1 s2.0 S0378517315300776 Main

International Journal of Pharmaceutics 493 (2015) 313327
Contents lists available at ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Review
Magnetic nanoparticles: In vivo cancer diagnosis and therapy

Michele K. Lima-Tenrio a,b , Edgardo A. Gmez Pineda b , Nasir M. Ahmad c , Hatem Fessi a ,
Abdelhamid Elaissari a,
a
University of Lyon, University Lyon-1, CNRS, UMR 5007, LAGEP-CPE, 43 bd 11 Novembre 1918, F-69622 Villeurbanne, France
State University of Maring, Department of Chemistry, Av. Colombo, 5790, CEP 87020-900 Maring, Paran, Brazil
Polymers and Surface Engineering Laboratory, Department of Materials Engineering, School of Chemical and Materials Engineering (SCME),
National University of Sciences and Technology (NUST), NUST H-12 Campus, 44000 Islamabad, Pakistan
b
c
a r t i c l e
i n f o
Article history:
Received 5 June 2015
Received in revised form 6 July 2015
Accepted 21 July 2015
Available online 29 July 2015
Keywords:
Magnetic particles
In vivo
Cancer
MRI
Drug delivery
Hyperthermia
a b s t r a c t
Recently, signicant research efforts have been devoted to the nding of efcient approaches in order to
reduce the side effects of traditional cancer therapy and diagnosis. In this context, magnetic nanoparticles have attracted much attention because of their unique physical properties, magnetic susceptibility,
biocompatibility, stability and many more relevant characteristics. Particularly, magnetic nanoparticles
for in vivo biomedical applications need to fulll special criteria with respect to size, size distribution,
surface charge, biodegradability or bio-eliminability and optionally bear well selected ligands for specic targeting. In this context, many routes have been developed to synthesize these materials, and tune
their functionalities through intriguing techniques including functionalization, coating and encapsulation strategies. In this review article, the use of magnetic nanoparticles for cancer therapy and diagnosis is
evaluated addressing potential applications in MRI, drug delivery, hyperthermia, theranostics and several
other domains. In view of potential biomedical applications of magnetic nanoparticles, the review focuses
on the most recent progress made with respect to synthetic routes to produce magnetic nanoparticles
and their salient accomplishments for in vivo cancer diagnosis and therapy.
2015 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Preparation of magnetic nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .314
2.1.
Coprecipitation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
2.2.
Hydrothermal synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
2.3.
Microemulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
2.4.
Thermal decomposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
2.5.
Solgel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Encapsulation of magnetic nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
3.1.
Encapsulation via nanoprecipitation using from preformed polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
3.2.
Encapsulation via simple emulsion evaporation (SEE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
3.3.
Encapsulation using double emulsion evaporation based process (DEE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
3.4.
Encapsulation via Layer by layer (LbL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Magnetic nanoparticles in cancer diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Magnetic nanoparticles in cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
5.1.
Hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
5.2.
Drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Corresponding author at: University of Lyon, University Lyon-1, CNRS, UMR 5007, LAGEP-CPE, 43 bd 11 Novembre 1918, F-69622 Villeurbanne, France.
E-mail address: elaissari@lagep.univ-lyon1.fr (A. Elaissari).
http://dx.doi.org/10.1016/j.ijpharm.2015.07.059
0378-5173/ 2015 Elsevier B.V. All rights reserved.
314
6.
7.
M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327
Magnetic nanoparticles and theranostic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
1. Introduction
Cancer is one of the biggest challenges facing the medical
research in our time. It is considered as a difcult disease to treat
due to the fact that the available treatment options are limited
and, in many cases, the timely diagnosis and prognosis are difcult. Moreover, the approaches usually used for cancer treatment
such as surgery, radiotherapy and chemotherapy have considerable
harmful side effects. In this context, much effort has been devoted
on nding novel approaches (non-invasive and minimally invasive)
for its diagnosis and therapy.
Magnetic nanoparticles (MNPs), due to their unique physical
properties and ability to function at the cellular and molecular level
of biological interactions (Sun et al., 2008), are a major class of
nanoscale materials with the potential to be applied in biomedical
elds, such as, drug delivery, hyperthermia treatment, and magnetic resonance imaging (MRI) of cancer cells. The choice of MNPs
can be related to their high magnetic susceptibility, biocompatibility, stability and availability from various preparation methods
(Ahmed et al., 2012b). In addition, magnetic nanoparticles are easily
controlled by an external magnetic eld application, which provide
the releasing of the anticancer agent at a specic rate and at a specic site, overcoming the problems of conventional techniques for
diagnosis and therapy (Yoo et al., 2011).
As a result of their nanosize, and their increasing surfaceto-volume ratio, researchers have focused on the study of the
relationship between structure and properties of MNPs. Composition, size, morphology and surface chemistry can be tailored by
various processes to not only improve magnetic properties but also
affect the behavior of nanoparticles in vivo. The successful application of MNPs in biomedical eld is related specially with their
magnetic properties (which must be controlled by applying an
external magnetic eld), their dispersion and degree of aggregation. In this context, encapsulation process by coating the MNPs
using a biocompatible polymer during or after the synthesis to
increase the stability of the molecule, preventing the aggregates
formation, changes from the original structure and biodegradation
when exposed to the biological system (Mahdavi et al., 2013; Pedro
et al., 2003).
Several polymers, already approved by FDA, have been used for
the incorporation of iron oxide, such as poly(ethylene glycol) (PEG),
poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(lactic-coglycolic acid) (PLGA), dextran, chitosan, and so on (Filippousi et al.,
2013b). Some examples of MNPs coated with organic biodegradable
dextran- and carbohydrate-derivative-coated MNPs that have been
marketed for use in clinical setups include Ferridex , Resovist
and Combidex , which are successfully used as MRI contrast agent
(Singh and Sahoo, 2014). As contrast agents, magnetic nanoparticles can help improving imaging techniques resolution, emerging
as a powerful probes for both in vivo imaging in medical and biological diagnostics (Shokrollahi et al., 2014).
Regarding cancer disease, MNPs can be used also for therapy
purpose such as drug delivery and hyperthermia. Magnetic drug
delivery system is based on magnetic nanoparticles loaded with the
anticancer drug, and carried to the tumor site by using an external
magnetic eld. Concerning the hyperthermia therapy, once the particles are targeted to the cancer cells, it is possible to heat the tumor
by oscillating the applied magnetic eld. Instead of it, it is possible
to use MNPs for hyperthermia-based drug delivery, in which the
drug molecule is released due to the heating. Fig. 1 shows MNPs

applications in cancer disease. Above all of these applications for
cancer treatment, studies are being conducted on the preparation of
dual-purpose nanomaterials, with property for simultaneous diagnosis and therapy and hence a new area has emerged with the term
coined as theranostic.
Present review aims to report and to update the state of the art
of magnetic nanoparticles in cancer treatment. In this direction,
special attention is dedicated to the preparation, encapsulation,
functionalization of magnetic nanoparticles and their specic functionalization in order to be used for cancer disease treatment.
2. Preparation of magnetic nanoparticles
It is well known that the properties of the MNPs are related to the
process used for its preparation because of the strong dependence
of the magnetic properties on their morphology and structure.
In this context, different methods have been proposed for the
synthesis of MNPs of different compositions, morphologies, surface chemistry, with particular attention on synthesis of particles
nearly of uniform size and shape. Besides of it, the preparative
methods have to allow a good control of relevant vital properties. Among physical and wet chemical methods used for MNPs
synthesis, the later techniques are perhaps more effective for the
synthesis and control of the properties. Synthesis of monodispersed
nanostructures and reproducibility are the main challenge for these
chemical methods. The general strategy for preparing monodisperse nanoparticles in a liquid phase is to separate the nucleation
and growth of nanocrystals. A brief review of few typical processes
resulting in the efcient preparation of the magnetic nanoparticles
is discussed below.
2.1. Coprecipitation method
Coprecipitation technique is a facile and convenient method
to prepare magnetic nanoparticles. The synthesis is based on the
reduction of metallic elements, from salt solution, by adding NaOH
solution, at room temperatures or at elevated temperatures. It has
been shown that the properties of the magnetic nanoparticles such
as size, shape and composition depend on the type of salts used, the
reaction temperature, the pH value and ionic strength of the media.
However, once the synthetic conditions are xed, the quality of the
magnetic nanoparticles can be reproducible (Lu et al., 2007; Thanh,
2012).
The main advantage of the coprecipitation method is that a large
amount of nanoparticles can be synthesized (Laurent et al., 2008).
Since only kinetic factors are controlling the growth of the crystal
(Salunkhe et al., 2014), it is difcult to control particle size distribution. Nonetheless, despite such issues, uniform particles are
usually prepared via homogeneous precipitation reactions via a
process that involves the separation of the nucleation and growth
of the nuclei (Hao et al., 2010). Two stages are involved in this process: (i) a short burst of nucleation when the concentration of the
species reaches critical supersaturation and (ii) a slow growth of
the nuclei by diffusion of the solutes to the surface on the crystal
(Bitar et al., 2014). To obtain mono-dispersed nanoparticles, these
two stages should ideally be separated; i.e., nucleation should be
avoided during the period of growth.
315
Fig. 1. Magnetic nanoparticles applied in cancer disease: diagnosis (MRI) and therapy (hyperthermia, drug delivery and controlled release).
For example, Dong-Lin et al. (2006) synthesized Fe3 O4 nanoparticles by a coprecipitation method for localized hyperthermia
applications. To prevent agglomeration between the particles,
dodecyl benzene sulfonic acid sodium salt (NaDS) was employed.
However, the morphology of the particles observed to be almost
spherical with diameters ranging from 10 to 30 nm but showing
agglomerated and polydisperse particles. Krishna Surendra et al.
(2014) have shown that the magnetic nanoparticles size, synthesized by co-precipitation method, changes from 6 to 14 nm by
varying the precursor to surfactant concentration. Wang et al.
(2011) have prepared magnetic uid (MF) by the coprecipitation of
monodispersed Fe3 O4 magnetic nanoparticles (12 nm), using oleic
acid and Tween 80 as surfactants. The MF showed excellent stability
and fast magneto-temperature response, with potential application
in both magnetic resonance imaging and hyperthermia.
Besides of being cost-effective, coprecipitation is widely used
for the synthesis of MNPs for biomedical applications, such as cancer diagnosis and therapy (Kossatz et al., 2014; Sanjai et al., 2014;
Tsiapa et al., 2014). Its wide use can be explained by the ease of
implementation and need for less hazardous materials and procedures (Tiwari, 2013).
2.2. Hydrothermal synthesis
Hydrothermal synthesis is based on aqueous reactions taking
place under high pressure and high temperature to induce or affect
the formation of nanocrystals. It is based on a general phase transfer
and separation mechanism occurring at the interfaces of the liquid,
solid, and solution phases present during the synthesis in aqueous
system at high temperature (generally in the range from 130 to
250 C) and high vapor pressure (generally in the range from 0.3 to
4 MPa) (Wang et al., 2005). These conditions are reached by sealing
the solution mixture in Teon-line autoclaves. When the reaction
is complete, it is cooled to room temperature and washed with various solvents to remove impurities and non-conjugated stabilizing
agents (Lam et al., 2013).
A control of the properties of the nanoparticles is possible by
choosing the appropriate mixture of solvents and varying parameters such as temperature, pressure and reaction time. For example,
the particle size and size distribution increase with the precursor
concentration. However, the residence time had a more signicant
impact on the average particle size than feed concentration (Hasany
et al., 2013).
Good crystallization and easy control of product morphology,
among various other advantages of the hydrothermal synthesis,
turn it one of the most promising route for nanoparticles production.
Li et al. (2013) have reported a one-pot hydrothermal route to
the synthesis of stable PEI-coated Fe3 O4 nanoparticles (NPs). This
work reported that the obtained MNPs may be multifunctionalized with folic acid (FA) for MR imaging of different biological
systems. Li et al. (2014a) also developed a simple approach to forming multifunctional Fe3 O4 NPs for targeted MR imaging of tumors,
by hyaluronic acid-targeting. Other studies on MNPs preparation
(by hydrothermal method), and surface functionalization showed
that the synthesized particles have a great potential application in
MR imaging (Cai et al., 2013; Li et al., 2014b).
2.3. Microemulsion
Microemulsions consists in an isotropic, macroscopically homogeneous, and thermodynamically stable solution formed by at
least three components (a polar phase usually water, a nonpolar phase usually oil, and a surfactant). The stability of these
emulsions is due to the surfactant molecules, which form, on a
microscopic level, an interfacial lm separating the polar and the
316
Fig. 2. Scheme of an oil-in-water (O/W) microemulsion reaction method for synthesis of nanoparticles.
non-polar domains. Different microstructures are formed by the

interfacial layer, from droplets of oil dispersed in a continuous
water phase (O/W-microemulsion), over a bicontinuous sponge
phase to water droplets dispersed in a continuous oil phase (W/Omicroemulsion). These nanodroplets can be used as nanoreactors
to carry out the chemical reactions, and to provide a suitable environment for controlled nucleation and growth (Malik et al., 2012).
By a continuous collision of the nanodroplets, they tend to coalesce
and break, mixing the inorganic salt (A) and the precipitating agent
(B), forming the precipitate, after nucleation and growth (Fig. 2).
Finally, the nanoparticles are obtained by extracting the surfactants
and, washing several times.
In general there are two methods for nanoparticle synthesis using microemulsion techniques: water-in-oil (W/O) (reverse
micelle) and oil-in-water (O/W) (normal micelle). The main advantage of this method is that it has been shown to be adequate,
versatile and, particle size and shape can be easily controlled by
modulating the parameters of the aqueous droplets. However, it
also presents some disadvantages: the yield of nanoparticles is low
compared with the coprecipitation method, and the purifying procedures required for removing the surfactants used for emulsifying
the immiscible systems is complicated (Qiao et al., 2009; Shari
et al., 2012).
2.4. Thermal decomposition
Magnetic nanoparticles with control over size can be also synthesized through the thermal decomposition method. The process
requires relatively higher temperatures and a complicated operation (Wu et al., 2008). Highly monodisperse MNPs are generally
obtained with thermal decomposition of organometallic compounds followed by oxidation in high-boiling temperature organic
solvents containing stabilizing surfactants. The organometallic precursors consist of metal, acetylacetonates, [M(acac)n ], (M = Fe, Mn,
Co, Ni, Cr; n = 2 or 3, acac = acetylacetonate), metal cupferronates
[Mx Cupx ] (M = metal ion; Cup = N-nitrosophenylhydroxylamine,
C6 H5 N(NO)O ), or carbonyls (Shokrollahi, 2013). Fatty acids,
oleic acid, and hexadecylamine are often used as surfactants (Lu
et al., 2007). For the precise control of size and morphology, the
control of the temperature, reaction time, as well as aging period,

as well as the ratios of the starting reagents. Usually, nanoparticles with good properties (narrow size distribution, for example)
to be applied in magnetic resonance imaging (MRI) are obtained by
thermal decomposition method of metallic precursors.
Prashant et al. (2010) prepared iron oxide nanoparticles by thermal decomposition method of Fe(acac)3 . After coating, Xenograft
tumor model MRI conrmed the advantages of the synthesized
MNPs versus Resovist through the enhanced permeation and
retention (EPR) effect of the tumor vasculature. Lai et al. (2012)
also showed good results from the MNPs synthesized by thermal
decomposition method. The obtained particles showed potential
to be applied as contrast agent for the magnetic resonance imaging
(MRI).
Despite thermal decomposition method presents many advantages for monodisperse particles synthesis, however the main
disadvantage is that the resulting NPs are generally only dissolved
in non-polar solvents (Wu et al., 2008).
2.5. Solgel
Solgel is a solution chemistry-based technique to synthesize pure, stoichiometric, and monodisperse oxide nanoparticles
including magnetic nanoparticles. This method is also useful for
nanoparticles synthesis, and is based on the hydrolysis and polycondensation reactions of metal precursors, metal, or metalloid
element surrounded by various reactive ligands to form a colloidal system named sol. The sol is then dried by solvent
removal or by chemical reaction leading to the formation of a network containing a liquid phase, called gel (Kalia et al., 2014).
Because these reactions are performed at room temperatures,
further heat treatments are necessary for the nal crystalline
nanoparticles.
Solgel method can be used to synthesize pure, stoichiometric, monodisperse and large size nanoparticles (tens to hundreds
of nanometers) with relatively narrow size distribution in a large
scale. Some advantages related to this process of synthesis are the
good size control of the nanoparticles, the possibility to predetermine the structure of the nanoparticles, by the experimental
317
Table 1
Examples of materials used for magnetic nanoparticles encapsulation by the nanoprecipitation method and its applications.
Magnetic nanoparticle
Polymer
Solvent
Non-solvent
Application
Reference
Iron oxide
Iron oxide
Iron oxide
Iron oxide
Iron oxide
PLGA
PLA-TPGS
PLA-TPGS
mPEG-PPSu
PEG or mPEG-PPSu-mPEG
Acetone
THF
THF
THF
THF
Water
Water
Water
Water
Water
Drug delivery
MRI
MRI
Theranostic
Hyperthermia and Drug delivery
Zavisova et al. (2009)

Prashant et al. (2010)
Tan et al. (2011)
Filippousi et al. (2013b)
Filippousi et al. (2013a)
condition and, the possibility to obtain particles with pure amorphous phases (Salunkhe et al., 2014).
It is more suitable for producing magnetic particles under solid
state (powder); it is therefore not very suitable for producing MRI
contrast agents (Qiao et al., 2009), probably due to their low stability in aqueous solution. In spite of this, interesting works have
reported that magnetic materials prepared by solgel method have
showed potential applications especially in cancer therapy via heating (hyperthermia) (Saldivar-Ramirez et al., 2014; Snchez et al.,
2014).
3. Encapsulation of magnetic nanoparticles
Fig. 3. Set-up for MNPs encapsulation by nanoprecipitation method.
Preparations of magnetic materials have been extensively studied for a better control of the magnetic properties, size distribution
and chemical composition of the nanoparticles, in order to prepare
available systems for biomedical applications. A signicant challenge associated with the applications of these MNPs in biomedical
eld is their behavior during in vivo and in vitro study. In this
context, various physical and chemical properties of the particles
should be considered. MNPs should preserve their colloidal stability and resist aggregation if their magnetic interaction is reduced.
Besides of it, for in vivo biomedical applications, MNPs should be
biocompatible, with low toxicity, with small size to avoid vessel
embolism and they must have also high magnetization to be controlled by an external magnetic eld.
Without any surface coating, MNPs tend to aggregate (irreversibly) forming clusters, resulting in an increase in their size.
Strong attractions of magnetic dipoledipole among these clusters
imply in the reducing on their magnetization (inducing ferromagnetic behavior). Based on this, the modication of particles
surfaces is essential to counteract the attraction forces between
magnetic nanoparticles, and confer to the particles good stability
in dispersed medium, providing them a positive effect on biodistribution. A signicant inuence on magnetic properties by the
coating strategies can be also observed. The strategy on coating
the magnetic nanoparticles is to isolate them from environment
inuence by a shell, which can be organic or inorganic. Among
organic coating, polymer-coated magnetic nanoparticles are the
most used for in vivo application, specially the magnetic latex particles from preformed polymers. It enhances the biocompatibility
of the nanoparticles, as well it reduces the leaching susceptibility
and protects particles surface from oxidation. Few of the common
preformed polymer based techniques on MNPs encapsulation for
application in cancer diagnosis and therapy are discussed below.
both phases and instantaneous formation of a colloidal suspension

occurs by fast diffusion of organic solvent into the water. The most
common used organic solvents are ethanol and acetone, which
are miscible in water, and can be easily evaporated. However, it
is important to highlight that organic phase can be a mixture of
solvents, and similarly, the aqueous phase can consist of a mixture
of non-solvents.
This method was rstly reported by Fessi et al. (1989) for the
synthesis of synthetic polymeric nanoparticles and nowadays it
has been used to encapsulate also magnetic nanoparticles. Table 1
shows some works that used nanoprecipitation method for magnetic nanoparticles encapsulation.
3.2. Encapsulation via simple emulsion evaporation (SEE)
Simple emulsion evaporation method consists on simple emulsion formation, followed by a solvent evaporation, which permits
the precipitation of the polymer and, then, the formation of the
particles. Fig. 4 shows a set-up for oil in water simple emulsion method. According to this method, the drug used for the
encapsulation should be hydrophobic. Another alternative for a
hydrophilic drug encapsulation is to use water in oil emulsion
method. However, in this case, a double emulsion evaporation
method is required (Elaissari, 2003). It is important to highlight
that, in simple emulsion method, the organic phase should be
non-miscible, like chloroform, dichloromethane, and the polymer
3.1. Encapsulation via nanoprecipitation using from preformed

polymers
The nanoprecipitation method (also called coprecipitation) is
based in two miscible phases: an organic phase containing the
preformed polymer dissolved and the magnetic nanoparticles dispersed, and an aqueous phase, in presence or absence of a surfactant
(Medeiros et al., 2013). The nanocapsules are obtained by the drop
wise addition of the organic phase to the aqueous one, under moderate agitation (Fig. 3). Polymer deposition on interface between
Fig. 4. Set-up used for a simple emulsion evaporation method. In this case, an
oilwater emulsion is exemplied.
318
Fig. 5. General emulsication process based on the double emulsion evaporation method w/o/w, in which the MNPs are dispersed in an aqueous media.
should be soluble in it. Some parameters should be controlled for

a good control of the particles, such as organic phase/water phase
ratio, surfactants nature and concentration, stirring rate, polymer
amount and evaporation rate (Miladi et al., 2014).
Ling et al. (2011) developed tumor-targeting based in carboxylterminated poly(lactic-co-glycolic) and iron oxide nanoparticles for
the diagnosis (targeting imaging) and treatment of prostate cancer
(drug delivery and real time monitoring of therapeutic effect). Lai
et al. (2012) developed a simple emulsion evaporation approach for
the clustering of iron oxide nanoparticles using a non-ionic surfactant. The obtained nanoparticles showed great results as contrast
agent in MRI, exhibiting better contrast results than commercial
Resovist .
3.3. Encapsulation using double emulsion evaporation based
process (DEE)
The double emulsion methods can be classied as:
wateroilwater emulsion (w/o/w) or oilwateroil emulsion
(o/w/o), and are usually obtained by two emulsication processes.
It is a method used for nanocapsules preparation, and is considered
an interesting approach for both hydrophilic and hydrophobic
drugs and/or magnetic nanoparticles encapsulation.
A typical procedure (Fig. 5) for double emulsion encapsulation of nanoparticles is based on a primary emulsion, formed by
the dispersion of an aqueous phase (containing the MNPs) in a
non-miscible organic solvent, by ultrasound and stabilized by a
surfactant. This dispersion is added to a second solution, containing
the stabilizing agent (hydrophilic emulsier), for a second emulsion
formation, also by sonication process. Generally, the nanocapsules
are obtained after evaporation of the solvents (under low pressure
or at room temperature) (Prez-Artacho et al., 2012; Silva et al.,
2014; Wang et al., 2013b).
Sun et al. (2012) reported the synthesis of PLGA-coated iron
oxide microcapsules by a double emulsion (w/o/w). The obtained
material showed excellent contrast-enhanced imaging capability
for ultra sound (US) and magnetic resonance (MR) dual-modality
biological imaging, from both in vitro and in vivo tumor models. Niu
et al. (2013) developed a doxorubicin loaded superparamagnetic
PLGA-iron oxide multifunctional theranostic agent for dual-mode
US/MR Imaging of lymph node, and for low frequency US triggered therapy of metastasis in lymph nodes. Sun et al. (2014)
showed that the magnetic microcapsules based in PLGA and iron
oxide provides an alternative strategy for MR-guided non-invasive
high-intensity focused ultrasound (HIFU) synergistic therapy of
cancer.
Table 2 contains other research efforts that reported the use of
double emulsion technique on MNPs encapsulation and, the applications in cancer treatment/diagnostic.
3.4. Encapsulation via Layer by layer (LbL)
Layer-by-layer assembly process is based on spontaneous
electrostatic attraction between oppositely charged components
(synthetic and natural polyelectrolytes, proteins and nanoparticles), which leads to polyelectrolyte adsorption at supersaturating
polyelectrolyte concentrations. It is a stepwise adsorption of the
charged polymers onto an oppositely charge surface (particle), as
shown in Fig. 6. This assembly of colloidal particles on a solid core
was rstly proposed by Iler (1966) and, from 1990s, applications
were expanded (Sukhorukov et al., 1998). By LbL method is possible to produce coated latex of different shapes and sizes, with
uniform and controlled thickness of the layer without using high
cost equipment.
Polymer assembly occurs by the incubation of the template
(magnetic nanoparticles, for example) in the polymer solution,
followed by washing, or by decreasing polymer solubility with
a drop-wise addition of a miscible solvent (Radtchenko et al.,
2002). A second polymer and multiple polymer layers can be
deposit sequentially, by repetition of this procedure. However, the
molecules employed for assembly should have a sufcient number
of charged groups to provide stable adsorption on an oppositely
charged surface and non-compensated charges exposed to the
exterior. The LbL adsorption of polyelectrolyte onto the colloidal
particles is a well-recognized method for magnetic nanoparticle
encapsulation and functionalization.
A multilayer capsule synthesis can be obtained by the traditional electrostatic interaction and also by hydrogen bonding and
covalent bonding (Gattas-Asfura et al., 2014; Kharlampieva and
Sukhishvili, 2006), for example.
Table 2
Applications of the double emulsion evaporation method in cancer disease.
Active ingredient
Polymer
Organic phase
MNP
Application
Reference
Doxorubicin and paclitaxel
PVA
Chloroform
Iron oxide
Hu et al. (2012)
Stilbene (model hydrophilic

drug)
Cisplatin
NR*
Doxorubicin
PCL
Dichloromethane
Iron oxide
Magneto-chemotherapy
and hyperthermia
Theranostics
Ahmed et al. (2012b)
PLGA
PLGA
FA-PEG114 -PLAx -PEG46 -acrylate
and MPEG114 -PLAx -PEG46 -acrylate
Dichloromethane
Ethyl acetate
Chloroform
Iron oxide
Iron oxide
Iron oxide
Drug delivery
Hyperthermia
Theranostic
Ashjari et al. (2012)

Prez-Artacho et al. (2012)
Yang et al. (2010)
NR* no reported.
319
Fig. 6. Magnetic nanoparticles encapsulated via layer-by-layer technique based on electrostatic interaction.
The LbL method presents some advantages over several conventional coating methods, including simplicity, versatility, low
operating costs, precise structure control and high loading capacity
for the guest. Generally, natural biodegradable polyelectrolytes are
used to LbL assembling process of particles, for biological application (Crouzier et al., 2010; Pavinatto et al., 2010).
Yoon et al. (2014) prepared MNPs coated with PAH (positively
charged) and DP (negatively charged) by electrostatic LbL attraction. The authors suggested the polymer based nanoparticles as a
promising platform for diverse application in cancer therapy and
diagnosis. Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres have been prepared by Li
et al. (2014c), via electrostatic interaction (layer-by-layer) between
the poly(ethylene glycol) grafted chitosan (CS-g-PEG) as polycation
and the citrate modied iron oxide nanoparticles (Fe3 O4 -CA) as
hybrid anion onto the uniform polystyrene sulfonate (PSS) microsphere templates. The obtained material showed potential for
tumor-specic delivery in the tumor diagnostic and therapy.
By the surface charge alternation, it is also possible to perform
a continuous assembly between positively and negatively charged
materials, affording a great freedom in the number of layers and layering sequence (Ariga et al., 2011). Manju and Sreenivasan (2011)
have coated MNPs by six double layers of (HA-Cur/PVP-Cur). The
synthesized approach opens up the feasibility of designing MNPs
capable of carrying multiple drugs, with possible application in
anticancer drug release.
4. Magnetic nanoparticles in cancer diagnosis
MRI (Li et al., 2013, 2014a; Wang et al., 2013a) principle is based
on the magnetic properties of hydrogen protons and its interaction
with both a large strong external magnetic eld (responsible for the
alignment of the magnetic eld) and a transverse radiofrequency
pulse to produce the highly detailed images of the human body
(Shokrollahi et al., 2014). The application of radio waves tends to
perturb the aligned protons, which return to their original state
by a relaxation phenomenon. During the relaxation phenomenon,
a local variation in proton density of a tissue that produces the
MRI image is observed. There are two relaxation process: longitudinal (T1 recovery) and transverse one (T2 decay), that can be
monitored to a MR image formation (Sun et al., 2008). Magnetic
nanoparticles accumulated in the tissue are responsible to provide
MR contrast enhancement by shortening both T1 and T2 relaxation
of surrounding protons (Singh and Sahoo, 2014).
Iron oxide magnetic nanoparticles have been used as contrast
agents to improve cancer detection, diagnosis, and also therapeutic management of solid tumors. Abdoscan , GastroMARK ,
Lumiren , Resovist , CliavistTM , Feridex and EndoremTM are
some examples of iron oxide contrast agents which are commercialized for use in MRI. But due to the exciting research in this eld,
various interesting works have reported. Song et al. (2015) synthesized biofunctionalized chitosan@Fe3 O4 NPs by combining Fe3 O4
and chitosan (CS) chemically modied with PEG and lactobionic
acid in one step. These functional groups enable the nanoparticles more biocompatible (PEG) and the liver targeting (lactobionic
acid groups). In vivo MRI of the livers of SD rats nanoparticles was

evaluated before and after intravenous administration of PEG/LACS@Fe3 O4 NPs. Before intravenous administration of MNPs, no
difference was observed to the parenchymal signal strength of the
rat livers. However, this signal was decreased after the nanoparticles administration, providing that these nanoparticles has liver
targeting function and represents potential tools for applications
in the biomedical eld.
Ahmad et al. (2015) reported the synthesis of nickelferrite by
a chemical co-precipitation method with simultaneous chitosan
coating. Chitosan-coated nickelferrite nanoparticles showed to be
suitable as both T1 and T2 contrast agents in MRI, in animal experimentation. Both a 25% signal enhancement in the T1 -weighted
image and a 71% signal loss in the T2 -weighted image were
observed to this sample. The authors have noted also that the applicability of these nanoparticles as both T1 and T2 contrast agents is
due to their cylindrical shape, which gives rise to both inner and
outer sphere processes of nanoparticles.
Wang et al. (2015) reported a simple process to prepare
PEG-superparamagnetic iron oxide (PEG-SPIONs) and PEG/PEIsuperparamagnetic iron oxide (PEG/PEI-SPIONs), by the thermal
decomposition of iron (III) acetylacetonate (Fe(acac)3 ) in the mixture of poly(ethylene glycol) (PEG) and poly(ethylene imine) (PEI).
The coated nanoparticles exhibited high r2 /r1 ratio, and in vivo
MRI of the mouse brains after intravenous injection of the SPIONs
showed their good contrast effect. Similarly tendency has also been
reported by Xie et al. (2015) by showing that nanoparticles exhibited vascular imaging effects (in vivo MRI of the mouse brains) after
24 h of intravenous injection.
Tumor-targeted magnetic micelles were prepared by selfassembling of SPIONs-loaded amphiphilic copolymeric micelles
based on 2,2,3,4,4,4-hexauorobutyl methacrylate, methacryloxyethyl trimethyl ammonium chloride and methoxy poly
(ethylene glycol) monomethacrylate (PEGMA), functionalized with
folate conjugated bovine serum albumin (FA-BSA) via electrostatic
interactions as reported by Li et al. (2015). In vivo studies were
performed by rst subcutaneous injection of human hepatoma Bel7402 cells to the lower back of each nude BALB/c mouse, followed
by the tumor growth to about 400 mm3 . The mices were, then,
divided into four groups for different contrast agents evaluation
(T1 contrast agent Gd-DTPA; T2 contrast agents Feridex ; unmodied magnetic micelles; and, FA-BSA modied magnetic micelles).
It was observed that the T2 signal intensity in the group treated
with the FA-BSA modied magnetic micelles decreases most significantly between 1 h and 24 h, while the tumors with Feridex and
unmodied magnetic micelles show minimal contrast change in
the same period (Fig. 7). The distribution of the four contrast agents
in the normal liver at 24 h post-injection of contrast agents were
measure to investigate magnetic micelle deposition and revealed
the high selectivity and sensitivity to hepatoma. PEGMA and FABSA modication of the magnetic micelles showed to prolong the
circulation time and enable the particles to be delivered to the
tumor tissue. It was also observed that the folate mediated active
targeting could improve the uptake of magnetic micelles by the
tumor.
320
Fig. 7. (a) In vivo MR images of Bel-7402 subcutaneous xenograft in nude mice acquired after administration of Gd-DTPA (top row), Feridex (the second row), unmodied
(the third row), and FA-BSA modied magnetic micelles (bottom row) at different time points (10 min, 1, 24, 48, and 72 h). (b) Tumor-to-muscle signal ratios observed on
T1 -images of the groups treated with Gd-DTPA at different time points different time points (10 min, 1, 24, 48, and 72 h). (c) Tumor-to-muscle signal ratios observed on
T2 -images of the groups treated with Feridex, unmodied magnetic micelles, and FA-BSA modied magnetic micelles at different time points (10 min, 1, 24, 48, and 72 h).
TMR: tumor-to-muscle signal ratios. Tumor volume: 400700 mm3 , n = 35 for each group (Li et al., 2015).
Reproduced with permission. Copyright 2015.
5. Magnetic nanoparticles in cancer treatment

5.1. Hyperthermia
Hyperthermia, from the etymological meaning, is generation of
heat (Kumar and Mohammad, 2011). It means abnormally high
body temperature that can be caused as part of treatment, by an
infection, or by employing heat at an affected site for remedial purposes. In cancer therapy, tissue is exposed to high temperatures (up
to 4147 C) that can damage and kill cancer cells.
The concept of hyperthermia applied as a treatment for cancer is
not new. The benecial effects of thermal therapy in the treatment
of cancer were rst observed in the 19th century (Hervault and
Thanh, 2014). At that time, it was observed that the administration
of living bacteria to cancer patients caused them an infection with
the appearance of fever, which caused a partial tumor regression.
Another scientic study was performed on hyperthermia, almost
simultaneously, to the treatment of uterine cervix cancer (Jaque
et al., 2014). In the 1970s, was discovered that the cancer cells show
greater sensitivity to hyperthermia (undergo apoptosis at temperatures of 4245 C), compared with the normal cells. It was possible
thanks to controlled clinical trials on hyperthermia that started to
be conducted.
Instead of the good results about inducing apoptosis of cancer
cells by increasing the intracellular temperature, some harmful side
effects was observed at the surrounding healthy tissues. In this context, some researches were devoted on nding new mechanisms
of controlling this temperature increasing (Li et al., 2010; Oliveira

et al., 2013; Wang et al., 2011). With nanotechnology, a solution
to this problem was possible with the magnetic uid hyperthermia (MFH), where MNPs are used as mediators of heat for a local
treatment.
MFH is based on the injection of MNPs colloidal suspension that
accumulates at the tumor either passively (by the enhanced permeability and retention (EPR) effect of magnetic nanoparticles) or
actively (by the use of ligands at MNPs surface, specic for the surface receptors present on cancer cells) (Hervault and Thanh, 2014).
By oscillating of the external magnetic eld, the MNPs homing at
tumor cells can transform the electromagnetic energy into heat,
increasing the local temperature. The advantage of using nanoparticles is to avoid the surrounding healthy tissue heating. Fig. 8 shows
a schematic representation of magnetic hyperthermia.
The use of magnetic nanoparticles is suggested as a noninvasive and relatively non-toxic method for cancer treatment,
differently of the traditional therapy methods. For treating cancer,
usually surgery, radiotherapy and chemotherapy are the most used
approaches. Nevertheless, they present considerable side effects
(healthy organs and cells may be also damaged), often without
success in case of metastatic cancer treatment.
In this context, magnetic hyperthermia rises as a new cancer
therapy in vivo with some advantages over the traditional ones:
(i) the small size of the particles allow them to pass through the
biological barrier and its injection is less invasive; (ii) MNPs targeting properties can be modulated by the use of specic agents on
321
Fig. 8. Schematic representation of magnetic hyperthermia. Magnetic nanoparticles accumulate in tumors, targeting the cancer cells. When exposed to an alternating
magnetic eld, the nanoparticles tend to align with the applied eld absorbing energy. MNPs oscillation transform this electromagnetic energy into heat, increasing the
temperature at this region.
the encapsulation process; (iii) MNPs applied to the hyperthermia

treatment can be also used as a diagnostic agent for MRI; (iv) magnetic hyperthermia has relative no damage to normal cells, even
killing a bigger number of tumor cells by a heat diffusion (Hervault
and Thanh, 2014).
Lee et al. (2011) have reported the synthesis of
CoFe2 O4 @MnFe2 O4 nanoparticles and their efcacy in antitumor hyperthermia therapy. U87MG human brain cancer cells were
xenografted to the abdomen of nude mice in several experimental
groups: untreated control group, treated with the coreshell
nanoparticles, another group of mice underwent hyperthermia
treatment with Feridex, and the other group was treated with
the chemotherapeutic drug doxorubicin (75 mg) with an identical
dosage of coreshell nanoparticles. All the groups were monitored
in the same way. The group treated with coreshell nanoparticles
hyperthermia showed the tumor elimination in 18 days, differently
from the results found for the groups of Feridex hyperthermia, a.c.
eld only, coreshell nanoparticles only and the untreated control
(Fig. 9). These results showed that these magnetically coupled
nanoparticles can be effective in magnetic hyperthermia therapy,
as well as on drug delivery.
Basel et al. (2012) synthesized paramagnetic iron/iron
oxide nanoparticles and loaded into RAW264.7 cells (mouse
monocyte/macrophage-like cells), which have been shown to
be tumor homing cells. It was observed that these nanoparticles
inltrate pancreatic tumors when injected intraperitoneally (i.p.)
without inltrating other organs. After the injection (three days),
mice were exposed to an alternating magnetic eld for 20 min
to cause the cell-delivered nanoparticles to generate heat. The
system described here holds potential for further development as
a specic delivery method for magnetic nanoparticle-generated
localized hyperthermia for targeted therapy of pancreatic and
other types of cancer.
The use of a magnetic nanoparticle in a subcutaneous squamous
cell carcinoma mouse model was reported by Huang and Hainfeld
(2013). A well-tolerated intravenous dose (1.9 mg Fe/g tumor) was
achieved, and with the application of an external magnetic eld,
tumors could be heated to 60 C in 2 min, durably ablating them
with millimeter (mm) precision, leaving surrounding tissue intact.
Coating of magnetic nanoparticles with peptides has also gained
attention as potent targeting ligands. Aminosilane coated iron
oxide nanoparticles (IO-NPs), conjugated with NPs-cRGDfK-Orn3 CGG (ornithine-modied peptide) radiolabeled with 99m Tc was
synthesized and reported by Tsiapa et al. (2014). After the conjugation of cRGDfK-Orn3 -CGG to IO-NPs, it was observed a high
specicity targeting of the NPs in U87MG glioblastoma tumors.
Hyperthermia sessions showed the increase on the temperature

of the external tumor (39 C), while abdominal area uctuated
at about 32 C. These results suggest that this hyperthermia system
using IO nanoparticles is able to heat the tumor specically without
affecting healthy tissue. Moreover, the dissection of tumor conrmed the tumor shrinkage and tissue necrosis, after the magnetic
induced hyperthermia treatment.
5.2. Drug delivery
The main drawback on chemotherapy treatment is the nonspecicity of the drugs, damaging both sick and healthy cells. To
overcome this problem, MNPs can be used to deliver the therapeutic agents to the desired target area, maintaining the particles at
the specic site during the drug release, when combined with an
external magnetic eld (Fig. 10). Moreover, a controlled drug delivery based on MNPs should be able to maintain drug levels within the
required concentration range for therapy, avoiding the over dosage
and reducing side effects.
Magnetic drug delivery systems are usually composed by the
therapeutic agent attached to the surface of the magnetic nanoparticles or encapsulated within a nanocomposites mixture of a
polymer and magnetic nanoparticles. This approach protects the
cytotoxic drug until reaching the cancer cells, where the drug
molecule will provide its therapeutic effect.
Polymer-based magnetic drug delivery vehicles can release the
encapsulated anticancer drug by degradation of the carrier particles or may be triggered by a condition-dependent manner (heat or
pH). To maximize the effect of drugs, the release of the active agent
must occur over a prolonged period of time, thus increasing the
efcacy of the drug and maximizing patient compliance. Furthermore, few administrations are necessary to the chemotherapeutics
release.
Among the external stimuli usually applied for drug release,
Zhang et al. (2009) reported that magnetic eld reveals a decrease
on drug release rates due to the aggregation of the magnetic
nanohybrid particles. Yu et al. (2013) reported that the MNPs based
in Fe3 O4 @SiO2 nanoparticles showed to be sensitive to both magnetic eld and pH environment.
The precursor idea about the transport and concentration of
MNPs through the vascular system was given by Freeman et al.
(1960), although they proposed to deliver a drug to the specic site
was been given by Paul Ehrlich (18541915) (Arruebo et al., 2007).
The use of magnetic particles for the delivery of chemotherapeutics has evolved since 1980s (Kato et al., 1984; Widder et al., 1981).
Since then, the use of magnetic nanoparticles have been attracted
322
Fig. 9. (a) Schematics of magnetic in vivo hyperthermia treatment in a mouse. Magnetic nanoparticles were directly injected into the tumor of a mouse and an a.c. magnetic
eld was applied. (b) Nude mice xenografted with cancer cells (U87MG) before treatment (upper row, dotted circle) and 18 days after treatment (lower row) with untreated
control, CoFe2 O4 @MnFe2 O4 hyperthermia, Feridex hyperthermia and doxorubicin, respectively. The same amounts (75 g) of nanoparticles and doxorubicin were injected
into the tumor (tumor volume, 100 mm3 , n = 3). (c) Plot of tumor volume (V/Vinitial ) versus days after treatment with coreshell nanoparticle hyperthermia, doxorubicin,
Feridex hyperthermia, a.c. eld only, coreshell nanoparticles only and untreated control. In the doxorubicin-treated group, tumor growth slowed initially, but then regrew
after 18 days. In the group treated with coreshell nanoparticles hyperthermia, the tumor was clearly eliminated in 18 days. The suppression of tumor growth was not
observed for the groups of Feridex hyperthermia, a.c. eld only, coreshell nanoparticles only and the untreated control. (d) Immunouorescence histological images of the
tumor region after hyperthermia treatment with coreshell nanoparticles (upper image) and the control tumor region (lower image). (e) Plot of dose dependency on tumor
volume measured 18 days after the treatment. For coreshell nanoparticle hyperthermia and doxorubicin treatments, doses of 75 g and 300 g, respectively, were needed
to completely eliminate a tumor with a volume of 100 mm3 . For Feridex hyperthermia, even a 1200 g nanoparticle dose did not adequately suppress tumor growth. Error
bars in (c) and (e) indicate standard deviation (n = 5) (Lee et al., 2011).
much interest for application in drug disease. The main goal is to

reduce the side effects caused by the traditional methods, by the
use of MNPs-based approaches.
Besides of the easy control of the drug release, MNPs offer also
other advantages: (i) the same particles injected in a patient can
be useful as contrast in MRI (diagnosis); (ii) the oscillation of the
Fig. 10. Schematic representation of a magnetic drug delivery system.
applied magnetic eld can produce hyperthermia and, thus, trigger

drug release (therapy).
Some therapeutic strategies for sequentially affecting multiple targets in advanced cancers are also being evaluated. Kumar
et al. (2015) developed an innovative cancer therapeutic approach
for the sequential release of two cytotoxic agents (combination of
endocrine tamoxifen and chemotherapy diosgenin) in breast
cancer cells. They were designed and synthesized multi-layered
polyvinyl alcohol tethered hollow manganese ferrite nanocarriers,
with unique attributes of sensitivity toward tumor acidic milieu,
mono-dispersive, compactness and high encapsulation efciency.
By this approach, it was observed that the cellular levels of the antiapoptotic Bcl2 protein decreased, and the proapoptotic Bim and
tumor suppressor p53 proteins were induced, promoting apoptosis as afrmed by the mitochondrial membrane potential, protein
proling and immunohistochemical investigations. This treatment
modality holds promise for the treatment of ER positive breast
cancer cells as well as other neoplastic diseases.
Another study focused on the application of magnetic nanoparticles on drug delivery was reported by Shakeri-Zadeh et al.
323
Fig. 11. Evaluation of in vivo therapeutic efcacy. (a) Treatment scheme of Dox SMNPs in mouse and results of the tumor volume change over the course of the treatment
(15 days) in DLD-1 xenografted mice (n = 3) treated with Dox SMNPs (w/and w/o application of AMF) and other controls (AMF only and PBS only). All injections were
done on day 0 (and day 7 for the double injection group) when the tumor volume reached 100 mm3 ; AMF application was performed at 36 h post-injection. The best tumor
suppression result was observed in the group treated with a double injection of Dox SMNPs with AMF application. The group treated with a single injection of Dox SMNPs
with AMF and the other control groups (i.e., treated with Dox SMNPs only, AMF only and PBS) show either a smaller degree or none of tumor suppression effects (**p 0.01;
***p 0.001). (b) Tumor images of groups treated with Dox SMNPs w/and w/o application of AMF and other controls, before treatment (left panels) and at the termination
point (right panels). *The termination point of the experiment occurred either on day 15 or when the tumor volume reached 1500 mm3 (Lee et al., 2013).
(2015). In this work 5-uorouracil (5-Fu) loaded magnetic poly

lactic-co-glycolic acid (PLGA) nanocapsules were obtained for
magnetically target toward CT26 colon tumor model in BALB/c
mice. The results demonstrated that the synthesized nanoparticles showed excellent anti-tumor activity against the colon cancer
allografts. It was veried that the application of the magnetic drug
targeting procedure after intravenous injection of drug-bearing
controlled-release nanoparticles, and irradiating the tumor with
ultrasound may be an effective drug delivery strategy, reducing the
amount of the needed dosages of drugs due to its concentration
at the cancer cells, and consequently, reducing the side effects of
the drug.
With the advances in nanotechnology, the drug delivery systems based in magnetic nanoparticles have recently attracted a
lot of attention, especially due to the fact that these particles can
be delivered to their desired target area under an applied external magnetic eld, reducing the side effects of the chemotherapy
drugs. Haupka-Bryl et al. (2014) used poly(ethylene glycol)-blockpoly(4-vinylbenzylphosphonate) block copolymer (PEG-b-PVBP)
to synthesize and characterize DOX-containing PEGylated iron
oxide NPs (PEG-PIONs/DOX), as a possible and potential drug carrier for magnetically mediated targeted drug delivery. The in vivo
distribution of the drug from PEG-PIONs/DOX or free DOX solution was evaluated in tumor-bearing 5- to 6-week-old male BALB/c
mice. It was observed that, even without external magnetic eld
PEG-PIONs/DOX easily accumulated in tumor region, showing its
high efcacy in future therapy.
Doxorubicine delivery/release was also evaluated by Lee et al.

(2013), using a magnetothermally responsive system (Dox SMNPs).
The authors demonstrated the high efciency of in vivo cancer
treatment of these particles, compared to the control studies (i.e.,
AMF only and PBS only; PBS = phosphate buffered saline). The
tumor volume over the course of treatment (15 days) shows that
any statistically signicant differences in tumor suppression were
observed to the control groups. In contrast, the group treated with
a double injection of Dox SMNPs shows continued and effective
inhibition of tumor growth (Fig. 11).
The efciency of magnetic target drug delivery systems was
also evaluated by Licciardi et al. (2013). Magnetic nanocarriers
(MNCs) were prepared by using ,-Poly(N-2-hydroxyethyl)d,l-aspartamide-co-(N-2-ethylen-isobutirrate)-graft-poly-(butyl
methacrylate) (PHEA-IB-p(BMA) Copolymer) as coating material,
containing the anticancer drug utamide (FLU). The in vivo biodistribution studies were carried out by the application of an external
magnetic eld in rats (prostate cancer cell line LNCaP). These studies revealed that application of an external magnetic eld over the
abdominal region in rats drastically modied the biodistribution
of FLU-MNCs, and showed to be a very good approach to obtain an
efcient magnetically targeted anticancer drug delivery system.
It is important to highlight that dual drug-loaded nanocapsule
can be also prepared, as reported by Fang et al. (2014). In this work,
authors have prepared a coreshell nanostructure, assembled from
polyvinyl alcohol (PVA), polyacrylic acid (PAA) and iron oxide
nanoparticles. The coreshell nanostructure could accommodate
324
Fig. 12. Representative T2 -weighted MR images in tumor (a1, b1 and c1), photothermal images of HeLa bearing tumor mice after the 808 nm laser irradiation for 10 min (a2,
b2 and c2), and tumor slices stained by Prussian blue (a3, b3 and c3) in control group 1, control group 2, and magnetic targeting group. Plots of temperature changes of tumor
as a function of the irradiation time (d) (Zhou et al., 2014).
doxorubicin and curcumin. As an interesting result, intravenous

injection followed by magnetic targeting in brain tumor-bearing
mice, allowed the high accumulation at the targeted site, and
suppressed cancer growth in vivo more efciently than does the
delivery of either drug separately.
6. Magnetic nanoparticles and theranostic applications
The potential use of nanotechnologies in cancer treatment,
especially magnetic nanoparticles have attracted the attention
of the researchers, also for their possible application as multifunctional materials. The main target is to render the magnetic
nanoparticles a dual-purpose for simultaneous diagnosis and treatment, by combining different active agents. Drugs or methods,
which combine both applications, are called theranostics. Such
systems could target the tumor site for diagnosis (by MRI), for therapeutic action (anticancer drug delivery and/or hyperthermia) and
for monitoring the therapy response (imaging-guided therapeutics) (Schleich et al., 2013).
This new technique could provide acceleration on cancer treatment, since it could reduce the related side effects of the traditional
methods and also its cost. The knowledge necessary for a successful obtaining of theranostic materials is wide, and requires
a solid understanding of detection and therapy mechanisms
(Ahmed et al., 2012a), as well as the conditions for nanoparticles
preparation.
Barick et al. (2014) prepared carboxyl decorated iron oxide
nanoparticles by a facile soft-chemical approach for magnetic
resonance imaging (MRI) and hyperthermia applications. The surface of functionalized Fe3 O4 nanoparticles exhibited good colloidal
stability in aqueous, physiological and cell culture media, and presented protein resistance characteristic. Huang et al. (2013) showed
that nanobubbles can be a promising, next-generation theranostic platforms for ultrasound and magnetic resonance imaging,
and combined magnetic targeting and high-intensity focused
ultrasound-triggered drug release for tumor therapy. The synthesis was based on hydrophobic peruoropentane PFP-encapsulated
hydrophilic polyacrylic acid PAA-F127 thermosensitive nanobubbles, loaded with superparamagnetic iron oxide nanoparticles in
the shells.
Zhou et al. (2014) developed a new triple functional photothermal therapeutic agent (PTA) PEGylated Fe@Fe3 O4 with
unique capacity of magnetic targeting, NIR photothermal therapy,

and MRI for efcient ablation of tumors (Fig. 12). The excellent
photothermal properties of PEGylated Fe@Fe3 O4 NPs encouraged
the authors to assess the potential application as PTAs for cancer.
In this sense, it was evaluated their in vivo toxicity, which compared to the control group, showed no signicant organ damage and
inammatory lesion for mice. Experimental results also conrmed
that the combination of Fe@Fe3 O4 NPs and NIR laser irradiation
is able to ablate cancer cells signicantly. Apoptosis occurs under
the low power density (photothermal therapy), and under the high
power density, both apoptosis and necrosis are observed. Furthermore, the magnetic targeting photothermal therapeutic efcacy of
these nanoparticles was also evaluated in mice. The tumor in magnetic targeting group exhibited substantial decreases in the relative
tumor volume. After photothermal treatment it was observed that
mice developed eschars on the tumors. Then, after fourteen days,
tumors were completely destroyed. Meanwhile, all mice groups
did not show weight loss, indicating the low toxicity of combined
photothermal treatment and magnetic targeting provided by synthesized PEGylated Fe@Fe3 O4 .
Intriguing and potential clinical application of a theranostic system was also veried in the study of doxorubicin (DOX) loaded
FePt@Fe2 O3 PEG-FA coreshell magnetic nanoparticles (Liu et al.,
2013). The surface engineering based on folic acid, was very important for effective targeting of specic types of tumor cells (folate
receptors). The releasing of DOX from the magnetic nanoparticles
was performed in vitro, and showed to be pH-dependent, showing
accelerated release under slight acidic pH. This property is favorable for drug delivery and controlled release to cancer cells, since
the tumor microenvironments are also slightly acidic. The potential application of these particles for in vivo MR imaging was, then
evaluated and the results showed that the particles could passively accumulate in the tumor site via EPR effect and decrease
the T2 -weighted MR signals of the tumor. It was also observed that
PEGylated FePt@Fe2 O3 coreshell nanoparticles exhibit no obvious
in vitro and in vivo toxicity, and could serve as cancer theranostic
probes relying on their passive or passive + active tumor targeting
ability.
Theranostic strategy combining MRI and hyperthermia was also
developed by Xie et al. (2014). MnZn ferrites nanostructured was
synthesized and coated with PEG-phospholipids (1,2-distearoylsnglycero-3-phosphoethanolamine-N-[methoxy(polyethylene
glycol copolymers, DSPE-PEG2000). By this specic coreshell

structure, the authors could drastically minimize the recognition
and phagocytosis of macrophages in vitro. To demonstrate the
MR imaging ability of tumors, the PEGylated nanoparticles were
injected into a female BABL/c mouse bearing 4T1 cells with the
dose of 9 mg Fe/kg body weight, and T2 *-weighted MR imaging
in situ was performed using a 7 T MR scanner. A fraction of the
tumor turned dark as early as 30 min after the injection, and
became darker and bigger until 240 min. This distinct MR signal
attenuation meant that the PEGylated nanoparticles passively
extravasated from vasculature and preferentially concentrated
in tumor region, which could be a potential approach for tumor
diagnosis. In this regard, the authors greatly increased the magnetic induced heat generation for tumor, by increasing the dose
of MNPs and MNPs injection times, and actualizing repeatedly
sufcient hyperthermia duration, accompanied by a real-time
detection and diagnosis of tumor using by MRI. For use in magnetic
hyperthermia, the obtained results did not show the reduction
of cancer cells, but could be used in theranostic, combining the
excellent efciency in MRI and heating, for further combination
with targeted molecules and anticancer drugs.
7. Conclusion
With the advances in nanotechnology, a large number of multifunctional nanomaterials has also emerged, with special focus in
biomedical applications. One of the biggest challenges facing the
medical research is to develop new strategies to reduce side effects
related to both traditional diagnosis and therapy for cancer disease. Magnetic nanoparticles are of signicant interest in this eld
due to their unique physical properties of superparamagnetism,
biocompatibility and very low cost. Their intrinsic magnetic properties enable them to be used as contrast agent in MRI (diagnosis),
as a therapeutic agent (drug delivery and hyperthermia) and as a
theranostic approach (diagnosis and therapy).
There is a continuous progress in the development of MNPs
with potential to be applied in cancer disease, also due to its selective targeting under the guidance of an external magnetic eld.
Some of the progress related to the synthesis, functionalization and
in vivo application of magnetic nanoparticles were summarized in
this work. MNPs showed great potential to be applied in MRI, as
contrast agents. By the application and oscillation of an external
magnetic eld (with proper amplitude and frequency), the magnetic energy of the particles is converted to thermal energy (heat),
killing the cancer cells by the temperature increasing (hyperthermia), or allowing the release of the anticancer therapeutic agent
at the specic targeted cells (hyperthermia-based controlled drug
delivery).
A future goal on magnetic nanoparticles application is to combine cancer diagnosis and therapy to enable these to perform as
theranostic agent in a dual-purpose nanoparticulate system. Since
the cancer is considered as one of the biggest challenges facing
the medical research, improvements can be expected concerning magnetic particles in cancer therapy published in the recent
years indicate that further improvements are coming in the near
future. In this sense, these proposed technologies have potential
to overcome the problems that the conventional cancer treatment
(diagnosis and therapy) presents, such as the invasive procedure
and side effects to healthy tissues.
Acknowledgements
M.K.L is grateful to the Conselho Nacional de Desenvolvimento
Cientco e Tecnolgico (CNPq) and the Science Without Borders
Brazilian Program for the nancial support.
325
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International Journal of Pharmaceutics 493 (2015) 313327

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

Magnetic nanoparticles: In vivo cancer diagnosis and therapy

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

Magnetic nanoparticles and theranostic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

drug molecule is released due to the heating. Fig. 1 shows MNPs

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

non-polar domains. Different microstructures are formed by the

control of the temperature, reaction time, as well as aging period,

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

Zavisova et al. (2009)

both phases and instantaneous formation of a colloidal suspension

3.1. Encapsulation via nanoprecipitation using from preformed

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

should be soluble in it. Some parameters should be controlled for

Doxorubicin and paclitaxel

Stilbene (model hydrophilic

Ahmed et al. (2012b)

Ashjari et al. (2012)

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

acid groups). In vivo MRI of the livers of SD rats nanoparticles was

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

5. Magnetic nanoparticles in cancer treatment

of controlling this temperature increasing (Li et al., 2010; Oliveira

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

the encapsulation process; (iii) MNPs applied to the hyperthermia

Hyperthermia sessions showed the increase on the temperature

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

much interest for application in drug disease. The main goal is to

Fig. 10. Schematic representation of a magnetic drug delivery system.

applied magnetic eld can produce hyperthermia and, thus, trigger

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

(2015). In this work 5-uorouracil (5-Fu) loaded magnetic poly

Doxorubicine delivery/release was also evaluated by Lee et al.

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

doxorubicin and curcumin. As an interesting result, intravenous

unique capacity of magnetic targeting, NIR photothermal therapy,

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

glycol copolymers, DSPE-PEG2000). By this specic coreshell

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

Silva, M.F., Ciciliatti, M.A., Hechenleitner, A.A.W., Penalva,

M.K. Lima-Tenrio et al. / International Journal of Pharmaceutics 493 (2015) 313327

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