Recent advances in superparamagnetic iron oxide...

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International Journal of Pharmaceutics 496 (2015) 191–218 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Review Recent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics Ganeshlenin Kandasamy, Dipak Maity Nanomaterials Lab, Department of Mechanical Engineering, Shiv Nadar University, Uttar Pradesh 201314, India article info Article history: Received 19 August 2015 Received in revised form 20 October 2015 Accepted 22 October 2015 Available online 28 October 2015 Keywords: Magnetic nanoparticles Superparamagnetic iron oxide Synthesis and surface engineering Spin canting Cancer theranostics Magnetic resonance imaging Hyperthermia abstract Recently superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used in cancer therapy and diagnosis (theranostics) via magnetic targeting, magnetic resonance imaging, etc. due to their remarkable magnetic properties, chemical stability, and biocompatibility. However, the magnetic properties of SPIONs are influenced by various physicochemical and synthesis parameters. So, this review mainly focuses on the influence of spin canting effects, introduced by the variations in size, shape, and organic/inorganic surface coatings, on the magnetic properties of SPIONs. This review also describes the several predominant chemical synthesis procedures and role of the synthesis parameters for monitoring the size, shape, crystallinity and composition of the SPIONs. Moreover, this review discusses about the latest developments of the inorganic materials and organic polymers for encapsulation of the SPIONs. Finally, the most recent advancements of the SPIONs and their nanopackages in combination with other imaging/therapeutic agents have been comprehensively discussed for their effective usage as in vitro and in vivo theranostic agents in cancer treatments. © 2015 Elsevier B.V. All rights reserved. Contents 1. Introduction ........................................................................................................................................... 192 2. Magnetic properties of SPIONs ........................................................................................................................ 192 2.1. Effect of size and crystallinity ................................................................................................................. 193 2.2. Effect of surface coatings ...................................................................................................................... 194 2.3. Effect of shape .................................................................................................................................. 194 3. Synthesis methods of SPIONs ......................................................................................................................... 196 3.1. Co-precipitation method ....................................................................................................................... 196 3.2. Thermal decomposition method .............................................................................................................. 196 3.3. Hydrothermal method ......................................................................................................................... 196 3.4. Microemulsion method ........................................................................................................................ 197 3.5. Sonochemical method ......................................................................................................................... 197 3.6. Microwave-assisted synthesis ................................................................................................................. 197 4. Encapsulation of SPIONs ............................................................................................................................... 197 4.1. Organic encapsulation ......................................................................................................................... 197 4.1.1. Synthetic polymer encapsulation .................................................................................................... 197 4.1.2. Natural polymer encapsulation ...................................................................................................... 198 4.2. Inorganic encapsulation ....................................................................................................................... 198 4.2.1. Silica encapsulation .................................................................................................................. 198 5. Cancer theranostic applications of SPIONs ............................................................................................................ 199 5.1. Magnetic resonance imaging (MRI) ........................................................................................................... 199 5.1.1. SPIONs as T2 MRI contrast agents ................................................................................................... 200 5.1.2. SPIONs as T1/dual mode (T1–T2) MRI contrast agents .............................................................................. 202 Corresponding author. E-mail address: [email protected] (D. Maity). http://dx.doi.org/10.1016/j.ijpharm.2015.10.058 0378-5173/© 2015 Elsevier B.V. All rights reserved.

Transcript of Recent advances in superparamagnetic iron oxide...

Page 1: Recent advances in superparamagnetic iron oxide ...specificpolymers.fr/medias/publications/2015-09.pdfvolume arising from variations in magnetic nanoparticle prepa-ration methods (Serna

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International Journal of Pharmaceutics 496 (2015) 191–218

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

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ecent advances in superparamagnetic iron oxide nanoparticlesSPIONs) for in vitro and in vivo cancer nanotheranostics

aneshlenin Kandasamy, Dipak Maity ∗

anomaterials Lab, Department of Mechanical Engineering, Shiv Nadar University, Uttar Pradesh 201314, India

r t i c l e i n f o

rticle history:eceived 19 August 2015eceived in revised form 20 October 2015ccepted 22 October 2015vailable online 28 October 2015

eywords:agnetic nanoparticles

a b s t r a c t

Recently superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used in cancertherapy and diagnosis (theranostics) via magnetic targeting, magnetic resonance imaging, etc. due totheir remarkable magnetic properties, chemical stability, and biocompatibility. However, the magneticproperties of SPIONs are influenced by various physicochemical and synthesis parameters. So, this reviewmainly focuses on the influence of spin canting effects, introduced by the variations in size, shape, andorganic/inorganic surface coatings, on the magnetic properties of SPIONs. This review also describes theseveral predominant chemical synthesis procedures and role of the synthesis parameters for monitoring

uperparamagnetic iron oxideynthesis and surface engineeringpin cantingancer theranosticsagnetic resonance imaging

the size, shape, crystallinity and composition of the SPIONs. Moreover, this review discusses about thelatest developments of the inorganic materials and organic polymers for encapsulation of the SPIONs.Finally, the most recent advancements of the SPIONs and their nanopackages in combination with otherimaging/therapeutic agents have been comprehensively discussed for their effective usage as in vitro andin vivo theranostic agents in cancer treatments.

yperthermia © 2015 Elsevier B.V. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1922. Magnetic properties of SPIONs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

2.1. Effect of size and crystallinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1932.2. Effect of surface coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1942.3. Effect of shape. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .194

3. Synthesis methods of SPIONs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1963.1. Co-precipitation method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1963.2. Thermal decomposition method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1963.3. Hydrothermal method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1963.4. Microemulsion method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1973.5. Sonochemical method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1973.6. Microwave-assisted synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

4. Encapsulation of SPIONs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1974.1. Organic encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

4.1.1. Synthetic polymer encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1974.1.2. Natural polymer encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

4.2. Inorganic encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1984.2.1. Silica encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

5. Cancer theranostic applications of SPIONs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

5.1. Magnetic resonance imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.1.1. SPIONs as T2 MRI contrast agents . . . . . . . . . . . . . . . . . . . . . . . .5.1.2. SPIONs as T1/dual mode (T1–T2) MRI contrast agents . . .

∗ Corresponding author.E-mail address: [email protected] (D. Maity).

ttp://dx.doi.org/10.1016/j.ijpharm.2015.10.058378-5173/© 2015 Elsevier B.V. All rights reserved.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

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192 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

5.2. Magnetic hyperthermia therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2025.3. Magnetic targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2045.4. Magnetofection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2055.5. SPIONs in combination with dopants/other imaging agents for multimodal imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085.6. SPIONs in combination with other therapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .210

5.6.1. In combination with photodynamic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2105.6.2. In combination with photothermal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2115.6.3. In combination with sonodynamic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

6. Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213. . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Cancer is one of the most dreadful diseases among all humaniseases. According to World Health Organization (WHO) statistics,lose to 8.2 million cancer related deaths had happened till 2012nd more than 14 million people are newly diagnosed with can-er (www.who.int/en/). All over the world, cancer related researchs ongoing to control cancer as well as to kill cancer cells com-letely. Nanotechnology has garnered a great deal of attention

n medical research and has created a vast impact on the econ-my (www.nano.gov) in recent days. A commission for regulatinghe usage of nanotechnology in biological applications is expectedy approximately 43% of people, in a poll recently taken fromore than 18,000 people via social media throughout the world

Sechi et al., 2014). Nanomedicines are significantly involved inancer research because of their ability to provide an improvisedherapeutic and diagnostic (theranostic) approach by overcoming

ulti-drug resistance of cancer cells and drawbacks of conven-ional cancer treatments such as poor solubility of hydrophobicnti-cancer drugs, biocompatibility, usage of harmful radiations,tc. In cancer nanomedicine, different nanoparticles, anticancerrugs and imaging agents are encapsulated and/or embeddedithin the biocompatible organic/inorganic shell structures to formmultifunctional system for combined therapy and imaging.

Among various nanoparticles, superparamagnetic iron oxideanoparticles (SPIONs) particularly magnetite (Fe3O4) andeghamite (�-Fe2O3) nanoparticles are used primarily in can-

er theranostic applications such as magnetic resonance imagingMRI) and magnetic hyperthermia due to their significant magneticroperties and biodegradability. Yet, toxicity of SPIONs towardsormal cells has been pointed out by scientific communities,hen SPIONs are involved in in vivo cancer treatments. SPIONs

xhibit superparamagnetic behavior at size below 30 nm at roomemperature. Superparamagnetism can be defined as the abilityf magnetic nanoparticles to show robust paramagnetic natureith high susceptibility and saturation magnetization under the

nfluence of a magnetic field and the tendency of losing the sameature completely once the magnetic field is removed, resulting

n zero magnetic remanence and zero coercivity. The surfacesf SPIONs at reduced sizes are so reactive due to the increasedurface area-to-volume ratio. So, the surfaces of SPIONs are usuallyoated with surfactants/capping agents/polymers to preventgglomeration in colloidal solution, and to maintain the size andhape of SPIONs. Otherwise, SPIONs tend to aggregate to formulk structures and settle down in colloidal solutions. However,hese surface coatings affect the inherent magnetic properties ofPIONs depending upon the nature, amount/length, compositionnd thickness of the surface coatings.

The SPIONs are conjoined with other contrast agents, fluo-escence tags/dyes, quantum dots, etc. for effective imaging of

ancer cells/tissues through fluorescence imaging, near infra-redNIR) imaging, computed tomography (CT), ultrasound imaging,ositron emission tomography (PET), single photon emission com-uted tomography (SPECT), etc. The SPIONs are also combined with

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

chemotherapeutic drugs (such as anthracyclines, antimetabolites,platinum-based-drugs, taxanes, vinca alkaloids and so on), nucleicacids (deoxyribonucleic acids and ribonucleic acids), unconjugatedmonoclonal antibodies (for instance, rituximab, trastuzumab),targeting agents (peptides, proteins, and small biological), photo-dynamic, photothermal and sonodynamic agents/nanoparticles toform combinatorial nanopackages for effective cancer treatment.However, the magnetic properties of SPIONs are deteriorated bythe conjugation of these drugs/antibodies/other nanoparticles withSPIONs.

Many review articles have already discussed about various syn-thesis procedures, surface coatings, encapsulations and biomedicalapplications of the SPIONs. However, there is a serious lack of stud-ies on the magnetic properties of the SPIONs at the fundamentallevel. Moreover, there is a lack of comprehensive studies on therecently developed SPIONs and their in vitro and in vivo applica-tions for cancer theranostics. Therefore, we have discussed herethe effects of physicochemical parameters such as size, shape andsurface coatings on the magnetic properties of the SPIONs. Further-more, we have discussed the mechanism of different predominantchemical synthesis of SPIONs and their encapsulation using silicaand polymers. Finally, we have discussed the recent progress madein the usage of SPIONs independently and also in combination withother therapeutic and imaging agents for advanced in vitro andin vivo cancer theranostic applications.

2. Magnetic properties of SPIONs

The transformation from multi-domain phase to single-domainphase in a material begins at the nanometer scale. When themagnetostatic energy equalizes the domain-wall energy in mag-netic nanomaterials, the single-domain phase dominates at specificdimensions. The critical diameter for a spherical Fe3O4 nanopar-ticle to possess a single-domain is believed to be 128 nm. Atsingle-domain phase, SPIONs possess one huge magnetic momentand exhibit superparamagnetism above the blocking temperature(TB) (size and shape dependent phenomena), while the thermalenergy overcomes the anisotropy energy of magnetic materials. Therelationships for anisotropy energy (E(�)) and superparamagneticrelaxation time (�) (with respect to temperature) are given below:

E(�) = KV sin2 � (1)

� = �0 exp(

KV

kBT

)(2)

where K is the magnetic anisotropy constant, V is the particle vol-ume, � is the angle between an easy axis and a magnetization vector,kB is Boltzmann’s constant and T is the temperature. �0 is in therange of 10−13–10−9 s. Usually, in a colloidal solution, the mag-netic moments of suspended SPIONs align themselves along the

easy axis during the absence of magnetic field. However, the mag-netic moments tend to align themselves in a direction parallel tothe applied field, when magnetic field is applied, thereby resultingin high magnetization values. But, once the field is removed, the
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ournal of Pharmaceutics 496 (2015) 191–218 193

md

oftciitiiaseoMsfopssaAmfM(enbfid

2

morvm(

m

wcnaspait2er

ivvrtn

Fig. 1. Schematic illustration of change in composition of magnetic nanoparticlesthat evolve from meghamite for small sizes (typically <8 nm) to a core of ratherstoichiometric magnetite surrounded by an oxidized shell for large sizes (>12 nm)via a perturbed oxidized state for intermediate sizes along with change in surfaceand volume spin canting.

Reproduced with permission from Baaziz et al. (2014), © American Chemical Society.

Fig. 2. Schematic illustration of spin phenomena in small-sized (a) iron oxide (IO)and (b) gadolinium doped iron oxide (GdIO) nanoparticles. The gadolinium species(Gd2O3 nanoclusters) in GdIO nanoparticles (−5 nm in diameter) cause an innerspin-canting effect, while the IO nanoparticles (−5 nm in diameter) contain a spin-

G. Kandasamy, D. Maity / International J

oments of SPIONs revert back to their original easy axis positionsue to longitudinal and transverse relaxivities of SPIONs.

In SPIONs, the magnetic moments appear due to the presencef unpaired 3d electrons in Fe3+ and Fe2+ cations in the cubiccc lattice, where an electron spin coupling of Fe2+ and Fe3+ ionsakes place at octahedral sites and an anti-parallel electron spinoupling of Fe3+ ions takes place at tetrahedral sites. Exchangenteraction/coupling between these two sites across oxygen anionss called as superexchange interactions which are responsible forhe magnetic behavior of SPIONs. Destruction of superexchangenteractions can also happen at the surface of SPIONs, due to thenclination of the surface atomic spins of magnetic nanoparticles toparticular angle (called canting angle). The inclination effect (or

pin canting effect) is due to: (i) the lack of number of atoms nec-ssary for the formation of single magnetic moment and/or (ii) lessrganized spins at the surface as compared to the core of SPIONs.oreover, spin glass like layers (i.e., slow relaxation behavior of

urface atoms of SPIONs) may also occur with respect the magneticrustrations between the Fe2+ and Fe3+ atoms located on the surfacef SPIONs. Oxygen vacancies, edge roughness, defects in cationicositions (cationic vacancies), Laplace pressure and changes inurface and/or core chemical ordering and anisotropies (i.e., localymmetry breaking due to the presence of dead magnetic layernd/or anti-ferromagnetic layer formed by surfactants) (Maity andgrawal, 2007) of SPIONs could be the other factors that affect theagnetic properties of iron oxide nanoparticles, besides the sur-

ace spin canting effects. Hyperfine spectral lines (obtained fromossbauer spectroscopy), field cooled (FC) and zero field cooled

ZFC) methods (obtained from superconducting quantum interfer-nce device) are used for determining canted spins, presence ofon-magnetic layers (from surface coatings) and spin-glass likeehavior. All these magnetic phenomena change with the modi-cations in size, shape and surface coating of SPIONs, which areiscussed in following sections with typical examples.

.1. Effect of size and crystallinity

The size reduction of SPIONs results in the decrease of magneticoments of SPIONs, thereby reducing the saturation magnetization

f SPIONs. Nevertheless, the spin canting effect is increased at sizeeduced nanoparticles, ascribing to the increase in surface area-to-olume ratio of SPIONs. The inter-relationship between the size,agnetization and spin-canted surface layer can be given by Eq.

3):

s = Ms

[(r − d)

r

]3

(3)

here ms is saturation magnetization of size-reduced nanoparti-le, Ms is saturation magnetization of bulk materials, r is the size ofanoparticle and d is the thickness of disordered surface layer. Inrecent investigation, it was estimated that about 93.6% of surface

pins in 3-nm sized iron oxide nanoparticles were canted as com-ared to 38.6% of surface spins in 12-nm sized nanoparticles (byssuming 0.9 nm spin canting layer thickness). As a result of thencreased canting effects in 3 nm sized iron oxide nanoparticles,he magnetization values decreased correspondingly (Kim et al.,011). Similarly, in another study, 5 nm sized Fe3O4 nanoparticlesxhibited a low magnetization value of 27 emu/g, attributed to itseduced size (Chen et al., 2011).

Aside from surface spin canting, volume canting also occursn magnetic nanoparticles, attributed to the presence of cationicacancies, improper crystallinity and reduced magnetic core

olume arising from variations in magnetic nanoparticle prepa-ation methods (Serna et al., 2001). In a recent investigation,he internal/volume and surface canting effects were studied onanoparticles of 5 different sizes (5, 8, 11, 15 and 20 nm), where

canted surface and spin-oriented core.

Reproduced with permission from Zhou et al. (2013), © American Chemical Society.

5 nm iron oxide nanoparticles possessed a surface canting layerthickness of one atomic layer and exhibited a magnetization valueof 51 emu/g approximately (Baaziz et al., 2014). The thickness ofcanting layer increased to two atomic layer thicknesses for 8, 9, and11 nm sized SPIONs due to the disordered structure initiated byperturbed oxidation states, thereby brought both surface and vol-ume canting effect at these sizes (as shown in Fig. 1). However, thecanting layer thickness fell rapidly for large (>11 nm) nanoparticlesbecause of the changes of iron atoms in their respective interstitialsites, and the magnetite compositions of iron oxide nanoparticles,thus the larger sized magnetic nanoparticles (such as 15 and 20 nm)exhibited higher magnetization values (71 and 82 emu/g respec-tively). In another study, 15 nm sized spherical Fe3O4 nanoparticlesdisplayed magnetization value of 53.3 emu/g, ascribed to the reduc-tion in magnetic effective volume (Ge et al., 2009). Therefore, spincanting effect in a nanoparticle is a mixture of both surface andvolume spin canting effects. The spin canting effects are dependenton temperature and applied magnetic field. Moreover, volume andsurface spin canting effects also occur in magnetic nanoparticles,when the iron oxide nanoparticles are being doped with otheratoms (gadolinium) (as shown in Fig. 2) (Zhou et al., 2013).

In addition to the spin canting effects, anti-phase boundaries(APB – a crystal defect occurs on planes while chemical order-ing) also affect the magnetic properties of SPIONs at reduced sizes.Wetterskog et al. (2013) observed the presence of APBs in single-phase 20 nm sized SPIONs (shaped via oxidation of the core madeof rock salt (Fe1−xO)), resulting in low magnetization values. How-ever, in another investigation, APB and other magnetic disorders(preceding to exchange bias) were found to be absent even in multi-core highly-crystalline citrate-coated SPIONs due to their sharedcrystallographic orientations (Lartigue et al., 2012). Herein, the

multi-core SPIONs retained superparamagnetic properties at roomtemperature even at large sizes (19–30 nm) with magnetizationvalues up to 82 emu/g. Moreover, the multi-core SPIONs remainedequally dispersed as compared to single-core SPIONs even after the
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194 G. Kandasamy, D. Maity / International Journa

Fig. 3. Influence of surface ligands on the overall magnetic moment (�p) of a SPION.Canted surface spins are partially realigned upon exchange with strongly interactingc

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pplication of magnetic field. Further information on size con-rolled magnetic properties can be obtained from the other reviewsBatlle and Labarta, 2002; Obaidat et al., 2015).

.2. Effect of surface coatings

The organic/inorganic surfactants/capping agents form a pro-ective layer around SPIONs by attaching to the surface atoms ofPIONs via the end functional groups either through electrostaticnteractions or covalent bonding. The thickness of the protectiveayer can be in the range of 1–5 nm, if small organic molecules aresed as surfactants/capping agents. This protective layer thicknessan increase to more than 100 nm, if large polymers are used. Theurfactants/capping agents usually have different end functionalroups such as OH, COOH, PO(OH)2, S( O)2 OH, catecholsrefer Fig. 3), etc. which bring stoichiometric modifications on theurface of SPIONs (Yuen et al., 2012). Moreover, the influence on theagnetic properties of SPIONs differs with the type of end func-

ional groups that are attached to the surface atoms of SPIONs.or example, Darbandi et al. showed that the effects of surfac-ants (polyoxyethylene (5) nonylphenylether with OH end group)n the magnetic properties of SPIONs were negligible since noodifications on the surface structure or type of magnetic order

n SPIONs were observed (Darbandi et al., 2012). In contrast, theesults of canting angle measurements of SPIONs showed that theverage surface spin canting of SPIONs had decreased after coat-ng its surface with polyoxyethylene (5) nonylphenylether, owingo chemical affinity of OH end groups of surfactants towards theurface atoms of SPIONs. However, this negligence phenomenonas contradicting with another investigation (Roca et al., 2009),here the strong affinity of carboxylic end groups of oleic acid

owards the surface of SPIONs resulted in increased surface spinanting effects in SPIONs by victimizing the octahedral iron sites.evertheless, in another research (Guardia et al., 2007), high qualityPIONs (6–20 nm) produced using oleic acid showed high magne-ization values ascribing to the diminution of surface spin disordery oleic acid, and high crystallinity of SPIONs. Whereas, no notablehanges in magnetizations of SPIONs were observed even after theassivation of oleic acid with other organic and inorganic surfac-ants (with spin canting layer thickness near to 0.07–0.08 nm) ontohe surface of SPIONs (De Montferrand et al., 2014). In a recentnvestigation, based on the theoretical calculations and experi-

ental data (obtained using electron magnetic chiral dichroismEMCD)), Salafranca et al. (2012) found that the magnetization ofPIONs was enhanced near to magnetization of bulk nanoparti-les due to the satisfaction of orbitals occupations of surface atomsf SPIONs by the surfactants (oleic acid) through oxygen bonding.ut in another study, the moments of oleic acid (1 nm thickness)ncasing the magnetite nanoparticles exhibited a canting angle of

0◦ with respect to the moments of magnetic core, resulting inconclusion that the moments of oleic acid were of magnetic in

rigin (Krycka et al., 2010a,b). In another investigation, curcuminttachment (through citric acid) facilitated the re-ordering of

l of Pharmaceutics 496 (2015) 191–218

surface atoms of SPIONs, thus rendering more crystallinity toenhance the magnetization of the curcumin loaded SPIONs(60 emu/g) as compare to the bare and only citrate capped SPIONs(45 emu/g) (Kitture et al., 2012).

Surfactants having phosphonic acid ( PO(OH)2) functionalgroups tend (i) to improve thermal stability of nanoparticles and(ii) to show enhanced binding affinity (1.5 times more than car-boxylic acid) towards the core of iron oxide nanoparticles due tothe presence of an extra oxygen atom in phosphonic acid, therebyforming a strong Fe O P bond. The results of Mohapatra et al.showed that phosphonic acid moieties showed more preferenceto bind with the surface atoms of Fe3O4 nanoparticles as comparedto outward facing carboxylic or amine groups, when bifunctionalorganophosphorous based surfactant was used to cover the sur-face of magnetic nanoparticles (Mohapatra and Pramanik, 2009).Similarly, poly(amido amine) (PAMAM) showed enhanced bindingtowards the surface of SPIONs due to the presence of two phos-phonic groups at the same end, which provided more negativecharges for easy formation of bidentate phosphate-iron complexes(Di Marco et al., 2007). The direct functionalization of phosphonicacid based surfactant onto the surface of SPIONs may yield highersaturation magnetization as compared to the indirect functional-ization of surfactants/capping agents (i.e., complete replacementof oleic acid/any other coating with phosphonic acid/catechol endgroup based surfactant on the surface of SPIONs) because of reducedspin canting effects and enhanced binding affinity and superex-change interactions.

Gold coated SPIONs found to have more magnetization val-ues than the uncoated ones, since the gold coating helped in thereduction of surface magnetic disorders of SPIONs, and enhancedtheir crystallinity. In supporting to this fact, a combined (theoryand experiment) study was performed based on the interactionenergies between gold, iron and oxygen atoms (Yue et al., 2012).In experimental section, the gold atoms induced recrystallizationof the iron oxide surfaces to maintain structural stability. Theo-retically two cases were examined: (i) gold atoms exhibited lessinteraction over smooth surfaces of iron oxide and (ii) gold atomsshowcased higher interactions towards iron oxide surfaces withpores/defects (enhanced surface activeness). The theoretical inves-tigations reported that Van der waals forces dictated most of theinteractions between metal oxide and noble metal combinations.

In contrast to the improvements in magnetic properties, a recentinvestigation showed that at 5 K, the magnetization of SPIONs hadreduced drastically from 79 emu/g to 7.47 emu/g after their surfacewas covered with star shaped gold shells, owing to the diamagneticproperty of gold atoms (Quaresma et al., 2014). As similar to the pre-vious study, mostly the reduction in magnetizations of SPIONs wasnotified due to the presence of non-magnetic surfactants/cappingagents (Wortmann et al., 2014). However, the usage of surfac-tants/capping agents in the synthesis of SPIONs is inevitable tomaintain the colloidal stability for extended period of time.

2.3. Effect of shape

Barring the size and interface controls, shape is another factorto be premeditated in the control of magnetic properties of SPI-ONs. Generally, SPIONs with spherical morphologies are preparedand characterized since it has lesser complications in assessingtheir magnetic properties. But some investigations that assessedthe magnetic properties of SPIONs with diverse are reviewed. Theshapes of the SPIONs with definite surface facets (for instance, (111)facet) are decided by the concentration of reactants, reaction tem-

perature/aging time and interactions between surface of SPIONsand surfactants/capping agents (Khurshid et al., 2013), where thefacets may have cationic or anionic lattice index plane terminations(Lovely et al., 2006). In a recent study, the quantitative as well as
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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 195

Fig. 4. (I) Controlled synthesis of octapod iron oxide nanoparticles with different edge lengths. The octapod iron oxide nanoparticles with edge lengths of (a) 14, (b) 20, (c) 30and (d) 36 nm formed after 1, 1.5, 2 and 2.5 h reaction times in the presence of NaCl, respectively. (II) Schematic cartoon shows the ball models of octapod and spherical ironoxide nanoparticles with the same geometric volume (the black dotted lines represents the magnetic field of the octapod and spherical iron oxide nanoparticles. The samelength of black arrow means the same Ms of octapod and spherical iron oxide nanoparticles). With the same geometric core volume, the octapod nanoparticles have muchlarger effective volume (radius, R) than the spherical nanoparticles (radius, r) with R ∼ 2.4r under an external magnetic field B0. (b) The smooth M–H curves of Octapod-30,Octapod-20, Spherical-16 and Spherical-10 measured at 300 K using a superconducting quantum interference device magnetometer (inset: M–H curves of Octapod-30 andOctapod-20 in low-magnetic field areas). The Ms values of Octapod-30, Octapod-20, Spherical-16 and Spherical-10 are about 71, 51, 67 and 55 emu/g respectively.

Reproduced with permission from Zhao et al. (2013), © Macmillan Publishers Limited.

Table 1Size, shape, surface coatings, magnetization values of iron oxide (Fe3O4 and Fe2O3) nanoparticles.

Size (nm) Shape Surface coatings Magnetization (emu/g) References

14 ± 4 Spherical Uncoated 74.9 Ozel and Kockar (2015)

9–20 Quasi-spherical Uncoated 77 Klein et al. (2014)7–17 Citric acid 706–16 Maleic acid 74

24 Mixed shapes Uncoated 89 Kumar et al. (2014)21 Spherical Hexamine 5925 Poly(ethylene glycol) 6014 Polyvinylpyrrolidone 62

18 Spherical Oleic acid 67 Mojica Pisciotti et al. (2014)

10 Clusters Tri(ethylene glycol) and Triethanolamine 63 Maity et al. (2011)14 75

22 Octahedral Uncoated 80 Li et al. (2014c)100 Trisoctahedral Gold 20

10 Spherical Uncoated 70 Sundaresan et al. (2014)150 Poly(N-isopropylacrylamide-acrylamide-chitosan) 68

7 – Uncoated 61 León-Félix et al. (2014)8 – Gold 63

11 Spherical Uncoated 60 Ebrahiminezhad et al. (2012)8 l-Arginine 527 l-Lysine coating 42

13.1 ± 0.3 Mixed shapes Mannose 59.1 Demir et al. (2014)9.7 ± 0.99 Maltose 37.43.8 ± 0.21 Lactose 22.0212.4 ± 0.3 Galactose 58.08

maStwooSw

14 ± 4 Spherical Uncoated74 ± 9 Uncoated

icroscopic information about the magnetic moments stationedt the surface and core of the nano-cubical and nano-sphericalPIONs were reported using polarized small-angle neutron scat-ering (SANS) (Disch et al., 2012). Herein, more surface cantingas observed for the nano-cubical SPIONs due to larger amount

f non-magnetic layer thickness of the surfactants/capping agentsn the surface of SPIONs as compared to nano-spherical SPIONs.imilarly, lower magnetization values and high coercivity valuesere reported for the ellipsoidal (solid and hollow) magnetite

74.9 Ozel and Kockar (2015)93.5

nanoparticles than the spherical (solid) nanoparticles which wasattributed to the increased surface spin canting effects in ellipsoidalshaped nanoparticles (Choi et al., 2013).

On the contrary, SPIONs with quasi-cubic morphology displayeda higher magnetization value (79 emu/g) (Wortmann et al., 2014),

which could be due to an increase in the magnetic core volumeor low surface to volume ratio in such kind of distinct morpholo-gies. In another excellent study, octapod shaped SPIONs (referFig. 4) were produced by taking control of the concentration of
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96 G. Kandasamy, D. Maity / International J

odium chloride (NaCl) (Zhao et al., 2013). These octapod shapedPIONs displayed sustained magnetizations (∼71 emu/g) becausef reduced spin canting effects and enhanced core radius (i.e., 2.4imes more than spherical ones). In another investigation, varia-ions in the geometries (facet, twins, precipitates and spheres) ofron oxide crystals were introduced to study their effect in mag-etic behaviors of respective crystals (Luigjes et al., 2011). Based onhe results of dark and bright field images of high-resolution TEM,he magnetic nano-crystals (facet, twins, and precipitates) withear-to-perfect crystallinity presented comparative magnetizationalues (69, 65 and 53 emu/g) in opposition to spherical SPIONs∼30 emu/g), attributed to their enhanced coupling of atomic mag-etic spins in such distinct shapes. In a study, magnetizationalues of 61.73, 65.43 and 67.99 emu/g were attained for SPIONsith cubic, cuboctahedral and octahedral morphologies (formed by

ltering the synthesis parameters such as heating rate and growthime) respectively (Bateer et al., 2013). Nanoparticles with mixedhape distributions illustrated the magnetization values near tohat of bulk ones (Guardia et al., 2007). In summary, the size, shape,rystallinity and surface coatings play a significant role in deter-ining the magnetic properties of SPIONs by inducing/deducing

he spin canting effects. However, the size, shape and crystallinityf SPIONs are manipulated using different chemical synthesis pro-edures. Table 1 summarizes the size, shape, surface coatings andorresponding magnetization values of the iron oxide (Fe3O4 ande2O3) nanoparticles.

. Synthesis methods of SPIONs

The basic strategies involved in the formation of SPIONs arehysical, wet chemical, and microbial methods. Each method has

ts own advantages and disadvantages, and impacts over variousroperties of SPIONs. In this section, the predominant chemicalrocedures used for synthesizing SPIONs have been reviewed withypical examples.

.1. Co-precipitation method

Co-precipitation method is the widely used technique forynthesizing black and/or brownish SPIONs by precipitating anqueous solution mixture containing ferric and ferrous salts (in a:1 stoichiometric ratio) using a base, at room or elevated temper-tures (70–90 ◦C), in the absence of oxygen. The co-precipitationrocess occur through either one of the two topotactic phase trans-ormation pathways (as shown in Fig. 5): (i) akaganeite phasebirth of crystal nuclei) to goethite phase (to form arrow-shaped

anoparticles) or (ii) ferrous hydroxide phase to lepidocrocitehase to finally form SPIONs, depending upon the slow (for exam-le, 1.88 ml/min) or quick (at once) addition of base into theixture of precursor solution (Thanh et al., 2014). The above

ig. 5. Formation pathways of magnetite nanoparticles by co-precipitation method.ain intermediate phases are shown in yellow areas.

eproduced with permission from Thanh et al. (2014), © 2012 American Chemicalociety.

l of Pharmaceutics 496 (2015) 191–218

transformations include hydroxylation and condensation (eitherthrough olation or oxolation mechanisms) of Fe3+ and Fe2+ ionsbased on the pH of the colloidal solution. Moreover, surfac-tants/capping agents are used to control the growth of SPIONsduring the synthesis. However, the magnetic properties of SPI-ONs are significantly influenced by synthesis parameters such asreaction timings, base molarity, stirring rate, and the type of base.Recently, Vikram et al. (2014) showed that the stoichiometric ratioof Fe2+ and Fe3+ and the base addition rate also have control overthe regulation of the magnetic properties of SPIONs. They reportedthat the change in concentration of the base yielded nanomaterialswith ferromagnetic behavior instead of superparamagnetism.

The main drawback of this co-precipitation method is thelack of proper crystallinity and broad particle size distributionwhich leads to low saturation magnetization value (30–50 emu/g)of the SPIONs as compared to the bulk magnetization value ofFe3O4 nanoparticles (92 emu/g). Nevertheless, magnetic nanopar-ticles with uniform size of 9 nm were obtained via co-precipitationmethod using a tetramethylammonium hydroxide for MRI contrast(Cheng et al., 2005).

3.2. Thermal decomposition method

Highly crystalline and monodisperse SPIONs with diverse sizesand shapes can be synthesized via thermal decomposition methodin the presence of surfactants (for example, oleic acid and oleyl-amine) and organic solvents with high boiling points. Solvent freethermal decomposition of iron precursors can also be utilized forpreparing magnetic nanoparticles (Maity et al., 2009). However, theresulting hydrophobic SPIONs tend to show good dispersibility onlyin organic solvents (for example, tetrahydrofuran) because of theirhydrophobic interactions between surfactants and solvents. Manysynthesis parameters such as concentration of surfactants, reactiontemperatures, reaction timings, ratio of precursors to surfactants,solvents and heating rate during reflux govern the physicochemi-cal characteristics and magnetic properties of SPIONs (Maity et al.,2008).

The hydrophobic SPIONs are converted to water soluble onesby using either ligand exchange method or bilayer surfactant sta-bilization method to involve them instantaneously into cancertheranostic applications. For example, Xu et al. (2008) replacedthe hydrophobic surface coatings formed of oleate and oleylaminemolecules with a hydrophilic coating of dopamine attached PEGthrough ligand exchange method, since dopamine tended to showmore affinity to attach with the surface of iron oxide nanopar-ticles as compared to the hydrophobic coatings. In the bilayersurfactant stabilization, the bilayers are formed by the insertion ofhydrophobic part of an amphiphilic molecule in between the longhydrophobic chains of surfactants whose end functional groups, forinstance carboxyl groups, are attached to the surface atoms of mag-netic nanoparticles. Recently, oleic acid was used to form bilayerson the surface of magnetic nanoparticles after optimizing their con-centration with respect to the formed nanoparticles (Prakash et al.,2009). But, these conversion methods are tedious and seriouslyaffect the magnetic properties, colloidal dispensability and yield ofSPIONs (Liu et al., 2014). To overcome these problems, hydrophilicSPIONs can be directly synthesized by one-pot thermolysis methodusing polyol based surfactants and/or solvents (Maity et al., 2010).

3.3. Hydrothermal method

In hydrothermal method, the precursors are dissolved in an

aqueous solution along with surfactants/capping agents, and sealedin a Teflon coated autoclave, where high temperature and highpressure are maintained to synthesize SPIONs with definite sizesand shapes. Finally, the temperature of the autoclave is allowed
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G. Kandasamy, D. Maity / International J

o cool down to room temperature and the resultant supernatantolution is washed to remove unused surfactants/capping agents,mpurities and unreacted precursors. The parameters such as heat-ng temperatures, reaction timings and the ratio of the precursor tourface coatings are manipulated to obtain biocompatible SPIONsith various sizes, shapes and magnetic properties for MRI con-

rast and cancer hyperthermia. In a study, ethylene glycol playedn important role in synthesizing SPIONs with three different mor-hologies (polyhedron/rod shaped, porous sphere and flowerlike)ith saturation magnetization 66–73.5 emu/g, in which flower-

ike nanoparticles possessed the lowest magnetization (66 emu/g)scribed to the shape and size induced magnetic propertieseduction (Ramesh et al., 2012). Nonetheless, this method has dis-dvantages such as producing moderately crystalline SPIONs asompared to magnetic nanoparticles synthesized via thermolysisethod (Wang et al., 2013) and consuming more time.

.4. Microemulsion method

Two immiscible phases (oil and water) are used to form SPIONsnder the presence of stabilizing agents by forming a mono-

ayer at the interface between the immiscible phases. Water-in-OilW/O) and Oil-in-Water (O/W) are the two kinds of microemul-ions formed to synthesize different kinds of nanoparticles. Theydrophilic and hydrophobic parts of surface coatings play a majorole in (i) stabilizing nanoparticles, (ii) catering chemical reac-ions to happen and (iii) controlling physicochemical parameters.

/O microemulsion method is frequently used to form SPIONs,here the stabilizing agents in continuous oil phase initially pro-

ect the droplets formed of iron oxide reactants, which theneact to form SPIONs. The sizes and shapes are controllable byarying the concentrations of iron oxide precursor to base, surfac-ant and/or solvents. Recently, cetyl trimethylammonium bromideCTAB) (Okoli et al., 2011) and synperonic 10/6 (Okoli et al., 2012)ere used to tailor the size of the SPIONs. Similarly, SPIONs withifferent sizes (6.5, 4.2 and 8.7 nm) were synthesized by varying theatio of concentrations of iron oxide precursor to base (1:1 and 2:1)Chin and Yaacob, 2007). Nevertheless, the removal of unreactedrecursors, base and surfactants is intricate in this microemulsionethod.

.5. Sonochemical method

Sound energy such as ultrasound can be used for synthesizingPIONs, where the cavitation bubbles produced by such ultrasoundransform the reactants into desired products at ambient temper-tures. The size and shapes of SPIONs can be varied by controllinghe refluxing time, irradiation time and power. Recently, Dolorest al. (2015) reported that production of Fe3+ ions for making ironxide nanoparticles (using ethylene glycol as surfactant) increasedn a linear fashion with the increase in reaction time at a particularltrasonic frequency (581 kHz) as compared to other frequencies861 and 1141 kHz).

.6. Microwave-assisted synthesis

Microwave energy can also be utilized for synthesizing SPIONsn a very short period of time at low energy consumption. A uni-orm heat is provided by microwaves inside the reaction containersrom all sides for synthesizing stable and high crystalline iron oxideanoparticles. But these nanoparticles have reduced surface reac-ivity (due to the low energy surface crystalline facets), which is

ssessed based on their interaction with water and aggregate for-ation process (Pascu et al., 2012). Interestingly, the low surface

eactive nanoparticles can enhance the stability of SPIONs (Carenzat al., 2014), which is an advantage of this method. The magnetic

l of Pharmaceutics 496 (2015) 191–218 197

properties of SPIONs can be controlled by manipulating the con-centration of surfactants, microwave power, and reaction time.

4. Encapsulation of SPIONs

Both organic polymers and inorganic materials are extensivelyused for encapsulating the bare and surfactants/capping agentsmodified SPIONs (which are prepared using different chemicalsynthesis procedures) for improving the biocompatibility, increas-ing the cellular uptake, enhancing the circulation of SPIONs andpreventing protein corona adsorption. The encapsulated SPIONsshould be in definite sizes to prevent them from clearing throughkidneys and from reticulo-endothelial system (RES) (i.e., clearingthrough liver and spleen). In organic encapsulation, synthetic poly-mers (simple polymers and amphiphilic polymers such as di- andtri-block copolymers) and natural polymers (proteins/polypeptidesand polysaccharides) are commonly used for the encapsulationof SPIONs for direct use in cancer therapy and imaging. More-over, the polymeric systems can also be made stimuli sensitivefor pH, redox environment, and/or temperature sensitive to favorthe release of nanoparticles at the cancer site (Sundaresan et al.,2014; Wadajkar et al., 2013). Among inorganic materials, silicais commonly used to encapsulate SPIONs for cancer theranostics.Moreover, both organic and inorganic materials are used to envis-age simultaneous co-encapsulation and delivery of SPIONs withother chemotherapeutic, photothermal drugs and so on for cancertherapy and imaging. Herein, some recent developments in organicpolymers and inorganic materials for encapsulation of SPIONs forcancer theranostics have been discussed.

4.1. Organic encapsulation

4.1.1. Synthetic polymer encapsulationIn synthetic polymer encapsulation, new kinds of di- or tri-block

copolymers are prepared through different polymerization processfor encapsulating and/or growing SPIONs. Recently, free radicalpolymerization process was utilized to prepare poly(poly(ethyleneglycol) methacrylate-co-dimethyl-(methacryoyloxy)methyl phos-phonic acid) [poly(PEGMA-co-MAPC)] for encapsulation of twobatches of SPIONs, where the sizes of SPIONs increased to 25 ± 2 nmand 37 ± 2 nm after polymer encapsulation (Torrisi et al., 2014).In another investigation, polymerization-induced self-assembly(PISA) method was used to prepare poly-(oligoethylene gly-col methacrylate)-block-(methacrylic acid)-block-poly(styrene)(POEGMA-b-PMAA-b-PST) triblock copolymer (Karagoz et al.,2014). The carboxylic acid groups in this copolymer initiated theformation of iron oxide nanoparticles (as shown in Fig. 6), wherethe length of methacrylic acid (MAA) units in the copolymerhelped in tuning the sizes of SPIONs (i.e. 15, 9 and 5 MAA unitsresulted in 15, 12 and 9 nm SPIONs respectively). In another study,poly(methylmethacrylate-acrylic acid-divinylbenzene) (P(MMA-AA-DVB)) formed using emulsion polymerization was manipulatedto produce janus-kind Fe3O4 nanoparticles with sizes ranging from200 to 250 nm (Ali et al., 2014). Nanoparticles were grown in a sin-gle direction based on the reduced interfacial energy between thepolymer and nanoparticle magnetic domains. Another group useda biocompatible shell made of poly(N-methyl-2-vinyl pyridiniumiodide)-block-poly(ethylene oxide) diblock copolymer (P2QVP-b-PEO) (Mw/Mn: 1.13) and ferritin molecule to encapsulate SPIONs,where the cationic and anionic charges of hydrophilic copolymerand ferritin surface respectively were manipulated to form string-

like magnetic clusters (with hydrodynamic size of 200 nm) (Tähkäet al., 2014).

In a recent investigation, polymerization of 2-(2-methoxyethoxy)ethyl methacrylate and 2-(dimethylamino)ethyl

specific-polymers
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specific-polymers
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198 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

F rmatp

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eproduced with permission from Karagoz et al. (2014), © 2014 American Chemica

ethacrylate (through atomic transfer radical polymerizationATRP) process) was induced on the bromine modified surface ofPTES-coated SPIONs to form brush like structures on the surface ofPIONs for use in cell transfection (Liu et al., 2013). Similarly, ATRPethod was used to form the polymer, polyamidoamine-b-poly(2-

dimethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol)ethyl ether methacrylate) (PAMAM-b-PDMAEMA-b-PPEGMA),hich formed a dendritic–linear–brush like structure on the

urface of the SPIONs when combined with PPEGMA (He et al.,012). Likewise, poly(glycidyl methacrylate-co-poly(ethylenelycol) methyl ether methacrylate) (P(GMA-co-PEGMA)) (formedia ATRP method) was used to encase high crystalline SPIONsHuang et al., 2012). Importantly, the magnetization value of(GMA-co-PEGMA) coated SPIONs (82 emu/g) sustained near toagnetization value of oleic acid coated SPIONs (88 emu/g) as

hown in Fig. 7, where the authors claimed that the polymeruenched the magnetic moments of SPIONs through electronxchange between SPIONs and polymer. Similarly, poly(acryliccid) (PAA) decorated SPIONs (with hydrodynamic diameterf 39.4 ± 2.0 nm) showed a magnetization value of 78.1 emu/g,hich reduced in further encapsulations (Lin et al., 2009). PAA

overed SPIONs showed a high magnetization of 103 emu/gnitially and reduced to 76 emu/g after subsequent chemicaloating/modification (Sun et al., 2012), but the reasons for highagnetizations at the initial stage were not discussed in detail.

.1.2. Natural polymer encapsulationChitosan (a pH sensitive polysaccharide and a derivative of

hitin) was cross-linked with SPIONs through tripolyphosphateTPP) molecules. The results showed that the SPIONs were stablen wide range of pH levels and the release of SPIONs and otherrugs (bortezomib) increased at low pH (4.2) due to swelling ofhitosan at this pH level (Unsoy et al., 2014a,b). Dextran (anotheratural polysaccharide) can be used as-such and/or cross-linked orsed as a derivative form for protecting SPIONs from agglomera-ion. Many commercially available SPIONs used for clinical MRI,re coated with dextran only. In a recent study, carboxymethylextran was used to coat SPIONs, but the magnetization value ofPIONs was only 35 emu/g due to the lack of crystallinity of SPI-

Ns (Jiang et al., 2014). A recent study reported that hyaluroniccid (HA) can be used in combination with dextran coated SPIONso target CD44 receptor of cancer cells and to increase the loadingfficiency of SPIONs (Unterweger et al., 2014). Similarly, collagen

ion in poly-(oligoethylene glycol methacrylate)-block-(methacrylic acid)-block-

ety.

proteins can be linked with heparin (a sulfur-containing polysac-charide that inhibits blood coagulation and induces their uptakemore by cancer cells) (Lee et al., 2012a) and starch (Li et al., 2013a)to deliver more SPIONs for MRI application purposes.

Two different kinds of gelatin such as gelatin A and B (extractedfrom collagen of pork and beef respectively) were used for encap-sulating and delivering SPIONs (Gaihre et al., 2009). Their results ofbioactivity and cellular uptake studies showed that the efficiencywas improved when co-encapsulated SPIONs and chemotherapeu-tic drugs (both inside gelatin) were used for cancer therapy. Ina very recent study, gelatin cross-linked SPIONs (prepared usingemulsion and co-precipitation methods) showed an enhancementin the degradability of SPIONs as well as the cellular intake in can-cerous cells (Tomitaka et al., 2014). In another work, rhodamineisothiocyanate (RITC) modified gelatin was used as a substrate toseed and grow magnetic nanoparticles to improve the stability sothat they can be conjugated with neurotrophic factors to improveperipheral nerve regeneration (Ziv-Polat et al., 2014).

Three dimensional alginate (an anionic polysaccharide) basedhydrogel network can be established through ionotropic gelationmethod by adding cations with alginate. SPIONs with an averagesize of 13–15 nm were formed by sonicating iron oxide precursorswith alginate to explore the potential of SPIONs in photon activatedtherapies (Choi et al., 2012), which is usually carried out via X-raysin lieu gold nanoparticles.

4.2. Inorganic encapsulation

4.2.1. Silica encapsulationSilica encapsulation presents substantial columbic repulsion in

a colloidal solution to maintain the stability of SPIONs for long timeand influences the magnetic properties of SPIONs by modifying thethickness of surface spin canting layer of SPIONs. Usually silica shellon the surface of SPIONs is formed through Stöber process, whichinvolves hydrolysis and condensation of silica precursors. The sur-face of silica shell can be used to attach ligands/polymers (such asamine/carboxylate/PEG) to increase the biocompatibility of SPIONsand to cater chemotherapeutic drugs for effective cancer therapy.

Sodipo and Aziz group modified the surface of co-precipitated

SPIONs with (3-aminopropyl)triethoxysilane (APTES) and silica intwo different studies (Sodipo and Abdul Aziz, 2015; Sodipo andAziz, 2014) using ultrasonic energy, where the magnetization val-ues of 77.7 and 20–30 emu/g were reported for APTES and silica
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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 199

Fig. 7. (I) Schematic representation of the synthesis of SPIONs-poly(glycidyl methacrylate-co-poly(ethylene glycol) methyl ether methacrylate)-folic acid (P(GMA-co-PEGMA)-FA). (II) TEM images of (a) pristine oleic acid-stabilized SPIONs dispersed in hexane, and (b) SPIONs-P(GMA-co-PEGMA)-FA dispersed in DI water. (III) Magnetizationc )-FA

R Societ

cscelduSwTdtwoo1sfnlTwtal

urves of (a) pristine oleic acid-stabilized SPIONs and (b) SPIONs-P(GMA-co-PEGMA

eproduced with permission from Huang et al. (2012), © 2014 American Chemical

oated magnetic nanoparticles respectively. Similarly, in anothertudy, a magnetization value of 77 emu/g was obtained for silicaoated iron oxide nanoparticles (Islam et al., 2013). Recently, Yangt al. (2014a) formed a microemulsion containing cetyltrimethy-ammonium bromide (CTAB)/SPIONs (formed through thermalecomposition) whose surface was modified with silica coatingsing tetraethyl orthosilicate. A core/shell/shell nanostructure ofPIONs/zinc oxide (ZnO)/silica was developed, where ZnO layeras used for microwave-triggered drug release (Qiu et al., 2014).

he porous surface of silica enhanced the opportunity to caterrugs but degraded the magnetic properties of SPIONs (i.e., reduc-ion in magnetization value from 85 to 64.7 emu/g). In a similaray, the magnetization value diminished to more than half of the

riginal value (i.e., from 79 to 38 emu/g), when the SPIONs dec-rated with silica coatings (refer Fig. 8) and reduced further to8 emu/g for subsequent functionalization of folic acid over silicaurface (Wortmann et al., 2014). Polyelectrolytes based DNA trans-ection was successfully carried out using silica-coated magneticanoparticles, where DNA was attached to silica surface through

ayer-by-layer (LBL) assembly method (Dávila-Ibánez et al., 2013).he quasi-cubic shaped magnetic nanoparticles were developed

ith silica coating to improvise shelf life and biological stability of

he nanoparticles (Campbell et al., 2011). In another investigation,minosilane coating over the surface of SPIONs improved their cel-ular uptake efficiency in cell lines such as RAW264.7, L929, HepG2,

at 25 ◦C.

y.

PC-3, U-87 MG, and mouse mesenchymal stem cells (MSCs) (Zhuet al., 2012).

Silica can also act as a linkage molecule between SPIONsand other polymer coatings to make tunable chemical struc-tures. Takafuji exploited the reaction between 4-vinylpyridinewith 3-mercaptopropyl trimethoxysilane to form a polymer com-plex of poly(4-vinylpyridine) with alkoxysilyl group to enhanceDNA transfection efficiency (Takafuji et al., 2014). Another studyinvolved coating of silica (for stability) and mesoporous silica (forfurther functionalization with gold) on top of ellipsoidal shapedSPIONs to organize a core–shell structure to adopt chemothera-peutic drugs for effective cancer therapy (Chen et al., 2010).

5. Cancer theranostic applications of SPIONs

5.1. Magnetic resonance imaging (MRI)

In general, MRI is a biomedical imaging technique used to imagesoft tissues of human body in very thin slices in two dimensionalas well as three dimensional spaces. The water present in our bodyplays an important role in obtaining MRI images. The hydrogen

nucleus in water tends to align them in a direction parallel toapplied external magnetic field. Then a radiofrequency (RF) sig-nal is applied to change the direction of alignment of protons inthe hydrogen nucleus, where the frequency of the RF signal must
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200 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

Fig. 8. (I) Schematic outline of the synthetic pathway for folic acid-attached silica-coated iron oxide (FA@SiO2@Fe3O4) nanoparticles, where �-Fe2O3 quasicubic particleswere synthesized by a facile solvothermal process (i), followed by the silica shell formation with tetraethyl orthosilicate (TEOS) (ii) and the core reduction to magnetite (iii).T and vm perat

R ical S

btnSemsat–nbTnortnti

uGaassfoi(mfic(

he surface of the SiO2@Fe3O4 nanoparticles was activated with amine groups (iv)easurements of the nanoparticles after each step of functionalization at room tem

eproduced with permission from Wortmann et al. (2014), © 2011 American Chem

e in resonance with the frequency of the hydrogen nucleus. Ashe directions of the protons are changed after applying the RF sig-al, the protons tend to re-align with the applied magnetic field.o while returning to its original position, these protons releasenergy as an RF signal that can be detected by detectors in MRIachine. The re-alignment speed of protons varies for various tis-

ues in our body, which is helpful in imaging such tissues preciselynd the time taken for this re-alignment is called as the relaxationime. T1 (longitudinal – spin–lattice relaxation) and T2 (transversespin–spin relaxation) are the relaxation times based on the timeeeded for the components of respective magnetization vectors, inoth the cases, to return to their original thermal equilibrium state.he relaxivities (r1 and r2), that changes with the applied mag-etic field in longitudinal and transverse directions, are the inversef the relaxation times at the respective directions (i.e., r1 = 1/T1;2 = 1/T2), where the ratio of relaxivities is significant in decidinghe fate of the nanoparticles to be used either as a positive or aegative contrast. Both T1 and T2 relaxations are dependent onhe saturation magnetization of nanoparticles and their magneticnteractions with the protons of surrounding water molecules.

Paramagnetic gadolinium (Gd(III)) complexes are commonlysed as MRI contrast agents for about three decades by combiningd(III) with kinetically and thermodynamically stable chelating lig-nds, where the tissues/cells appear bright (T1 or positive contrast)t the contact region (Khan et al., 2014). However, Gd(III) complexeshould be encapsulated into macromolecules such as protein, lipo-omes and dendrimers to deliver them into in vivo conditions, sinceree gadolinium ions are very toxic to the biological systems. Thether disadvantages of these Gd(III) complexes at in vivo scenarionclude the following: (i) short life span, (ii) poor cellular uptake,iii) limited to blood and/or extracellular space resulting only in

olecular imaging and (iv) induction of nephrogenic systemicbrosis (NSF). Since the pharmacokinetics of the synthetic Gd(III)omplexes are difficult to study in biological systems, manganeseMn(II) or Mn2+) based T1 MRI contrasts are introduced to image

ectorized by covalent attachment of FA as the targeting unit (v). (II) Magnetizationure (a). FC and ZFC curves of all samples measured at an applied field of 50 mT (b).

ociety.

the anatomical structure of brain. However, these Mn(II) com-plexes have lower thermodynamic stability, high toxicity (towardsheart and liver), low magnetization and less MRI signal sensitivity.Nevertheless, metal (Fe, Ni, Co)/metallic alloy (iron-cobalt and iron-platinum)/metal doped ferrites (for example, CoFe2O4, MnFe2O4)are developed as T2 MRI contrast agents for enhancing the sig-nal sensitivity by improving the saturation magnetization. In T2MRI contrast, the relaxivities have a tendency to decay rapidly intransverse direction (faster than r2 relaxivities of protons of watermolecules) to yield T2* relaxation (corresponding relaxivity – r2*)due to the coupled factors such as spin–spin relaxation and mag-netic field inhomogeneities, resulting in negative contrast effects(i.e., darkening effect) at the region of contact (molecular/cellularlevels). But, the T2 MRI contrast based metals/metallic alloys arechemically more reactive, resulting in oxidation of these agentsunder biological conditions. Moreover, the in vivo biodegradabil-ity and cytotoxicities of metals/metallic alloys/metal doped ferritesshould be investigated for extensive period of time before theirusage in clinical trials.

5.1.1. SPIONs as T2 MRI contrast agentsSPIONs have been approved to be used as T2 MRI contrasts

(negative contrast) for liver imaging by food and drug adminis-tration (FDA) department, as shown in Table 2. MRI signal contrastof SPIONs is higher than the contrast of Gd(III) and Mn(II) com-plexes, since the relaxivities of SPIONs are enhanced via highsaturation magnetization due to the presence of more number ofFe atoms that are responsible for such magnetization in SPIONs(Gossuin et al., 2009). Moreover, SPIONs are chemically stable, bio-compatible and biodegradable in in vivo conditions due to theirability to mix as normal iron ions in the blood as compared to

metal/metal alloy based contrast agents. In addition, high sig-nal sensitivity and quick detectability via electron microscopymade SPIONs as potential candidates for in vivo MRI contrast(Yang et al., 2009). Despite the ban on some commercial SPIONs
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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 201

Table 2MRI relaxivity values of commercial iron oxide (Fe3O4 and Fe2O3) nanoparticles having different sizes and surface coatings.

Name/company Magnetic coresize (nm)

Totalhydrodynamicsize (nm)

Surface coatings r1 relaxation(mM−1 s−1)

r2 relaxation(mM−1 s−1)

Magneticfield (T)

References

Ferumoxides, AMI-25Endorem/Feridex Guerbet, AdvancedMagnetics

– 120–180 Dextran 10.1 120 1.5 Corot et al. (2006)

Ferumoxtran-10, AMI-227,BMS-180549 Sinerem/Combridex,Guerbet, Advanced Magnetics

– 15–30 Dextran 9.9 65 1.5

Ferumoxytol Code 7228, AdvancedMagnetics

– 30 Carboxylmethyldextran

15 89 1.5

Ferucarbotran SHU-555A, ResovistSchering

– 60 Carboxydextran 9.7 189 1.5

SHU-555C Supravist Schering – 21 Carboxydextran 10.7 38 1.5VSOP-C184 Ferropharm – 7 Citrate 14 33.4 1.5

AMI-121 Lumirem and Gastromark 300 – Silica 3.2 72 1.5 Lodhia et al. (2010)AMI-25 Endorem and Feridex 5.6 – Dextran 23.9 98.3 1.5SHU-55A Resovist 4.2 – Carbo-Dextran 25.4 151 1.5AMI-227 Sinerem and Combidex 4–6 – Dextran 21.6 44.1 1.5NC1001 50 Clariscan 5–7 – Carbohydrate-

PEG20 35 1.5

SHU-55C Supravist 3–5 – Carbo-Dextran 7.3 57 1.5

Resovist 4.6 60 Carboxydextran 10.9 190 1.5 Xiao et al. (2011)boxym

xtranxtran

dcSwbci7tShfcrcS5trtwts

cp(1Ui2rWec5hi(

Ferumoxytol (Combidex) 6.4 30 carde

Sinerem 4–6 15–30 De

ue to its toxicity, ferumoxytol (Feraheme), ferumoxides, feru-arbotran, ferumoxtran-10, ferristene and ferumoxsil are otherPIONs based MRI contrast agents at current clinical trials (https://ww.clinicaltrials.gov/). Nevertheless, many investigations have

een performed by global researchers to improve the T2 MRIontrast effects of SPIONs for enhanced cellular and molecularmaging. Very recently, exceptional transverse relaxivity values of35.3 mM−1 s−1 and 450.8 mM−1 s−1 at 3 T MRI were achieved forerephthalic acid (TA) and 2-amino terephthalic acid (ATA) coatedPIONs respectively (Maity et al., 2012). The authors explained thatigh crystallinity and the effective spin transfer between the sur-

ace atoms of SPIONs and surrounding molecules through �–�onjugation of TA/ATA facilitated the actualization of high T2* MRIelaxations with low cytotoxicity towards fibroblast cells (NIH3T3ell lines). In a recent study, the manipulation of distribution ofPIONs inside the encapsulants yielded a high r2 relaxivity of82 mM−1 s−1 at 9.4 T MRI (Karagoz et al., 2014). Similarly, PEI (withwo different formulations) coated SPIONs exhibited relatively high2 relaxivity values of 514.7 mM−1 s−1 and 596.8 mM−1 s−1 respec-ively at 1.5 T (Lin et al., 2014) but the reasons behind this incrementere inconclusive. Table 3 summarizes MRI relaxivity values of syn-

hetic iron oxide (Fe3O4 and Fe2O3) nanoparticles having differentizes and surface coatings.

Many studies have been performed to investigate the MRIontrast efficiency of SPIONs in in vivo scenarios. For exam-le, Saraswathy et al. prepared citrate-coated ultra-small SPIONsC-USPIONs) with particle size and r2 relaxivity of 12 nm and02 mM−1 s−1 respectively. The hepatocellular uptake of C-SPIONs was identified by a 39% decrease in signal intensity

n post-contrast MRI images of rat liver (Saraswathy et al.,014a). In another study, dextran-coated SPIONs (DSPIONs with1: 2.5 mM−1 s−1 and r2: 140.7 mM−1 s−1) were injected into male

istar rats at a dose of 2.17 mg/ml Fe/kg body weight via tail vein tovaluate the liver fibrosis in these animal models, where the post-ontrast T2 weighted images showcased a hypointense liver with a

5% decrease in the average MRI signal intensity, indicating a higherepatocellular uptake of DSPIONs (Saraswathy et al., 2014b). Sim-

larly, folate-targeted, poly(ethylene glycol)-poly(�-caprolactone)FA-PEG-PCL) coated USPIONs were injected into BEL-7402 tumor

ethyl- 15 89 1.5

9.9 65 1.5

bearing nude mice via tail vein, where the MRI signal intensitydecreased to 41.2% within 3 h of injection resulting in clear tumorimages. Moreover, the intensity further decreased to 32.4% at 6 hafter injection, which showed that the accumulation of folate recep-tor based SPIONs at the target tumor site increased as compared tonon-targeted ones (Hong et al., 2012).

In one investigation, poly(lactic acid)-d-alpha-tocopherolpolyethylene glycol 1000 succinate copolymer (PLA-TPGS) coatedSPIONs were injected into MCF-7 induced severe combinedimmune deficiency (SCID) female mice at a dose of 5 mg Fe/kgbody weight (Prashant et al., 2010). In vivo MRI images ofthe liver of SCID mice were evaluated before and 0.33, 2, 5and 12 h after the injection of PLA-TPGS coated SPIONs, wherethe MRI signal intensity at the tumor site decreased after theinjection of the SPIONs indicating their potential diagnosticusage in clinical trials. In another investigation, the core size(14 nm) of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG) copolymer coatedSPIONs were tuned resulting in an increase of T2 relaxivity bymore than 200-fold in non-biological conditions (Tong et al., 2010).Moreover, these DSPE-PEG coated SPIONs had more half-life (i.e.23.2 min) in blood circulation of human U87 glioblastoma cellsinduced mice. Similarly in another study, PEG coated SPIONs (9 nmsize) and PEG/polyethylenime (PEI) coated SPIONs (10 nm) showedenhanced MRI contrast effects after injecting them at a dose of10 mg Fe/kg of body weight of Kunming mice (Wang et al., 2015b)as shown in Fig. 9. In addition, the PEG-SPIONs decreased theMRI signal contrast at bulbus olfactorius, frontal cortex, tempo-ral cortex and thalamus portions of mice after 24 h of its injectionas compared to PEG-PEI coated SPIONs due to their improvedhalf-life in blood circulation. In another research, CXCR4-peptide-attached-PEG-coated-iron-oxide nanoparticles were formed viaself-assembly by initial modifying the surface of nanoparticles withbioorthogonal azide and alkyne groups (Gallo et al., 2014). A 25%decrease in MRI signal intensity in U87.CD4.CXCR4 (implanted

in BALB/c nude mice) based tumor after the intratumoral injec-tion of peptide modified nanoparticles, whereas a 14% intensitydecrement at the tumor site (within 4 h) was observed when thenanoparticles were intravenously injected.
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202 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

Table 3MRI relaxivity values of synthetic iron oxide (Fe3O4 and Fe2O3) nanoparticles having different sizes and surface coatings.

Name Magnetic coresize (nm)

Totalhydrodynamicsize (nm)

Surfacecoatings

r1 relaxation(mM−1 s−1)

r2 relaxation(mM−1 s−1)

Magnetic field(T)

References

SPIO-14 13.8 28.6 DSPE-mPEG 1000 – 385 0.47 Tong et al. (2010)

SPIO-5 4.8 14.8 – 130

MIONs 10.96 ± 1.9 12.5 ± 1.3 DSPE-PEG-500 12.7 ± 3.7 317 ± 58.8 0.47 LaConte et al. (2007)

13.63 ± 1.3 10.35 ± 2.6 DSPE-PEG-750 12.6 ± 2.4 360 ± 4013.23 ± 1.1 12.0 ± 0.8 DSPE-PEG-1000 25.2 ± 4.9 194 ± 5714.6 ± 0.34 16.4 ± 3.1 DSPE-PEG-2000 24.4 ± 5.88 147 ± 3416.2 ± 1.3 21.6 ± 3.6 DSPE-PEG-5000 21.5 ± 3.22 173 ± 30

USPIO-PEG 7.7–7.9 24 PEG 30.4 62.2 0.47/1.41 Pourcelle et al. (2015)

USPIO-PEG-RGD 17 31.9 73.9USPIO-PEG-RGDp 34 30.1 106.5

Fe3O4 – – Uncoated – 100.4 0.5 Shen et al. (2012)

Fe3O4@APTS 6.5 ± 1.3 247.8 ± 18.6 APTS 83.8

Iron oxide 7.4 80–170 Poly(ethyleneoxide-b-d,l-lactide)

2.4–3.4 90–229 1.4 Balasubramaniamet al. (2014)

SPIOs 11 107.5 PEI-b–PCL-b–PEG – 256 1.41 Pöselt et al.(2012)

BSA-SPION 8 18 Bovine serumalbumin

11.6 154.2 1.41 Wang et al.(2014d)

D-SPIONs 12 50 Dextran – 140.7 1.5 Saraswathyet al. (2014b)

SPIONs 10 100 Chitosan 1.56 ± 0.19 369 ± 3 1.5 Szpak et al.(2013)

WFION 22 – – – 761 3 Lee et al.(2012b)

PEG/PEI-SPIONs(200 ◦C)

6.8 – PEG/PEI 3.11 58.8 7 Wang et al. (2015b)

PEG/PEI-SPIONs(260 ◦C)

10 21.8 ± 1.5 1.65 142.99

SPIONs 5 30 Ascorbic acid 0.95 22 9.4 Sreeja et al.

N (polp G/PEI

5

ab2aalme2srsOceldSt(Tb(r

ote: DSPE-mPEG, distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxyoly(ethylene imine)-block–poly-(�-caprolactone)-block–poly(ethylene glycol); PE

.1.2. SPIONs as T1/dual mode (T1–T2) MRI contrast agentsThe potential of SPIONs as a T1 MRI contrast (positive contrast)

gent has been identified recently, where the size of SPIONs shoulde optimum (<5 nm) to achieve good T1 contrast effect (Chan et al.,014). Moreover, both T1 and T2 relaxations can be enriched insingle iron oxide nanoparticle by optimizing their size, shape

nd surface coatings. In a recent investigation, SPIONs with bothongitudinal and transverse relaxivities were obtained by simply

anipulating the morphology and exposed facet (111) of SPIONs tonhance both positive and negative contrasts in SPIONs (Zhou et al.,014). The size-optimized magnetic nanoplates (8.8 and 4.8 nm)howed r2 values of 311.88 ± 7.47 and 182.2 ± 7.73 mM−1 s−1 and1 values of 38.11 ± 1.04 and 43.18 ± 3.33 mM−1 s−1 at 0.5 T ashown in Fig. 10. In another investigation, dendron modified SPI-Ns showed better T1 and T2 contrasts (Ghobril et al., 2013), whenompared with commercial SPIONs used for MRI contrast (Baslyt al., 2013, 2011). Likewise, liposomes were used to encapsu-ate ultra-small SPIONs at increased concentrations to improveual-mode (T1 and T2) MRI contrast efficacy (Prassl et al., 2012).imilarly, ultra-small SPIONs produced T1 contrast effect bet-er than other commercially available SPIONs at specific sizesSandiford et al., 2013). Analogously, Jung et al. achieved T1 and

2* MRI contrast concomitantly in in vivo and in vitro conditionsy controlling the size of the SPION (∼7 nm), where r1 relaxivities13.31 mM−1 s−1 at 1.43 T and 6.84 mM−1 s−1 at 3 T) of SPIONs wereelatively higher than the conventional ones (gadolinium based)

(2015)

yethyleneglycol)]; APTS, 3-aminopropyltrimethoxysilane; PEI-b–PCL-b–PEG,, poly(ethylene glycol)/poly(ethylene imine).

and r2* relaxivity was maintained at 49.50 mM−1 s−1 at 3 T (Junget al., 2014). Similar set of studies on this dual-mode MRI contrastenhancement was lately done (Pourcelle et al., 2015). Recently, anumerical analysis for finding an optimal aggregation for betterrelaxivities was also studied (Vuong et al., 2011).

5.2. Magnetic hyperthermia therapy

Hyperthermia therapy (HTP) which is a heat inducedmalignant cancer treatment by promoting SPIONs as heatproducers, can be performed as either localized therapy orsystemic therapy. After localization of SPIONs near the can-cer site using magnetic targeting, an alternating magnetic field(AMF) is applied for a period of time to induce heat of about42–45 ◦C for initiating apoptosis in cancer cells, where this heatcan be controlled by manipulating the size, shape, crystallinity, cor-responding magnetic properties of SPIONs and the applied AMF.Specific absorption rate (SAR) is a parameter to qualitatively andquantitatively measure the efficiency of SPIONs which take part inconverting AMF into heat based on Brownian and Néel relaxationsof individual SPIONs. The occurrence of whole body and localizedside effects can be minimized during magnetic hyperthermia, if the

AMF and frequency are below 5 × 109 A m−1 s−1 and 1 MHz respec-tively. In support to the previous study, Cervadoro et al. (2013)reported that the relaxations required for inducing heat from SPI-ONs (5, 7 and 14 nm sized) started to take place at a frequency
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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 203

Fig. 9. T2* MR images of the mouse brains before and after intravenous injection of poly(ethylene glycol) (PEG)-SPIONs (a1–a7) and PEG/polyethylenimine (PEI)-SPIONs(b1–b7), relative T2* value of different brain regions extracted from T2* MR images of mouse brains before and 24 h after the injection of PEG-SPIONs and PEG/PEI-SPIONs(c). The white arrows highlight the brain blood vessels enhanced by the SPIONs.

Reproduced with permission from Wang et al. (2015b), © Elsevier.

Fig. 10. MRI relaxivity and phantom study. (a) Columns to show the r1 and r2 values (0.5 T) of the three nanoplates, respectively. (b) T1 (left) and T2 (right) MRI phantomstudies (0.5 T) of the IOP-8.8 (top), IOP-4.8 (middle), and IOP-2.8 (bottom) at different iron concentrations (mM) in 1% agarose. The capability of displaying T1 or T2 contrastsis denoted as ON for good contrast and OFF for poor contrast. (c) T1 nuclear magnetic relaxation suspension (NMRD) profiles of the three nanoplates as the function of appliedm

R .

rwrMsvnc2atwtB

agnetic fields, measured by aqueous colloidal suspensions of each samples.

eproduced with permission from Zhou et al. (2014), © American Chemical Society

ange i.e., less than 1 MHz and stopped above this frequency rangehen tested for wide range of frequencies (up to 30 MHz), thereby

ecently confirming the operational frequencies for heat induction.oreover, magnetic nanoflakes, made of deoxy-chitosan polymer

tabilized 20 nm sized nanocubes, yielded a comparatively high SARalue of 73.8 ± 2.3 W/gFe for a frequency of 512 kHz than individualanocubes (Cervadoro et al., 2014). In a similar fashion, multi-ore magnetic nanoparticles exhibited a high SAR value of almost000 W/g (applied field of 29 kA/m and frequency of 520 kHz) withn increase in temperature rate of 1.04 ◦C/s for an iron concentra-

ion of 0.087 M (Lartigue et al., 2012). Moreover, doping of SPIONsith other metal atoms (for instance, manganese) can also be done

o improve the hyperthermia activity of magnetic nanoparticles.ut, copper (5%, 10%, 15%, mol/mol) doped iron oxide core (7 nm)

resulted in very low SAR values, owing to the lower size of fer-ritin molecules coated magnetic core (Fantechi et al., 2014). Table 4summarizes the SAR values of the iron oxide nanoparticles withrespect to different sizes and surface coatings. Though, optimal SARvalues are obtained for magnetic nanoparticles outside the biolog-ical environment, those values tended to decrease when SPIONsare introduced into in vitro and in vivo conditions because of thedissipation of heat to the surrounding tissues through blood flow(inside and outside tumor area).

However, SPIONs showed good therapeutic results in cancer

treatments in in vitro and in vivo scenarios. For example, 14 nmmagnetic nanoclusters (with SAR value of 500 Watt/g) killed almost74% of MCF-7 cancer cells in in vitro conditions, where a therapeu-tic temperature of 45 ◦C for 1 h was maintained (Maity et al., 2011)
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204 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

Table 4SAR values of iron oxide (Fe3O4 and Fe2O3) nanoparticles having different sizes and surface coatings.

Core size (nm) Surface coatings Magnetic fieldintensity

Magnetic fieldfrequency (kHz)

SAR (W/g) References

5–13 Dextran 58 kA/m 292 83.5 Kruse et al. (2014)

8APTES 7.5 kA/m 522.3

10De la Presa et al. (2012)11 40

13 55

24 Citrate 21.5 kA/m 700 1992 Hugounenq et al. (2012)11 Oleic acid 47.7 kA/m 194 33.4 Shah et al. (2015)9.5

DMSA 30 kA/m 10029 Song et al. (2012)

9.6 35.1

10 Methylmethacrylateand glycine modified

0.251, 0.335 and0.419 kOe

265 58.5, 131.7 and 204.0 Barick et al. (2014)

155.2 ± 0.17 PLA-TPGS/TPGS-COOH 43 kA/m 240 146 Mi et al. (2012)19 ± 3 Decanoic acid 29 kA/m 520 2452 Guardia et al. (2012)21.8 Uncoated

26.7 kA/m 26.579.32

Shete et al. (2014)15.1 Chitosan 118.857

DPPC and DSPC 27 kA/m 300 kHz to 1.1 MHz164

Béalle et al. (2012)9 438

5

Pluronics 127 24.5 kA/m 400

180

Gonzales-Weimuller et al. (2009)10 13012.5 20014 447

18PEG

13 kA/m 256320

Mojica Pisciotti et al. (2014)Dextran 400

Note: APTES, (3-aminopropyl)triethoxylsilane; DMSA, 2,3-dimercaptosuccinic acid; PLA-TPGS, poly(lactide)-d-a-tocopheryl polyethylene glycol 1000 succinate copolymer;D PC, 1,

ar(fiIhot2mtJionsosc(s∼twH

ndwatromtt

PPC, 1,2-dipalmitoylsn-glycero-3-phosphocholine; PEG, poly(ethylene glycol); DS

s shown in Fig. 11. Similarly, the cell viability of HeLa cells waseduced to 42% as these cells were exposed to a temperature of 43 ◦Cfor 1000 s) which was induced by applying an alternating magneticeld to silica coated iron oxide nanoparticles (Majeed et al., 2014).

n another study, the magnetic nanoparticles reached their in vitroyperthermia levels (42–45 ◦C) in less than 200 s at a frequencyf 26.48 kA/m, when these nanoparticles were incubated withhree different cancer cell lines (DA3, MCF-7 and HeLa) (Gkanas,013). Moreover, the induction of apoptosis in cancer cells throughagnetic nanoparticles increases with an increase in the concen-

ration/quantity and the size of these nanoparticles. For instance,adhav et al. (2013) reported that the induction of apoptosis processn WEHI-164 tumor cells increased near to 80%, when the quantityf sodium carbonate-stabilized-oleic acid-functionalized magneticanoparticles was increased from 0.22 mg to 0.44 mg. In anothertudy, only 40% of Jurkat cells survived for a low dose (490 �g Fe/ml)f 16 nm magnetic nanoparticles as compared to 80% and 90%urvival rate for 12 nm and 13 nm nanoparticles at 600 �g Fe/mloncentration (Khandhar et al., 2012). In a recent study, polymercombination of poly(vinyl alcohol) and polyvinylpyrrolidone)-tabilized-iron oxide-graphene nanocomposite attained a heat of42 ◦C for a concentration of 2.5 mg/ml within 15 min of applica-

ion of AMF at 418 Oe, where −40 ± 4% and −76 ± 3% of cell deathas observed after 4 and 8 h incubation of nanocomposites witheLa cells (Swain et al., 2015).

Hayashi et al. (2013) reported that the exposure of magneticanoclusters to AMF intensity of 8 kA/m and frequency of 230 kHzecreased the size of tumor in Female CB17/Icr-Prkdcscid mice,here the folic acid attached magnetic nanoclusters (with an aver-

ge SAR value of 248 W/g) were injected intravenously. A rise in theemperature of 6 ◦C was observed at 20 min as compared to the sur-ounding tissues. Moreover, the volume of the tumor decreased to

ne-tenth times of the tumor in control mice after 35 days of treat-ent (as shown in Fig. 12), where the life-span of hyperthermia

reated mice extended by 4 weeks. In a similar way, intraperi-oneally injected magnetic nanoparticles helped in the reduction of

2-distearoyl-sn-glycero-3-phosphocholine.

tumor created via injection of Pan02 cells into C57BL/6 mice, aftergetting exposed to 15–20 min of AMF, thereby improved the lifeexpectancy rate of mice by 31% (Basel et al., 2012). In another case,the volume of SCCVII squamous cell carcinoma induced in mice wascomparatively reduced through magnetic nanoparticles at specificintravenous dose and applied field of 38 kA/m at 980 kHz (Huangand Hainfeld, 2013). In a similar fashion, polypyrrole coated Fe3O4nanoparticles showed an SAR value of 487 W/g, where the nanopar-ticles considerably inhibited the growth of myeloma tumor inducedin Female CB17/Icr-Prkdcscid mice but completely when a combi-nation of Fe3O4 nanoparticles and a chemotherapeutic drug at aquantity of 5 mg/kg was used for cancer therapy (Hayashi et al.,2014). Similar in vivo hyperthermia studies using SPIONs are sum-marized in Table 5.

5.3. Magnetic targeting

Magnetic targeting is the targeting of iron oxide nanoparticlesto a specific cancer site by applying an external magnetic field.In one study, the transcellular transport of heparin coated mag-netic nanoparticles into the cellular membrane of MDCK strainII cells was made easy with the presence of magnetic field ascompared to the absence of magnetic field (Min et al., 2010).In another investigation, N-methyl-2-pyrrolidone mediated lipidbased iron oxide nanoparticles were combined with green fluo-rescence protein (GFP)-nucleic acids system, where the nucleicacid transfection efficiency inside HeLa cells was improved withmagnetic targeting as compared to the untargeted ones (Jianget al., 2010). Human mesenchymal stem cells (used in regenera-tive cell therapies) were incubated and attached with PEG coatednanoparticles through concentrated magnetic field exposure up toa range of time (1–24 h), where no changes in the cell viability

and cell structure were observed after the internalization of mag-netic nanoparticles into those stem cells (Landázuri et al., 2013)as shown in Fig. 13. Later, the magnetic nanoparticles loaded stemcells showed enhanced accumulation in both in vivo and in vitro
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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 205

Fig. 11. (a) Time dependent temperature rise of 1 ml aqueous suspension of MNC-14 nanoclusters with different iron concentrations on exposure to 89 kA m−1 AC field at240 kHz frequency. Inset shows field dependent SAR values of 1 ml sample with 0.5 mg/ml iron concentration. (b) Cell viability plot shows the cytotoxic effect on MCF-7breast cancer cells treated with magnetic hyperthermia (∼45 ◦C), treated with MNC-14 nanoclusters only, and treated with magnetic field only in comparison with the controlcells. (c and d) Optical microscope images of control MCF-7 breast cancer cells treated with magnetic field only and magnetic hyperthermia using 14 nm sized magneticn

R istry.

siia2

Pwatsnt((iVmLepachtmcia

anoclusters (MNC-14) (scale bar 100 mm).

eproduced with permission from Maity et al. (2011), © The Royal Society of Chem

ituations, after the application of magnetic field. Similarly, thenternalization of poly(dopamine) coated magnetic nanoparticlesncreased by 14–15% more in case of HeLa cells and HepG2 cellsfter exposing them to a magnetic field for about 4 h (Wu et al.,015).

In a recent investigation, the in vivo magnetic targeting ofEI-modified magnetic nanoparticles to intracerebral 9L tumorsas achieved using an exposure to magnetic field of 350 mT for

bout 30 min, after the injection of 12 mg Fe/kg of nanoparticleshrough intra-carotid catheter (Chertok et al., 2010). The resultshowed a 30-fold improvement of accumulation of magneticanoparticles onto tumors. The cellular uptake and the accumula-ion of iron oxide nanoparticles at two different 4T1-tumor sitesinduced in a mice) were enhanced through magnetic targetingLi et al., 2013b). In another study, the magnetic targeting helpedn improving the intake efficiency of dextran coated SPIONs inERO and MDCK cell lines as well as in tumor induced BALB/cice (nearly 160% improvement) (Mojica Pisciotti et al., 2014).

ikewise, �,�-poly(N-2-hydroxyethyl)-d,l-aspartamide-co-(N-2-thylen-isobutirrate)-graft-poly-(butyl methacrylate) (PHEA-IB-(BMA)) copolymer-coated SPIONs were acted as nano-carriers forchemotherapeutic drug (flutamide), where the retention con-

entration of magnetic flutamide in kidneys of Wistar rats wasigher after the application of magnetic field (0.3 T) as comparedo non-magnetic flutamide (Licciardi et al., 2013). In addition to

agnetic targeting, active targeting of the magnetic nanoparticlesan also be performed with the help of surface attached target-ng ligands such as folic acid, peptides, aptamers, proteins, andntibodies.

5.4. Magnetofection

Transfections performed using SPIONs are called magnetofec-tion, where different types of negatively charged nucleic acids (DNAand RNA) are conjugated with magnetic nanoparticles throughpositively charged polymers such as polyethylenimine (PEI) orpolyaziridine via electrostatic interactions. PEI polymer is widelyused in encapsulating SPIONs for magnetofection applications sincePEI has a tendency to induce “proton sponge effect” in order toescape from lysosomal degradation inside the cell. Moreover, thesize and zeta potential of polymer coated SPIONs complexes shouldbe optimized for effective nucleic acids delivery.

In an investigation, SPIONs were encapsulated with twokinds of polymers such as (i) a polycationic polymer, i.e.,poly(hexamethylene biguanide) (PHMBG) and (ii) PEI, (Castilloet al., 2012). Then small interfering RNA’s (siRNAs) responsiblefor luciferase gene knockdown were functionalized onto both ofpolymer encapsulated SPIONs, where PEI modified siRNA/SPIONsdelivery system showed high magnetofection efficiency andreduced toxicity towards CHO-K1 tumor cells as compared withPHMBG modified siRNA/SPIONs delivery system. Polyacrylic acid(PAA)-PEI modified SPIONs were conjugated with a therapeu-tic gene for plasmid DNA interleukin 12 (pDNAIL−12 – immuneresponse stimulant against tumors), where a 12.6-fold increasein transfection was observed in B16F1 cells after applying mag-

netic field (Prijic et al., 2012). In another study, the magnetofectionefficiency of SPIONs–PAA–PEI complexes had improved when thefunctionalization of PEI over SPIONs–PAA system was done in analkaline medium (Prosen et al., 2013). Branched PEI-SPIONs were
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206 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

Fig. 12. (a) Photograph (left) and thermal image (right) of a mouse 24 h after intravenous injection of folic acid-modified poly(ethylene glycol)-coated SPION nanoclustersFA-PEG-SPION NCs under an AC magnetic field with H = 8 kA m−1 and f = 230 kHz. (b) Tumor-growth behavior and (c) survival period of mice without treatment and treatedby intravenous injection of FA-PEG-SPION NCs, application of an AC magnetic field, 24 h after intravenous injection of FA-PEG-SPION NCs (n = 5). (d) Photographs of mice 35days after treatment.

R ublish

cvecb

(eh(c

eproduced with permission from Hayashi et al. (2013), © Ivyspring International P

onjugated with pDNA (containing gWIZ (an eukaryotic expressionector)-IL-10 (interleukin 10)) for transfecting primary vascularndothelial cells (HUVEC), where the expression of PAI-1 in HUVECells was effectively inhibited after the magnetofection of IL-10-ranched PEI-SPIONs (Namgung et al., 2010).

An effective silencing of melanoma cell adhesion moleculeMCAM) was achieved in both in vitro and in vivo lev-ls through magnetofection, when pDNA (encoding for short

airpin RNA against MCAM) was combined with PEI-SPIONsProsen et al., 2014). Similarly, the growth of HepG2 can-er cells was inhibited effectively by transfecting them with

er.

human telomerase reverse transcriptase (hTERT) gene silencingsiRNA modified disulphide-PEI-SPIONs (SSPEI-SPIONs) (Li et al.,2014a). In another study, the luminescence expression of pGL3-control plasmid (with Hind III/Xba I firefly luciferase cDNAfragment – introduced into Escherichia coli strain DH5a) in HEK293T cells was improved with the increase in w/w ratio ofpGL3-control plasmid loaded PDMAEMA-iron oxide nanoparticles(Huang et al., 2013) (as shown in Fig. 14). However, a 1000-fold

increase in transfection efficiency was observed on the applica-tion of magnetic field onto nanoparticles incubated HEK 293Tcells.
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G.K

andasamy,D

.Maity

/InternationalJournalofPharmaceutics

496(2015)

191–218207

Table 5Comparison of different animal models used to evaluate cancer hyperthermia therapy using magnetic nanoparticles.

Surfacecoatings

SAR Fe3O4 weightadministrated

Cell line and animal Tumor size Injection site Maximumtherapeutictemperature(in ◦C)

Time to reachtherapeutictemperature(in minutes)

Application time ofmagnetic field forhyperthermia (inminutes)

Hyperthermiaassessmentmethod

Reference

TMAG, DLPC,DOPe, 1:2:2cationic

175 W/g 2 mg DMBA-inducedmammary cancerin Sprague-Dawleyrats

10 mm Direct injectionto tumor

45 – 30 Immunologicalreaction

Motoyamaet al. (2008)

TMAG, DLPC,DOPe, 1:2:2cationic

– – EL4 T-lymphomaand C57BL/6 mice

6 mm Subcutaneousspace

45 5 30 Tumorsuppression

Tanaka et al.(2005)

TMAG, DLPC,DOPe, 1:2:2cationic

– 20 mg-magnetite/ml MM46 mammarycarcinoma andC3WHeN mice

15 mm Subcutaneousinjection

45 5 30 Tumor volume,Heat ShockProtein 70,Immunohisto-chemistry(CD3, CD4,CD8, and NK)

Ito et al. (2003)

Carboxydextran – 1.8 mol/l RG-2 and Fisher ratF-344

3–4 mm Thalamusregion

39 10 40 Prussian blue/immunohisto-chemistry

Jordan et al.(2006)

Aminosilane – 2.0 mol/l 43–47

Dextran 286 W/g 3 mg/150 �L C6 and Fisher ratF-344

5–10 mm Subcutaneous(anteriorbregma region)

– – – Hematoxylin–eosin

Rabias et al.(2010)

Uncoated 864.1 ± 16.6J g−1m−1

1 ml, 80 mg of Fe3O4

dissolved in 10 mlglycerin

Ehrlich carcinomaand Swiss albinomice

78.2 ± 3.5 mm3 Subcutaneousinoculation

47 ± 1 15 ± 2.2 40 Histologicalexaminationand Apoptosispercentagefrom 30 days ofthe starting oftherapy

Elsherbini et al.(2011)

DMSA 658 ± 53 W/g 0.226 mg Fe per 100mm3 of tumor volume

BxPC-3 andAthymic mice

80–500 mm3 Subcutaneousimplantation

43 24 60 Immunohisto-chemical KI-67Staining

Kossatz et al.(2014)

0.535 mg Fe per 100mm3 of tumor volume

MDA-MB-231 andAthymic mice

900 ± 22 W/g 0.24 mg Fe per 100mm3 of tumor volume

MDA-MB-231 andAthymic mice

0.087 mg Fe per 100mm3 of tumor volume

BxPC-3 andAthymic mice

TCPP 64 ± 2 W/g 3 times injection of120 �L with 1 mg Fe/ml

B16-F10 melanomacells and C57/BL6mice

50 mm3 Subcutaneoustransplantationinto rear limb

10 HistologicalAnalysis

Balivada et al.(2010)

Poly(styrene-co-acrylicacid)

– 0.3–0.4 mg Sarcoma 180 cellsand Swiss mice

6 mm × 6 mm Subcutaneoustransplantation

45–49 – 30 – Nguyen et al.(2012)

Anionicsurfactant

535 W/kg 0.5 ml Tu212 cell line andNude (NCr) mice

1 cm3 – 40 5 20 Histopathology Zhao et al.(2012)

TMAG, DLPC,DOPe, 1:2:2cationic

– 3 mg/0.4 ml osteosarcoma andSyrian femalehamsters

– Subcutaneousinjection

42 10 30 Tumor volume Matsuoka et al.(2004)

Note: TMAG, N-(�-trimethylammonioacetyl)-didodecyl-d-glutamate chloride; DLPC, dilauroylphosphatidylcholine; DOPe, dioleoylphosphatidyl-ethanolamine; DMBA, 7,12-dimethylbenz(a)anthracene; DMSA, 2,3-dimercaptosuccinic acid; TCPP, 4-tetracarboxyphenyl porphyrins.

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208 G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218

Fig. 13. Labeling with SPIOs does not affect the viability or functionality of human mesenchymal stem cells (hMSCs). (a) hMSCs were incubated with various concentrationsof SPIOs for 24 h over a magnet. Their enzymatic activity was assessed immediately after or 7 days after labeling. (b–h) hMSCs were incubated with 10 �g cm−2 of SPIOsfor 24 h over a magnet. (b–e) SPIO-labeled and unlabeled cells were immunophenotyped, and (f–h) cultured under conditions to induce differentiation into adipogenic,osteogenic, and chondrogenic lineages. Cells were stained with Oil Red O (a marker of adipocytes), Alizarin Red (a marker of osteocytes), or collagen II antibody (a marker ofc differ(

R bH & C

5f

aofFFat

hondrocytes). (f and g) The presence of DiI-labeled SPIOs inside the cells after theh) by Prussian blue stain.

eproduced with permission from Landázuri et al. (2013), © Wiley-VCH Verlag Gm

.5. SPIONs in combination with dopants/other imaging agentsor multimodal imaging

Dual mode MRI contrast (T1 and T2 contrasts) can also bechieved either by doping gadolinium (Gd) atoms into the coref SPIONs or by attaching the Gd-complexes onto the sur-ace of SPIONs for retaining their corresponding relaxivities.or example, Xiao et al. (2014) prepared PEG-coated-Gd-doped-

e3O4 nanoparticles (mean diameter of 4.74 ± 0.51 nm) with r1nd r2 values of 65.9 and 66.9 mM−1 s−1, where these nanopar-icles showed an enhanced in vivo T1–T2 dual MRI contrast

entiation period was assessed by red fluorescence emitted by DiI-labeled SPIOs or

o. KGaA, Weinheim.

effects (performed using 7 T MRI scanner) in C6 glioma-bearingmice after post-injection of nanoparticles at a dose of 5 mgFe/kg. In another recent study, a dual-mode contrast wasachieved by forming a hybrid dumbbell-shaped nanostructure,in which one bell consisting iron oxide core (covered withPEG) was connected through platinum cubes with another bell(formed of Gd coated gold core) (Cheng et al., 2014). Ther1 and r2 relaxivities were optimized by controlling the dis-

tance between the two bells (i.e., the size of platinum cubes)to prevent the magnetic influences between iron oxide andgadolinium.
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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 209

Fig. 14. (a) Gene expression of poly(2-dimethylamino)ethyl methacrylate-boundiron oxide nanoparticles with pDNA (IO-PDMAEMA)/pDNA incubated with andwithout an applied magnetic force for 20 min and analyzed 48 h post-incubationin the presence of 10% FBS (n = 3, *p < 0.05). Confocal microscopy images of IO-PDMAEMA/pDNA, (b) without, and (c) with an assisted magnet for 20 min; (d)quantification of the pDNA fluorescence intensity (*p < 0.05).

Reproduced with permission from Huang et al. (2013), © The Royal Society of Chem-istry.

Fig. 15. T1- and T2-weighted MR images of glioma-bearing brain before and afterintravenous injection of iron oxide/manganese oxide conjugated with Cy5.5 andchlorotoxin (CTX) (Fe3O4/MnO–Cy5.5–CTX) (a) and Fe3O4/MnO–Cy5.5 NPs (c) witha dose of 10 mg Mn per kg, respectively. Corresponding CNR analysis of T1 (b) and

T2 (d) MR images.

Reproduced with permission from Li et al. (2015), © The Royal Society of Chemistry.

Likewise, Fe3O4/Manganese oxide (MnO) hybrid nanocrystals inthe form of core/shell, dumbbell and flower-shaped were respec-tively synthesized from 5, 11, and 21 Fe3O4 nanoparticles todetect in vivo human hepatocellular carcinoma (HCC) (Im et al.,2013). The T1 and T2 MRI signal intensities were effectivelyenhanced, since the Fe3O4 nanoparticles remained in the Kupffercells of the liver, after the release of Mn2+ ions in the extra-cellular area (for T1 contrast) after opsonization of the hybridnanocrystals, thereby the quenching of T2 contrast effect due toMn2+ ions was avoided. In another similar study, a brain-tumor-targeting-agent (chlorotoxin) and a fluorescence agent (Cy5.5)were attached to the dumbbell shaped Fe3O4/MnO nanoparti-cles through N-(trimethoxysilylpropyl) ethylene diamine triaceticacid, trisodium salt (TETT) and N-succinimidyl-3-(2-pyridyldithiol)propionate (SPDP) conjugated with PEG2000 (Li et al., 2015). TheT1–T2 dual modal signal enhancement was significantly obtainedat the glioma-bearing brain of mice, after the intravenous injec-tion of respective doses of 10 and 5.5 mg of Mn and Fe per kg ofbody weight (with respective relaxivities (r1 and r2) of 5.37 and203.82 mM−1 s−1) as shown in Fig. 15.

SPIONs based MRI can be combined with other imagingmodalities such as CT/PET/gamma (�) imaging/PET/fluorescenceimaging/Cherenkov luminescence imaging for better diagnosisand treatment of cancers with different resolutions, by couplingSPIONs with radio nuclides, optical imaging enhancers, and lumi-nescence/fluorescence enhancers. The activity of non-phagocyticprimary T cells labeled with SPIONs-64Cu (Copper-64) nano-complex in the tumor cells was studied using a combined imagingof PET-MRI (Bhatnagar et al., 2014). In this analytical study, con-focal microscopy images ensured that dimethyl sulfoxide (DMSO)

facilitated the entry of nano-complex into the cellular mem-brane and after the entry, charged SPIONs-labeled T-cells wereused in targeting the B-cell lymphoma model. 64Cu-attached SPI-ONs were prepared for MRI/PET hybrid imaging by using dextran
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2 ourna

aa1afleDampMtwloi2

OyoS1trsftSn(iCpc2iad

F((a

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10 G. Kandasamy, D. Maity / International J

s a conjugation medium (Wong et al., 2012). Human serumlbumin (HSA) decorated SPIONs were functionalized with 64Cu-,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA)nd Cy5.5 dye (1:5:5 ratio) for combined MRI/PET and near-infrareduorescence imaging of U87MG tumor induced in a mice (Xiet al., 2010). In similar manner, PEG molecules decorated 64CuOTA-SPIONs decorated were formed to provide high resolutionnd high sensitive PET/MR imaging in in vivo conditions (BALB/cice) (Glaus et al., 2010). 99mTc was conjugated with SPIONs to

rovide an effective MRI/PET imaging in Balb/C mice in addition toRI angiographic imaging. Moreover, PET imaging studies showed

hat some amount of SPIONs were expelled by kidneys and othersere re-circulated inside the body (Sandiford et al., 2013). Simi-

arly, the surface of SPIONs was modified with radionuclides (68Gar 89Z) and ligand molecules to provide coupled MRI/PET imag-ng analysis of in vivo angiogenesis in a single step (Groult et al.,015).

Iodide-131 (131I) was conjugated with l-tyrosine modified SPI-Ns to amalgamate the SPECT imaging property with the MRIielding SPIONs (Park et al., 2011). In another study, radio-labelingf Indium-111 (111In) was done on the surface of APTES-PIONs using thiolated 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-(15),11,13-triene-3,6,9,-triacetic acid (PCTA) bifunctional chela-ors for facilitating SPECT imaging. MRI/SPECT in vivo imagingesults indicated that the radio-labeled SPIONs reached the tumorite (Zolata et al., 2015). Similar MRI/SPECT imaging study was per-ormed using 111In modified SPIONs (Misri et al., 2012). Recently,hree radionuclides such as 59Fe, 14C and 111In were attached withPIONs to identify the biodistribution of oleic acid, iron oxideanoparticles and their togetherness at different time intervals,Freund et al., 2012; Wang et al., 2015a), where 111In label-ng was suggested to be used for combined MRI/SPECT imaging.ommercially available SPIONs were conjugated, through bis-hosphonates, with 99mTc-dipicolylamine(DPA)-alendronate forombined in vivo MRI/SPECT and PET imaging (De Rosales et al.,

011) (refer Fig. 16). In another study, in vivo SPECT/CT imag-

ng of Female BALB/c mice showed that 99mTc-labeled-lactobioniccid-coated SPION selectively accumulated (38.43 ± 6.45% injectedose/gram) in hepatocytes, where the specific uptake of the SPIONs

ig. 16. Dual-modality in vivo studies. Short-axis view (top) and coronal view (bottom)b) T2*-weighted MR image 15 min postinjection, and (c) nanoSPECT-CT image of the samS) changes after injection due to accumulation of 99mTc-DPA-ale-Endorem, in agreemenccumulation of radioactivity. MR images were acquired with a TE of 2 ms.

eproduced with permission from De Rosales et al. (2011), © American Chemical Society

l of Pharmaceutics 496 (2015) 191–218

by liver was confirmed by the in vivo MRI images (Lee et al.,2009).

5.6. SPIONs in combination with other therapeutic agents

5.6.1. In combination with photodynamic therapyIn photodynamic therapy (PDT), a photosensitizer/

photosensitizing agent and a light source are used to kill cancerbearing tissues by initiating photonecrotic effects through theproduction of free radicals/singlet oxygen (highly reactive state ofoxygen) in those tissues. Silicon phthalocyanine photosensitizerPc 4 [HOSiPcOSi(CH3)2(CH2)3N-(CH3)2] is introduced as a newgeneration photosensitizer to overcome disadvantage of Porfimersodium or Photofrin® (a former FDA approved photosensitizingagent). SPIONs are combined with these photosensitizers for com-bined MRI imaging, magnetic targeting, HTP and PDT. Recently, anano-system comprising carboxylic acid functionalized SPIONs,Pc 4 photosensitizer and a fibronectin mimetic peptide (Fmp) wasdeveloped to target integrin �1 overexpressed in head and necksquamous cell carcinoma (HNSCC) xenograft tumors. The magnetictargeting of hybrid SPIONs helped in the enhanced inhibition oftumor growth (in) as compared with magnetically non-targetedIO-Pc 4 hybrid nano-system (Wang et al., 2014a) as shown inFig. 17. Similarly, a combination of SPIONs and chlorin e6 (Ce6 –a photosensitizer) showed increased therapeutic effect at in vivolevel with low cytotoxicity to normal cells (Li et al., 2013b).

Carbon fullerene (C60) was mixed with SPIONs and Hematopor-phyrin monomethyl ether (HMME) (a photodynamic anti-cancerdrug) to create hybrid C60-IONP-PEG/HMME drug delivery system,which exhibited good therapeutic efficacy with a 23-fold improve-ment in in vitro studies involving magnetic targeting using SPIONs(Shi et al., 2013a). The surface of gold-coated-Fe3O4 nanoparticleswas modified with thiolated heparin–pheophorbide a (PhA) conju-gate to form a Fe3O4/Au/H–PhA nanocomplex (Li et al., 2014b). Thispheophorbide-based nanocomplex caused 89.4% cell death in A549

cells, and considerably reduced the tumor volume (129.22 mm3)in A549 tumor-bearing mice considerably as compared to freePhA (tumor volume – 162.22 mm3) and saline (tumor volume –282.47 mm3) treated mice, on exposure to 670 nm laser.

images: (a) T2*-weighted MR images before injection of 99mTc-DPA-ale-Endorem,e animal in a similar view 45 min postinjection. Contrast in the liver (L) and spleent with the nanoSPECT-CT image which shows almost exclusively liver and spleen

.

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G. Kandasamy, D. Maity / International Journal of Pharmaceutics 496 (2015) 191–218 211

Fig. 17. Inhibition of xenograft tumor formation by Pc 4 PDT delivered by IO nanoparticles. (a–d) Tumor growth and representative images of tumors on both sides of themice in the PBS control, free silicon phthalocyanine (Pc 4), combination of iron oxide and Pc-4 (IO-Pc 4), and combination of fibronectin mimetic peptide, iron oxide andPc-4 (Fmp-IO-Pc4) groups, respectively. Pc 4 was given at a concentration of 0.4 mg/kg. Laser treatment was performed 48 h after the drug administration. Three out of sixmice from each group are shown as representatives. Statistical analysis indicated a significant difference in the longitudinal tumor volume across the 5 groups within theright side (laser treated) (p < 0.0013). Both IO-Pc 4 and Fmp-IO-Pc 4 groups had a significantly lower tumor growth volume than the PBS control group (p < 0.022 for IO-Pc 4and 0.0038 for Fmp-IO-Pc 4). The Pc 4 group had a marginally significantly lower tumor growth volume than the control group (p < 0.071). The Pc 4 group had a significantlyhigher tumor growth volume than both the IO-Pc 4 and Fmp-IO-Pc 4 groups (p < 0.049 for IO-Pc 4 group and 0.040 for Fmp-IO-Pc 4). No tumor growth difference was foundbetween IO-Pc 4 and Fmp-IOPc 4 groups (p = 0.98). There was no significant difference in the longitudinal tumor volume across the 4 groups on the left side tumor (nolaser treatment, p = 0.4987). None of the pairwise comparisons in tumor volume between any two groups with untreated left tumors was significantly different (results areomitted). (e) Tumor growth curve using a lower dose (0.06 mg/kg) and shorter period of time between drug administration and laser treatment than used in (a–d). Tumorsi Pc 4 g

R ty.

5

rcuwi

n the Fmp-IO-Pc 4 (targeted) group grew significantly slower than those in the IO-

eproduced with permission from Wang et al. (2014a), © American Chemical Socie

.6.2. In combination with photothermal therapyNormally, photothermal therapy (PTT) does not use any free

adical oxygen from photosensitizers to cause damage to cancer

ells (as happening in photodynamic therapy). This method manip-lates the nanomaterial’s absorbance of light in infrared and longeravelength ranges to induce damage in the tumor cells by convert-

ng the absorbed photons into heat. So the materials absorptivity

roup (nontargeted) (p < 0.025).

or molar extinction coefficient (ability to attenuate light of givenwavelength) of nanomaterials is necessarily to be high to pro-duce high thermal ablations. Significantly, the near infrared (NIR)

therapeutic window absorbance should be more for nanoparticles-to-be-used. The disadvantage (i.e., photo bleaching in organic andpolymer materials) can be overcome by using inorganic materials,for instance, mixing SPIONs with graphene oxide, gold, etc.
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212 G. Kandasamy, D. Maity / International Journa

Fig. 18. (a) Representative photos of SUM-159 tumor-bearing mice of bothimmediate and 3 weeks after laser treatment. Laser wavelength = 885 nm. Powerdensity = 2.5 W cm2. Irradiation time = 10 min. Arrows point to the tumor sites. H&Estaining of tumor tissues from mouse treated with nanoparticles plus laser irradia-tion (b) and control mouse without any treatment (c). (d) Anti-tumor efficacy of fourdifferent groups of mice before and 3 weeks post various treatments. Four groups (5mice for each group) are magnetic nanocrystals injected mice with laser irradiation(G1), nanocrystals injected mice without laser irradiation (G2), laser treated micewithout injection of nanoparticles (G3), and control mice injected with PBS (G4).Error bars are based on standard deviations.

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eproduced with permission from Chen et al. (2014), © The Royal Society of Chem-stry.

In a recent study, a correlation between molar extinction coef-cient and self-assembling nature (chainlike/hollow vesicles) of

ron oxide nanomaterials was found (Zhang et al., 2014). A twofoldmprovement in the molar extinction coefficient of SPIONs wasttained when the size-dependent-packaging density of SPIONsas optimized with respect to polypyrrole (a PTT agent), thereby

ig. 19. (a) A microscope image of Prussian blue dye stained tissue. The iron in the muicrobubbles encapsulating Fe3O4 nanoparticles and chemotherapeutic drug) injected l

issue slices from lymph nodes injected with microbubbles that do not contain Fe3O4. (c)ensity revealed the presence of iron. It also can be observed that the Fe3O4 nanoparticlelectronic density in the microbubbles without Fe3O4 injected lymph nodes. Magnificatio

eproduced with permission from Niu et al. (2013), © Elsevier.

l of Pharmaceutics 496 (2015) 191–218

resulted in increased photothermal effect on HeLa cancer cells(Zhang et al., 2014). Recently, Prussian blue, another PTT agent(ordinarily used for staining and clinically approved drug), wasgrown on the surface of SPIONs to a thickness of 3–6 nm. The blue-colored Prussian blue coated SPIONs system killed more than 80%of HeLa cells at minimal concentration and achieved 87.2% tumorinhibition rate due to NIR irradiation and magnetic targeting (Fuet al., 2014). Fluorescent carbon, one dimensional (1D) magnetic NPchains and doxorubicin were combined to form a nano-package forimproved MRI contrast, fluorescent imaging (using different exci-tation wavelengths), and PTT/chemotherapy at in vitro level (Wanget al., 2014b).

SPIONs coupled with graphene oxide and stabilized by PEG(GO-IONP-PEG) were injected into randomly selected three micegroups induced with metastasis in their regional lymph nodes forstudying NIR/MR imaging and NIR treatment modality. The combi-natorial nano-package showed the possibility of in vitro and in vivodual-modality mapping and treatment of metastatic lymph nodes(Wang et al., 2014c). Similarly, another group formed GO-IONP-PEGnanocomposite loaded with DOX for combined targeted drug deliv-ery, PTT, chemotherapy and MR imaging (Ma et al., 2012). Gold, ironoxide and graphene oxide based nanocomposite system was pre-pared for enhanced PTT and MR imaging by creating electrostaticinteraction through the introduction of PEI after the incorporationof SPIONs onto graphene oxide (Shi et al., 2013b). After the removalof excess PEI, negatively charged gold nanoseeds were embeddedonto PEI, confirmed by increase in NIR absorption band. Finally,modified PEG was attached to increase the stability and biocom-patibility. 4T1 tumor induced female BALB/c mice was injectedwith GO-IONP-Au-PEG nanocomposite and subjected to 808 nmlaser irradiation for about 5 min, where a thermal camera notedthe change in temperature due to NIR irradiation. It was concluded

that reduction in tumor volume in laser irradiated mice indicatedthat the formed nanocomposite acted as an effective PTT agent,which was not witnessed in control group and not-laser-radiatedgroup.

ltifunctional polymer microbubbles (MPMBs–poly(lactic-co-glycolic acid) (PLGA)ymph nodes tissue slices was stained blue; (b) no blue stain was observed in theA TEM image of MPMBs injected lymph nodes. The black mass with high electronics are distributed in the shell of the microbubbles. (d) There was no detectable highn, 100× (a and b), 40,000× (c), 10,000× (d).

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Not only graphene oxide, silica was also used as a shell for octa-edral shaped SPIONs to produce stimuli sensitive and targetedDS for photon induced heat therapy (Li et al., 2014c). Initially,ctahedral SPIONs were truncated and then coated with trisocta-edral gold to improve the photothermal efficiency. Finally, theesoporous silica shell was formed outside to provide space for

ligonucleotide and doxorubicin attachment, where these combi-ations showed enhanced PTT effect in both in vivo and in vitroonditions. Similarly, polydopamine (PDA – another PTT agent) wassed to cover the clustered Fe3O4 nanoparticles (with r2 value of8.1 mM−1 s−1) for MRI (Zheng et al., 2015). The Fe3O4@PDA com-osite nanoparticles showcased a higher killing efficiency in A549ells, when these nanoparticles-incubated-cells were exposed toIR irradiation with a power density of 6.6 W/cm2. Moreover, theolume of A549 subcutaneous tumor (induced in Male Balb/c)ice was completely inhibited after post injection and subsequent

08 nm-NIR laser irradiation of the composite nanoparticles formin. Nevertheless, Chen et al. (2014) proved that high crystallinePIONs with proper surface coating acted as a good PTT agent ashown in Fig. 18. In their study, the surface temperature of SUM-159umor (induced in BALB/c mice) was increased from 35 ◦C to 60 ◦Cy exposing PEO-b-P�MPS coated SPIONs to 880 nm for 10 min.

.6.3. In combination with sonodynamic therapyCancer therapies performed using ultrasound is called as sono-

ynamic therapy (SDT) therapy and agents/chemicals used in thisethod are called SDT agents or sonosensitizers. The photosen-

itizers such as TiO2 and HMME can be used as sonosensitizersecause of their ability to produce hydroxyl/peroxy/alkoxy radi-als when exposed to ultrasound, thereby increasing the chances ofilling cancer cells. Magnetic nanoparticles can be combined withhese sonosensitizers to increase the efficiency of cancer therapy. Aanocomposite constituting Fe3O4–NaYF4@TiO2 and doxorubicinas formed to test both sonodynamic and chemotherapeutic effi-

iency in MCF-7 cells (Shen et al., 2014). The rate of apoptosis inCF-7 cells was found to be increased in the combined therapy

iven through these hybrid materials in association with magneticargeting as compared to individual therapies.

PLGA microbubbles co-encapsulating SPIONs and doxorubicinmean diameter after encapsulation – 868.0 ± 68.73 nm) performedell in simultaneous chemotherapy and ultrasound/MR imaging

gainst in vivo metastatic lymph nodes (Niu et al., 2013) as shownn Fig. 19. In a recent investigation, a combination of iron oxideanoparticles, SDT, and microwave treatment showed almost 97%eduction of in vivo tumor volume (Gebreel et al., 2014). PVAicrobubbles encapsulating SPIONs were created by conjugating

ilane coated SPIONs with surrounded bubbles through the amino-ldehyde coupling in respective surfaces, where the microbubblesncapsulated SPIONs showed enhanced ultrasound/MR imagingBrismar et al., 2012). The air gap formed between magneticanorattles and poly(vinylsilane) with perfluorohexane (PFH) wasoncealed to make use of the formed nano-system for improvisedltrasound/MR imaging (Yang et al., 2014b).

. Conclusion and perspectives

Much advancement has been achieved in preparing high qualityPIONs as compared to other nanoparticles/nanostructures for can-er theranostic applications. The SPIONs with different sizes, shapesnd surface coatings have been engineered for achieving high crys-allinity, very narrow size distribution, and improved magnetic

roperties for their better performance in biomedical applications.owever, the usage of SPIONs is only limited to in vitro level except

ew in vivo studies and clinical investigations till date. The intrinsiceasons behind these limitations are related to the diminishing of

l of Pharmaceutics 496 (2015) 191–218 213

magnetic properties of SPIONs at the fundamental level. It can beseen from this review that tailoring of the magnetic properties ofSPIONs by reducing the surface and volume canting effects is verytedious. The influence of size dependent spin canting effects on themagnetic properties of SPIONs is comparatively high as comparedto the shape dependent canting effects. Moreover, some surfactantssuch as polyoxyethylene (5) nonylphenylether have less influenceover the magnetic properties of SPIONs as compared to other sur-factants, but the crystallinity of SPIONs should also be considered.Moreover, it can also be seen that the high temperature synthe-sis strategies yielded high crystalline monodisperse SPIONs withsignificant magnetic properties, where the synthesis parametersplayed important roles in preparing such high quality SPIONs withdiverse sizes and shapes.

Previous reviews on various cancer theranostic applications,such as hyperthermia, MRI, magnetofection, and magnetic target-ing, indicated that the improvements in magnetization, relaxivitiesand SAR values of the SPIONs have led to enhance the thera-nostic efficacy. However, SPIONs for early diagnosis of cancersand treating them concurrently are still under-developed. More-over, the formation of SPIONs with maximum relaxivities andSAR values (at the synthesis level and after organic/inorganicencapsulations/chemical modifications) for effective in vivo can-cer theranostics still remains challenging. Many developmentsin the synthesis/encapsulation procedures of SPIONs and coatingthem with novel surfactants/encapsulants/targeting agents havebeen done lately for effective cancer treatment at the in vitro andin vivo scenarios. In this review, the following are significantlyoutlined: the recent advancements in (i) improving the magneticproperties of SPIONs by manipulating the size, shape and surfacecoatings, (ii) developing novel biocompatible polymers to encap-sulate SPIONs with and without cancer drugs/targeting agents,(iii) applying SPIONs as in vitro and in vivo T1, T2 and dual mode(T1–T2) MRI contrast agents individually (by modifying size andshape of SPIONs) and in combination with other contrast agents(manganese/gadolinium complexes), (iv) combining SPIONs withradio nuclides/optical imaging/fluorescence enhancers for multi-modal in vivo cancer imaging, (v) enhancing the cancer therapyusing recently developed SPIONs (with different size, shape andsurface coatings) via in vivo magnetic hyperthermia, magnetofec-tion and magnetic targeting. This review also showed that theefficacy in cancer theranostics can be further enhanced by form-ing SPIONs based nanopackages via combining SPIONs with otherchemotherapeutic drugs, photosensitizers, photothermal agents,and sonosensitizers. Nevertheless, very limited studies on com-binatorial cancer theranostic agents at in vivo level are involved,and the side effects (acute and chronic) at this level due to thesetheranostic agents are still unknown. Thus, more elaborate stud-ies are required on co-encapsulation and delivery, protein coronaformation, destruction pathways in tumor cells, pharmacokinet-ics/pharmacodynamics of combinatorial theranostic agents andtheir inter-interactions to further involve them in clinical studies.Moreover, the advancements in contemporary techniques are verymuch expected to overcome the constraints in characterization ofthe physicochemical properties of the surface engineered SPIONsand their combination with other drugs/targeting agents.

In summary, an efficient in vivo cancer treatment can beachieved via multimodal imaging and therapy by enlargingthe therapeutic window via the usage of SPIONs (with highrelaxivity and SAR values) along with other contrast/chemicalagents/drugs. Although the advancements of combinatorial SPIONbased nanopackages are at their preliminary stages, the researchers

around the world are developing new strategies/designs to enhancethe performance of these combinatorial nano-packages in bothin vitro and in vivo cancer theranostics. Thus, these multi-modalSPIONs based nanopackages might enable the complete inhibition
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f cancer in the human trials in future, if intensive research is per-ormed by global scientists on these nanopackages.

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