Qiao Y, Guo Y, Meng S, Yang G, Wu M, Zhao J (2014) Facile co-precipitation synthesis ofshape-controlled magnetite nanoparticles. Ceram Int 40:1519–1524

Silva LP, Lacava ZGM, Buske N, Morais PC, Azevedo RB (2004) Atomic force microscopy andtransmission electron microscopy of biocompatible magnetic fluids: a comparative analysis.J Nanopart Res 8:209–213

Soni S, Salhotra A, Suar M (2014) Handbook of Research on Diverse Applications of Nanotech-nology in Biomedicine, Chemistry, and Engineering. IGI Global

Sood A, Arora V, Shah J, Kotnala RK, Jain TK (2017) Multifunctional gold coated iron oxide core-shell nanoparticles stabilized using thiolated sodium alginate for biomedical applications. MaterSci Eng C Mater Biol Appl 80:274–281

Sosnovik DE, Nahrendorf M, Weissleder R (2007) Molecular magnetic resonance imaging incardiovascular medicine. Circulation 115(15):2076–2086

Stankic S, Suman S, Haque F, Vidic J (2016) Pure and multi metal oxide nanoparticles: synthesis,antibacterial and cytotoxic properties. J Nanobiotechnol 14(1):73

Stephen ZR, Dayringer CJ, Lim JJ, Revia RA, Halbert MV, Jeon M, Bakthavatsalam A, EllenbogenRG, Zhang M (2016) Approach to rapid synthesis and functionalization of iron oxide nano-particles for high gene transfection. ACS Appl Mater Interfaces 8(10):6320–6328

Strojan K, Lojk J, Bregar VB, Erdani-Kreft M, Svete J, Veranič P, Pavlin M (2017) In vitroassessment of potential bladder papillary neoplasm treatment with functionalized poly-ethyleneimine coated magnetic nanoparticles. Acta Chim Slov 64(3):543–548

Sulaiman GM, Tawfeeq AT, Naji AS (2017) Biosynthesis, characterization of magnetic iron oxidenanoparticles and evaluations of the cytotoxicity and DNA damage of human breast carcinomacell lines. Artif Cells Nanomed Biotechnol 21:1–15

Sun Z, Song X, Li X, Su T, Qi S, Qiao R, Wang F, Huan Y, Yang W, Wang J, Nie Y, Wu K, Gao M,Cao F (2014) In vivo multimodality imaging of miRNA-16 iron nanoparticle reversing drugresistance to chemotherapy in a mouse gastric cancer model. Nanoscale 6(23):14343–14353

Sundaram PA, Augustine R, Kannan M (2012) Extracellular biosynthesis of iron oxide nano-particles by Bacillus subtilis strains isolated from rhizosphere soil. Biotechnol Bioprocess Eng4:835–840

Tarvirdipour S, Vasheghani-Farahani E, Soleimani M, Bardania H (2016) Functionalized magneticdextran-spermine nanocarriers for targeted delivery of doxorubicin to breast cancer cells.Int J Pharm 501(1–2):331–341

Thorek DLJ, Chen A, Czupryna J, Tsourkas A (2006) Superparamagnetic iron oxide nanoparticleprobes for molecular imaging. Ann Biomed Eng 34(1):23–38

Unterweger H, Janko C, Schwarz M, Dézsi L, Urbanics R, Matuszak J, Őrfi E, Fülöp T, Bäuerle T,Szebeni J, Journé C, Boccaccini AR, Alexiou C, Lyer S, Cicha I (2017) Non-immunogenicdextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable con-trast agent for magnetic resonance imaging. Int J Nanomedicine 12:5223–5238

Vazhnichaya YM, Mokliak YV, Kurapov YA, Zabozlaev AA (2015) Role of mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) in the obtaining of stabilized magnetite nanoparticles forbiomedical application. Biomed Khim 61(3):384–388

Wan JQ, Cai W, Feng JT, Meng XX, Liu EZ (2007) In situ decoration of carbon nanotubes withnearly monodisperse magnetite nanoparticles in liquid polyols. J Mater Chem 17:1188–1192

WangWW, RuanML (2007) Microwave-assisted synthesis and magnetic property of magnetite andhematite nanoparticles. J Nanopart Res 9(3):419–426

Wang MD, Shin DM, Simons JW, Nie S (2007) Nanotechnology for targeted cancer therapy. ExpertRev Anticancer Ther 7:833–837

Wang J, Meng G, Tao K, Feng M, Zhao X, Li Z, Xu H, Xia D, Lu JR (2012) Immobilization oflipases on alkyl silane modified magnetic nanoparticles: effect of alkyl chain length on enzymeactivity. PLoS One 7(8):e43478


Wang R, Hu Y, Zhao N, Xu FJ (2016a) Well-defined peapod-like magnetic nanoparticles and theircontrolled modification for effective imaging guided gene therapy. ACS Appl Mater Interfaces8:11298–11308

Wang J, Wang F, Li F, ZhangW, Shen Y, Zhou D, Guo S (2016b) Amultifunctional poly (curcumin)nanomedicine for dual-modal targeted delivery, intracellular responsive release, dual-drugtreatment and imaging of multidrug resistant cancer cells. J Mater Chem B Mater Biol Med4(17):2954–2962

Wang R, Degirmenci V, Xin H, Li Y, Wang L, Chen J, Hu X, Zhang D (2018) PEI-coated Fe3O4

nanoparticles enable efficient delivery of therapeutic siRNA targeting REST into glioblastomacells. Int J Mol Sci 19(8):pii: E2230

Weissleder R (2006) Molecular imaging in cancer. Science 312:1168–1171Wu W, Jiang CZ, Vellaisamy AL (2016) Roy designed synthesis and surface engineering strategies

of magnetic iron oxide nanoparticles for biomedical applications. Nanoscale 8:19421Xiong F, Hu K, Yu H, Zhou L, Song L, Zhang Y, Shan X, Liu J, Gu N (2017) A Functional iron

oxide nanoparticles modified with PLA-PEG-DG as tumor-targeted MRI contrast agent. PharmRes 34(8):1683–1692

Yalcin S, Unsoy G, Mutlu P, Khodadust R, Gunduz U (2014) Polyhydroxybutyrate-coated magneticnanoparticles for doxorubicin delivery: cytotoxic effect against doxorubicin-resistant breastcancer cell line. Am J Ther 21(6):453–461

Yalcin S, Khodadust R, Ünsoy G, Garip IC, Mumcuoğlu ZD, Gündüz U (2015) Synthesis andcharacterization of poly-hydroxybutyrate (PHB) coated magnetic nanoparticles: toxicity ana-lyses on different cell lines. Synth React Inorg M 45:700–708

Yang G, Ma W, Zhang B, Xie Q (2016) The labeling of stem cells by superparamagnetic iron oxidenanoparticles modified with PEG/PVPor PEG/PEI. Mater Sci Eng C Mater Biol Appl62:384–390

Yang Z, Duan J, Wang J, Liu Q, Shang R, Yang X, Lu P, Xia C, Lin W, Dou K (2018)Superparamagnetic iron oxide nanoparticles modified with polyethylenimine and galactose forsiRNA targeted delivery in hepatocellular carcinoma therapy. Int J Nanomedicine13:1851–1865

Yin PT, Shah BP, Lee KB (2014) Combined magnetic nanoparticle-based microRNA and hyper-thermia therapy to enhance apoptosis in brain cancer cells. Small 10(20):4106–4112

Yin PT, Pongkulapa T, Cho HY, Han J, Pasquale NJ, Rabie H, Kim JH, Choi JW, Lee KB (2018)Overcoming chemoresistance in cancer via combined MicroRNA therapeutics with anticancerdrugs using multifunctional magnetic core-shell nanoparticles. ACS Appl Mater Interfaces 10(32):26954–26963

Zavareh S, Mahdi M, Erfanian S, Hashemi-Moghaddam H (2016) Synthesis of polydopamine as anew and biocompatible coating of magnetic nanoparticles for delivery of doxorubicin in mousebreast adenocarcinoma. Cancer Chemother Pharmacol 78(5):1073–1084

Zhao-Liang L, You C-L, Wang B, Lin J-H, Hu X-F, Shan X-Y, Wang M-S, Zheng H-B, Zhang Y-D(2016) Construction of Ang2-siRNA chitosan magnetic nanoparticles and the effect on Ang2gene expression in human malignant melanoma cells. Oncol Lett 11:3992–3998

Zhu GT, Li XS, Gao Q, Zhao NW, Yuan BF, Feng YQ (2012) Pseudomorphic synthesis ofmonodisperse magnetic mesoporous silica microspheres for selective enrichment of endogenouspeptides. J Chromatogr 1224:11–18

Zhu L, Zhou Z, Mao H, Yang L (2017) Magnetic nanoparticles for precision oncology: theranosticmagnetic iron oxide nanoparticles for image-guided and targeted cancer therapy. Nanomedicine(Lond) 12(1):73–87

Zolata H, Afarideh H, Davani FA (2016) Triple therapy of HER2+ cancer using radiolabeledmultifunctional iron oxide nanoparticles and alternating magnetic field. Cancer Biother Radio-pharm 31(9):324–329

Zuckerman JE, Davis ME (2015) Clinical experiences with systemically administered siRNA-basedtherapeutics in cancer. Nat Rev Drug Discov 14:843–856


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