Send Orders for Reprints to reprints@benthamscience.

ae
239

Current Drug Targets, 2018, 19, 239-247

REVIEW ARTICLE
ISSN: 1389-4501
eISSN: 1873-5592

Functionalized Magnetic Nanostructures for Anticancer Therapy Impact

Factor:
3.236

BENTHAM
SCIENCE

Eugenia Dumitra Teodor1,*, Florentina Gatea1, Anton Ficai2 and Gabriel Lucian Radu3
1
Centre of Bioanalysis, National Institute for Biological Sciences, Bucharest, Romania; 2Department of Science and
Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University
POLITEHNICA of Bucharest, Bucharest, Romania; 3Department of Analytical Chemistry and Instrumental Analysis,
Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Bucharest, Romania

ARTICLE HISTORY
Received: September 16, 2015
Revised: November 10, 2015
Accepted: November 19, 2015
Current Drug Therapy
Abstract: Background: In the last years, the production and applications of nanoparticles based on
iron oxides in the field of biomedicine presented a great interest due to their particular properties. Be-
cause of the expansion of the pharmaceutical industry numerous new systems for drugs delivery have
appeared, and those centered on magnetic nanoparticles are in a particular attention and in different
promising developmental stages.
Objective: In this mini review, some representative, interesting and feasible magnetic nanostructures ob-
tained recently (from last 5-6 years) with possible use in antitumor/anticancer therapy are presented.

DOI:
10.2174/1389450117666160208145835
Results: The synthesis of these nanostructures with magnetic properties implies very simple assembling
procedures and presents one of the lowest cytotoxic profiles. Magnetic nanostructures displayed possible
appliance in a large diversity of biotechnological and medical fields, both for diagnose and therapy.
Conclusion: Different types of magnetic nano-carriers loaded with different antitumor/anticancer
agents and the cases tested in vivo are considered.

Keywords: Functionalized magnetic nanostructures, anticancer therapy, drug delivery, combined drug release, imaging and
hyperthermia.

1. INTRODUCTION applications (in vitro and in vivo), and other magnetic

In the last 10 years, many aspects about nanotechnologies
had a great impact on the researchers, mainly, but even on
administrations, industries, investors, finance organizations,
and for ordinary people. Numerous studies and experiments
were done; thus, to have a contribution in the field of new
magnetic nanostructures with biomedical applications it is
important to have a multidisciplinary approach and to have a
harmonized knowledge in many domains such us physics,
chemistry and biochemistry, biology, materials science, for
the reason that this issue is very complex. In this context, it
is important to design nanoparticle formulations with mag-
netic behavior, appropriate sizes and charging for penetrate
cells/tissues and, in the perspective of clinical applications,
with the capacity to avoid or cross the main biological barri-
ers which disturb nanoparticles to reach their target tissue or
organ [1].
For biomedical applications, nanoparticles based on iron
oxides are the main widely explored because of their specific
magnetic behavior and insignificant cytotoxicity. Magnetite
(Fe3O4) and maghemite (γ -Fe2O3), are the most frequently
used for synthesis of magnetic nanoparticles with biomedical
*Address correspondence to this author at the Centre of Bioanalysis, Faculty
Name, National Institute for Biological Sciences, Bucharest, Romania;
Tel: +40 0212200900; Fax: +40 0212200900; E-mail: eu_teodor@yahoo.com
nanostructures based on metal alloys (e.g. FeCo, FePt,
CoPt3) are used, at this time, only for applications in vitro
because of their high toxicity toward living cells [2-6]. The
magnetic nanoparticles have specific physical and chemical
properties which make them applicable for different objec-
tives as well as magnetic resonance imaging and hyper-
thermia, drug delivery, cell targeting, cell labelling and bio
separation [1, 7-11]. For all mentioned purposes, high
magnetic saturation and appropriate surface functionaliza-
tion of nanoparticles are required; in addition, high bio-
compatibility is necessary [12].
In recent years, the design and application of new nano-
sized carrier systems provoked emergent attention in
nanotechnologies area [13, 14]. The nanostructures are tar-
geted to deliver different substances in a passive or in an
active way. For tumor tissues passive targeted drug delivery
can be used because of the reduced lymphatic systems of
tumor tissues and their permeable vasculature with pore di-
mensions ranging between 100 and 780 nm [15, 16]. These
features allow what is called the “enhanced permeability and
retention” effect, which permits greater accumulation of de-
livered nanoparticles at the solid tumor site. On the other
hand, for active targeted drug delivery is necessary a compli-
cated system which implies a covalent conjugation of target-
ing molecules on the nanoparticle surface, molecule which
can identify and can link to particular ligands specifically
expressed in cancer cells [17, 18].

1873-5592/18 $58.00+.00 © 2018 Bentham Science Publishers

240 Current Drug Targets, 2018, Vol. 19, No. 3
Speaking about “drug delivery” that term refers to the
biologic active agents of interest which are immobilized in,
or linked to an organic or bio-polymeric shell or to an inor-
ganic particle. In most of such cases the therapeutic sub-
stances are more protected by immobilization and their effi-
ciency can be enhanced, and in that way, novel targeted
therapies could be possible [19]. Many methods were pro-
posed for a good strategy for delivery of drugs. After Laurent
et al., 2011 [20], this strategy could be: (1) modification of
drugs using chemical procedures [21, 22]; (2) drug immobi-
lization in vesicles [23-25] or drug immobilization in inor-
ganic hollow nano-shells [26-28]; (3) systems with con-
trolled release of drugs based on polymers [29-31] or based
on vectors hydrogel-type [32-35], and (4) integrated systems
at small-scale such as microchip systems [36-39]. Moreover,
due to systemic circulation, the ways of delivery of drugs are
an important subject in the case of delivery of active sub-
stances on living systems. For improving the discrimination
in chemotherapy, intravenous [40, 41], intraperitoneal [42],
pulmonary [43], transdermal [44-46], nose [47, 48], vaginal
[49] and eye [50, 51] paths of administration were ap-
proached.
Even though there are substantial progresses in targeted
drug delivery systems, there are, yet, many conventional
practices, and have high benefits for more efficient strategies
for delivery of drugs. The general opinion is that the critical
zones of expectations for efficient systems for drugs delivery
should be: (1) high magnetization and narrow size distribu-
tion, (2) optimized zeta-potential values, (3) long half-life or
long period of circulation, (4) great bio accessibility and par-
ticular targeting, (5) capacity for intracellular distribution,
(6) receptiveness to stimuli (i.e. efficiency), (7) imaging ca-
pacity, and (8) biodegradation [52-54]. Wahajuddin & Arora
(2012), Tietze et al. (2015) published large reviews about
superparamagnetic iron oxide nanoparticles (SPIONs), mag-
netic core fabrication, coatings, drugs loading, and utility as
drug delivery vehicles, so we will refer here only to other
cases of magnetic nanostructures with possible use in anti-
tumor therapy [54, 55].
1.1. Different Types of Functionalized Magnetic
Nanoparticles for Antitumor Drug Delivery
Recently, Akbarzadeh et al. (2012) reported the associa-
tion of magnetic nanoparticles (iron oxide) and doxorubicin
hydrochloride as the anticancer agent. As polymeric support
was used poly (D, L-lactic-co-glycolic acid) poly (ethylene
glycol) (PLGA-PEG) and the obtained nanoparticles with
encapsulated anticancer drug were used for local treatment.
In the same work was reported the synthesis by ring-opening
polymerization using as initiator polyethylene glycol (with
different molecular mass) and D, L-lactide and glycolide to
obtain some similar PLGA-PEG triblock copolymers. The
obtained data pointed out that the chains of copolymer suc-
cessfully entrapped the Fe3O4 nanoparticles and the resulted
nanoparticles are biocompatible and have appropriate dimen-
sions for in vivo applications. The authors concluded that the
efficacy and the targeting ability of obtained nanoparticles in
lung cancer treatment during future experiments in vivo will
be assessed [56].
Teodor et al.
Singh et al. (2011) published an elaborated study about
utilization of paclitaxel loaded magnetic nanoparticles con-
jugated with lectin for leukemia therapy. It is known that to
use the magnetic nanoparticles as carriers for drugs delivery
and to avoid the in vivo aggregation of nanoparticles, these
must be covered with a hydrophobic or hydrophilic polym-
eric shell [57]. In addition, the obtained magnetic nanoparti-
cles ought to maintain their magnetic properties and aqueous
dispersibility besides the capacity of high drug loading, an-
ticipated drug release profile and a good tolerance of normal
cells and tissues [12]. Their earlier studies have demon-
strated that covering the magnetic nanoparticles with glyc-
eryl mono-oleate, which is a lipid polymer with a long am-
phiphilic chain, the aqueous dispersibility is supplied and
both types’ hydrophilic and hydrophobic drugs can be incor-
porated [58, 59]. The usage of specific molecular signature
aids in supplying the suitable therapeutic amount of drug at
the targeted site, and helps the benefit of receptor mediated
endocytosis. Further, the efficiency of cellular uptake for
magnetic nanoparticles with paclitaxel entrapped and for
paclitaxel loaded MNP conjugated with lectin was compared
with simply paclitaxel on a leukemic cell line (K562) [57].
Wang et al. (2011) have developed an innovative
DNRMNPs (Daunorubicin-magnetic nanoparticles) formula-
tion for sustained release of daunorubicin, an antitumor agent
from anthracycline class. First, the iron oxide core was cov-
ered with oleic acid containing daunorubicin, and then the
nanoparticles were stabilized by Pluronic F-127®. The
authors concluded that obtained DNR-MNP formulations are
very efficient systems for drug delivery because after intra-
venous injection they observed that the dosing interval of
drug is extended and the side effects for high plasma daun-
orubicin amounts are decreased and all these facts improved
patient compliance for a potential application in systemic
administration [60].
Tumor cells have developed metabolic aptitudes to sur-
vive under unfavorable microenvironments therefore they
developed a phenotype more aggressive. An early-
recognized and distinctive biochemical marker of the altered
phenotype of tumor cells is the increased utilization of glu-
cose [61]. Consequently, a number of scientists had the idea
to propose that glucose transporter could be a target for di-
agnose and therapy and could moderate the emerging of tu-
mor [62, 63].
For improving some innovative vectorized magnetic
nanostructures and using the idea of increased glucose con-
sumption of tumor cells, Shan et al. (2012) described the
synthesis and the characterization (using transmission elec-
tron microscopy and infrared spectroscopy) of an innovative
conjugated SPIO NPs with 2-deoxy-D-glucose (2-DG), ab-
breviated as γ-Fe2O3-DMSA-DG NPs, which was assessed
on human breast cancer cells line MDA-MB-231 [64]. The
synthesis of γ- Fe2O3 -DMSA-DG NPs was done by assem-
bling the γ- Fe2O3 NPs coated with meso-2, 3-
dimercaptosuccinic acid (DMSA) by conjugation of surface
carboxyl groups of DMSA with the functional groups of 2-
DG. Later, the same group [65] reported an improved syn-
thesis and methodically study of the composition and charac-
teristics of γ- Fe2O3 -DMSA-DG NPs. They assessed the
obtained nanostructures on other cancer cells line (Human
Functionalized Magnetic Nanostructures for Anticancer Therapy Current Drug Targets, 2018, Vol. 19, No. 3 241

cervical cancer cells/HeLa) regarding its ability to improve solid tumors. The main complication which appears in leu-
the targeting effect for tumor cells in comparison with the γ- kemia chemotherapy is the phenomenon of resistance to dif-
Fe2O3-DMSA NPs in vitro. ferent chemotherapeutic agents of leukemic cells.
Rouhollah et al. (2013) used polyamidoamine dendrimer- This fact is determined by the same mechanism of induc-
coated magnetic nanoparticles (DcMNPs) as an operative ing apoptosis (by initiating the intrinsic mitochondrial, or
system of delivering doxorubicin to a target tissue. The sta- cytochrome c/Apaf- 1/caspase-9 pathway) for the majority of
bility of nanoparticles, the drug loading and drug release the anti-cancer agents. The apoptotic pathways in chronic
capacities were considered. It was noticed that the obtained myeloid leukemia are mostly blocked due to Bcr-Abl gene
low-generation nanoparticles had pH-sensitive characteris- expression, p53 mutation and deficiency of Fas receptor and
tics for drug release. functional Apaf-1 [74]. A hopeful strategy to avoid the
mechanism of resistance and in the same time to reduce the
The results are promising for the understanding and the
side effects during higher chemotherapy dosage is the com-
improvement of new pH- sensitive systems for the delivery
bination of usual chemotherapy with new approaches to ini-
of drugs with the intention of defeating the drug resistance
tiate apoptosis in leukemia cells.
for the duration of cancer therapy [66].
Recently, another promising approach was developed by In some cases, enzymes or natural antitumor substances
were used as anticancer agents. Teodor et al. (2009) obtained
Unterweger et al. (2014) who generated a novel magnetic
biocompatible hydrogel-magnetic nanoparticles based on
carrier system for cisplatin [67]. Nanoparticles were coated
chitosan and hyaluronic acid with L- asparaginase (anti-
by a hybrid structure of dextran and hyaluronic acid and
leukemia agent) entrapped (Fig. 1). The synthesized hydro-
showed excellent biocompatibility. Cisplatin functionaliza-
gel-magnetic nanoparticles presented dimensions lower than
tion led to a noticeable change in the biological outcome,
making these particles potent drug- delivery vehicles with 30 nm in dried phase, and lower than 300 nm in swelled
phase, being able to penetrate the cells and tissues (particu-
the desired efficacy against tumor cells [67]. The synthesized
larly tumor tissues) [35]. The obtained nanostructures are
nanoparticles were assessed only in vitro. The same team has
very stable in water and in physiological medium and the
a promising approach using fatty acid-coated SPIONs, sub-
enzyme activity could be long time preserved. The L-
sequent albumin shielding and adsorptive mitoxantrone func-
asparaginase release was preliminary assessed in neutral and
tionalization, in order to obtain both antitumor-effective
magnetic nanoparticles and reliable and easy scale-up syn- acid environment (in vitro) [75].
thesis pathways [68]. Particles derived from this approach
have proven their stability over time under appropriate stor-
age conditions [69]. These features are necessary for the at-
tempted manufacturing as investigational medicinal products
to be conforming to good manufacturing practice facilities.
Gu et al. (2014) synthesized a composite based on Fe3O4
and hydroxyapatite with mesoporous properties. The
Fe3O4/hydroxyapatite composite was investigated for effi-
ciency in drug release behavior using as model drug doxoru-
bicin (a chemotherapeutic agent). The release experiments
showed a low burst effect for doxorubicin and the composite
presented a pH-dependent behavior. The authors emphasize
that the method for the preparation of composite was acces-
sible, reliable and ecological [70].
Wu et al. (2014) synthesized clusters by assembling
Fe3O4 with SiO which could covalently link to bridges of
polyethylene glycol dicarboxylic acid modified by 3-
aminopropyltriethoxysilane and 2,2,2-trifluoroethanol. These
bridges can electrostatic interact with doxorubicin and form
clusters which were tested for delivery of doxorubicin and
demonstrated to be recyclable. These clusters could effec-
tively release doxorubicin and inhibit the progression of can-
cer cells in a breast cancer cells line MCF-7 [71]. The same
team, Zou et al. (2015) synthesized and characterized
doxorubicin loaded-mesoporous magnetic nanoparticles with
apoptotic effect on breast cancer cells [72]. Moreover, Elbi-
aly et al. (2015) synthesized doxorubicin loaded magnetic
gold nanoparticles with excellent antitumor properties which Fig. (1). TEM image (a) and schematic illustration (b) of hydrogel
were tested in vivo on nude mice [73]. magnetic nanoparticles.
Chemotherapy continues to be the leading policy for leu-
Chen et al. (2009) reported that MNPs-Fe3O4 could en-
kemia treatment since hematological malignant tumor cannot
dorse the apoptosis induced by gambogic acid (GA) in leu-
be resolved by surgical intervention or radiation therapy as
242 Current Drug Targets, 2018, Vol. 19, No. 3
kemic cells in vitro, and the combination of MNPs-Fe3O4
and GA could have a synergistic effect on apoptosis induc-
tion caused by the regulation of different proliferative and
anti apoptotic gene products, as well as caspase-3, bax, bcl-2,
NF-κB, and surviving [76]. The authors concluded that com-
bining MNPs-Fe3O4 with GA could provide a less toxic
agent for leukemia treatment. The same team (Wang et al.,
2011) continued the studies and demonstrated that the
MNPs-Fe3O4 combined with GA could be a potential ap-
proach in the pancreatic cancer treatment [77].
Yallapu et al. (2013) proposed for therapy of pancreatic
cancer a formulation composed from magnetic nanoparticles
loaded with curcumin, MNP-CUR, which was in vitro and in
vivo assessed for therapeutic effectiveness. Bio-distribution
studies demonstrated that a significant amount of MNP-CUR
formulation was able to reach the pancreatic xenograft tu-
mor(s), which suggests its clinical translational potential
[78]. Another experiment with curcumin was realized by
Sundar et al. (2014), who used 3-aminopropyltriethoxy si-
lane (APTES) coated magnetite nano-powders as carriers for
anticancer drug curcumin. Only physico-chemical charac-
terization, drug loading and drug release were done [79]. Zhu
et al. (2012) presented a study with the same curcumin and
with doxorubicin as model anticancer agent. The intracellu-
lar delivery of curcumin and doxorubicin, which are hydro-
phobic, from the shell of magnetic nanostructures was as-
sessed on the glioblastoma U-87 MG cell line [80].
Another aspect which is in attention nowadays is RNA
interference (RNAi), a modality for living cells to regulate
gene expression via small RNA molecules. Short interfering
RNA (siRNA) is defined as ”double stranded, non-coding
RNA, which binds to complementary mRNA to direct gene
silencing through argonaute, an endonuclease within the
RNA-induced silencing complex” (RISC) [81, 82]. In the
gene therapy area, RNAi mechanism is developing very fast
due to its great therapeutic potential in the management of a
variety of maladies based on abnormal gene expression, and
tumors are a most important objective where this knowledge
could be used [83-85]. Treatment with siRNA is capable to
control pathogenesis and can induce apoptosis in cancer cells
by silencing the genes involved in uncontrolled cell growth.
Because RNA molecules are anionic and hydrophilic, not
like usual chemotherapeutic agents, their internalization by
cells through passive diffusion is not possible [85]. There is
considerable attention in obtaining secure and efficient de-
livery devices to facilitate both delivery and intracellular
trafficking of siRNA. A wide range of systems for siRNA
delivery, as well as liposomes, viruses, cationic polymers
and dendrimers, cell-penetrating peptides, gold nanoparti-
cles, magnetic nanoparticles and semiconductor quantum
dots were investigated [86-92].
The main difficulty for siRNA application in therapy of
cancer continues to be the specific and useful delivery of
siRNA to target cancer cells. The vector-type nanostructures,
can be suitable to overcome these difficulties if are appropri-
ately designed. Veiseh et al. (2010) reported the assembling
of a siRNA nano-vector with magnetic core which was as-
sessed for internalization capacity of siRNA by tumor cells
and for intracellular transferring of siRNA towards enhanced
knockdown of targeted gene expression. In addition, they
Teodor et al.
established that this nano-vector could improve magnetic
resonance imaging (MRI) contrast in vitro, and could allow
the study of MRI treatment efficacy in vivo. The prominent
specificity and effectiveness of this vectorized nano-system
make it possible for using in gene therapy for malignant tu-
mors treatment [93, 94].
1.2. Combined Drug Release, Hyperthermia and Imaging
Among the imaging techniques, magnetic resonance im-
aging (MRI) is a compelling procedure for medical diagnos-
tic applicable on soft tissue [95]. The MRI technique in-
cludes also the benefit of using nonionizing radiation and
presents high sensitivity, great specificity, capacity of multi-
planar imaging and elevated anatomical resolution. The bio-
medicine domain witnessed an increasing attention, in the
last years, in the utilization of magnetic nanomaterials in bio
separation, in magnetic cells and tissues targeting, in hyper-
thermia therapy, in tumor drug delivery and treatment, and
other different diseases effective treatment [20, 52, 96-102].
Foy et al. (2010) proposed the development of a formula-
tion based on magnetic nanoparticles with both properties,
namely imaging and drug delivery, which could be used for
”image-guided drug therapy” [103]. Their proposed MNPs
are based on a magnetic core covered with oleic acid (OA)
and stabilized with an amphiphilic block copolymer. For-
merly, they confirmed that respectively MNPs assemblage
can present extended MRI contrast for tumors and hydro-
phobic anticancer drug can be attached to MNPs shells for
sustained drug delivery [104, 105]. Later, they developed
improved MNPs with optical imaging characteristics via
novel near infrared dyes to quantitatively determine their
long-term bio-distribution and tumor localization in mice
with xenograft breast tumors, with and without an external
magnetic field.
Sun et al. (2010) described the production of a new sort
of multifunctional fluorescent magnetic nanoparticles, (~30
nm in diameter), in which multiple fluorescent CdTe quan-
tum dots are attached around individual silica-coated super-
paramagnetic Fe3O4 nanoparticles. In addition, on the surface
of obtained nanoparticles were attached activated carboxylic
groups for facile bio-conjugation with bio-molecules [106].
The obtained nanostructures displayed both magnetic and
fluorescent properties, which are encouraging for their appli-
ance in bio separation, magnetic targeting and imaging. The
carboxyl groups attached on the nanoparticles surface pre-
sented chemical activity and were able to link different bio-
logically active compounds such as antibodies, enzymes, and
peptides, allowing the use of the nano-systems in identifica-
tion of specific targets. The Fe3O4/CdTe magnetic/ fluores-
cent nanostructures associated with some specific antibodies
were successfully employed for immuno-labeling and fluo-
rescent imaging of HeLa cells [106]. A similar experiment
was done by Chen et al. (2012) based on rotavirus structural
protein VP4-coated Fe3O4 nanoparticles for dual modality
magnetic resonance/fluorescence cellular imaging and drug
(doxorubicin) delivery [107] or by other team works for fluo-
rescence and photoacoustic imaging [108, 109].
Zhao et al. (2013) explored the feasibility and effective-
ness of chemotherapy combined with magnetic and thermal
Functionalized Magnetic Nanostructures for Anticancer Therapy
effect obtained through combination of magnetic nanoparti-
cles with methotrexate, an anti- cancer drug for breast cancer
comprehensive treatment. The in vitro cytotoxicity results on
human breast cancer cell MCF-7 indicated that the bi-modal
cancer treatment approach using combined magnetic fluid
hyperthermia and chemotherapy is more effective than
mono-modal treatment, indicating a thermal enhancement
effect of hyperthermia together with the drug cytotoxicity
[110].
Meenach et al. (2013) reported the synthesis of different
hydrogel nanocomposites which simultaneously can exhibit
hyperthermia and can deliver paclitaxel as anticancer agent
[111]. The synthesized nanostructures were assembled from
poly (ethylene glycol) (PEG) - based hydrogels containing
PEG (n = 1000) methyl ether methacrylate and PEG (n =
400) di-methacrylate ester, and the magnetic nanoparticles
(iron oxide) immobilized in polymeric structure. The capac-
ity to induce hyperthermia of the obtained hydrogel-
nanostructures was function of network crosslinking; hydro-
gels with lower swelling capacity showed higher hyperther-
mia in comparison with hydrogels with higher swelling ca-
pacity. The release of paclitaxel showed to be dependent of
the structure of hydrogel network and the drug exhibited
non-Fickian release from the hydrogel-nanostructures. The
experiments were done using hyperthermia, paclitaxel, and
both hyperthermia and drug (to observe eventually synergis-
tic cytotoxicity) on three cell lines: M059K (glioblastoma),
MDA MB 231 (breast carcinoma), and A549 (lung adeno-
carcinoma). The experiments showed that paclitaxel associ-
ated with hyperthermia was more efficient on A549 cell line,
but the other cell lines did not presented the same reaction.
A similar experiment presented Sahoo et al. (2014) who
obtained nano-systems based on superparamagnetic manga-
nese ferrite (MnFe2O4) nanoparticles covered with
mesoporous silica and with fluorescent moieties attached.
These nanostructures can be used in cancer cell imaging and
in cancer diagnosis and can deliver doxorubicin to cancer
cells. In addition was proved that these nano-systems were
specifically captured by HeLa cancer cells in contrast with
normal cells. In vitro biological experiments revealed that
the nanoparticles with folate attached and loaded with
doxorubicin presented high efficiency for both targeting and
killing the cancer cells. The in vivo studies using mice con-
firmed the usefulness and the biocompatibility of the de-
scribed nano-systems [112].
Ye et al. (2014) have synthesized PLGA-SPION-Mn:ZnS
vesicles as a multifunctional drug delivery system consisting
of a biodegradable polymeric shell containing a payload of
multiple imaging agents and an anti-cancer drug. Poly (lac-
tic-co-glycolic acid) (PLGA) vesicles were fabricated by
encapsulating inorganic imaging agents of SPIONs, manga-
nese-doped zinc sulfide (Mn:ZnS) quantum dots (QDs) and
the anticancer drug busulfan entrapped in PLGA nanoparti-
cles using an emulsion evaporation method. The quantum
dots enhanced the fluorescence visualization of cell uptake.
PLGA vesicles have also been demonstrated to have high
entrapment efficiency for the lipophilic drug busulfan and a
sustained release of drug. Some in vivo MRI and histological
studies were done in a rat model to elucidate the bio distribu-
tion of PLGA vesicles. The authors stipulated that further
Current Drug Targets, 2018, Vol. 19, No. 3 243
investigation of a PLGA drug delivery system for cancer
treatment is ongoing (including organ targeting, controlling
of drug release and in vivo evaluation of the treatment effi-
cacy of chemotherapy in tumor models) [113].
A hybrid combination which contains magnetic nanopar-
ticles (iron oxide), poly (vinyl alcohol) and doxorubicin en-
trapped was obtained by Wang et al. (2014) [114]. The com-
posite was tested in trans-catheter arterial release using a
liver tumor model led to embolization of the liver tumor
blood vessels in vivo. After the embolization the composite
was disassembled and then the nanostructures were capable
to penetrate the tumor tissue and release the doxorubicin.
The composite presented low cytotoxicity and was receptive
to MRI, so that it could consider a promising theranostic
agent [114].
Collagen, hydroxyapatite, cisplatin and magnetite were
utilized to obtain antitumor drug delivery systems (DDS) for
bone cancer treatment. There are some very important ad-
vantages correlated with the application of mentioned DDS.
First of all, collagen and hydroxyapatite are efficient in bone
defect regeneration especially after the surgical resection of
the cancerous tissue and also act as a support for cisplatin
delivery. Cisplatin and magnetite are two potential antitumor
materials with complementary activity. Moreover, the syner-
gic activity is more important because the produced hyper-
thermia is beneficial not only due to the antitumor activity
but also can enhance the delivery of the cisplatin. Based on a
recent patent [115], as well as some unpublished papers, the
delivery rate can be controlled by the applied electromag-
netic field. The delivery rate of cisplatin can be intensified
when hyperthermia is produced. For instance, the delivery
rate can be intensified by applying an adequate, medical fre-
quency alternative electromagnetic field after a while (for
instance 20 arbitrary units). At this moment, along with the
temperature increase, the delivery rate increase (Fig. 2).
From the point of view of the antitumor activity of these
systems, the improvement is due to the produced hyperther-
mia as well as the increased cisplatin delivery [116].
The use of these DDS is also recommended because can
also assure strong, short term antitumor activity and, at long
term, sustained antitumor activity, due to the presence of
magnetite and/or silver nanoparticles. Based on the literature
data, silver exhibits antimicrobial and antitumor activity and
its use in many implantable materials or devices can assure a
long term activity [117, 118]. The antitumor activity of dif-
ferent systems is presented in Fig. (3).
Multifunctional systems with more antitumor compo-
nents can be obtained by combining the activity of cytostat-
ics (with different antitumor mechanism), magnetite (which
induces antitumor activity due to the produced hyperthermia)
and nanoparticles (with intrinsic or photo thermal induced
antitumor activity). It can be seen that, the highest antitumor
activity (expressed as arbitrary units) can be obtained by
combining all the three mentioned mechanisms, and this
activity is dose dependent. If one of the components is miss-
ing, the antitumor activity is considerably lower. Usually,
these systems are designed containing cytostatics; if not, a
much lower antitumor activity is obtained even at short term.
At long term point of view, the antitumor activity is still pre-
sent, but at much lower level, corresponding to the activity
244 Current Drug Targets, 2018, Vol. 19, No. 3 Teodor et al.

100 1.57 25 1.2

120 1.81.58 25 1.4
140 1.59 25 1.6
160 1.6 25 1.8
1.6

Concentraation,AU 1.4

1.2
The two profiles corespond to the release in the presence (generating 42oC) and
in the absence (37oC) of the alternating electromagnetic field; the alternating
1 electromagnetic field is aplied at 25AU

0.8 AU - arbitrary concentration/time units

37oC
0.6
42oC
Electromagneticfieldapplication
0.4

0.2

0
0 20 40 60 80 100 120 140 160

Ti
Time,AU
AU

Fig. (2). Cisplatin delivery profile from magnetic cisplatin loaded DDS.

induced by magnetite and nanoparticles. Based on the above CONCLUSION

mentioned facts, function of the initial composition, the anti-
tumor activity can be designed at different antitumor level
(high enough to assure curative role) while, at long term it
can assure recurrence preventive purposes.
Based on the paper published by Andronescu et al.
(2010) [119] these systems can be easily used in clinics be-
cause, surgical removal of the tumor bonny tissue is an es-
sential step in the treatment protocol of bone cancer and, in
this step, without any supplementary surgical intervention,
these systems can be implanted. The use of these drug deliv-
ery systems is highly recommended because the cytostatics,
which are the most toxic components of these systems, are
delivered loco-regionally and consequently the systemic tox-
icity is lower, compared with the cases where, the cytostatics
are administrated via a systemic route [120].
Shortterm
Magnetic nanoparticles-based drug delivery systems con-
sist of a very promising category of nanoparticles for medi-
cal applications. Highly complicated nano-scaled drug deliv-
ery systems requiring complex materials science and engi-
neering and large work teams were designed in the past few
years. They are in strong contrast to very simple nano-
pharmaceuticals that have already been clinically applied,
such as DOXIL®18, a doxorubicin-encapsulated liposome.
The deficient clinical assessments of promising formulations
still remain a major problem for practical application of de-
signed antitumor nanostructures. More in vitro and in vivo
reproducible experiments and more medical investigations of
already obtained nanostructures with reproducible character-
istics instead of continuous process to obtain new more so-
phisticated nanostructures need to be done. Complex, multi-
component drug delivery systems can be promising antitu-
mor alternatives with good curative short term activity and
long term recurrence preventive anti-tumor systems.

C=Cytostatics CONSENT FOR PUBLICATION

H+N+C H=Hyperthermia
ntitumoralActivity,AU

Not applicable.
N=Nanoparticles
CONFLICT OF INTEREST
Longterm The authors declare no conflict of interest, financial or
H/N+C otherwise.
H+N+C

H/N+C ACKNOWLEDGEMENTS
H/N H+N
An

All the funds are provided by Romanian Agency for Sci-

H+N entific Research.
H/N
REFERENCES
[1] Krishnan KM. Biomedical nanomagnetics: a spin through possibili-
Time,AU ties in imaging, diagnostics, and therapy. IEEE Trans Magn 2010;
46(7): 2523-8.
Fig. (3). Short/long term activity of magnetic, cytostatic delivery [2] Behrens S, Bönnemann H, Matoussevitch N, et al. Surface engi-
drug delivery systems loaded with silver nanoparticles. neering of Co and FeCo nanoparticles for biomedical application. J
Phys Condens Matter 2006; 18: S2543-61.
Functionalized Magnetic Nanostructures for Anticancer Therapy
[3] Gu H, Ho PL, Tsang KWT, Wang L, Xu B. Using bifunctional
magnetic nanoparticles to capture vancomycin-resistant enterococci
and other gram-positive bacteria at ultralow concentration. J Am
Chem Soc 2003; 125: 15702-03.
[4] 4 Martins MA, Neves MC, Esteves ACC, et al. Biofunctionalized
ferromagnetic CoPt3/polymer nanocomposites. Nanotechnology
2007; 18: 215609.
[5] Guo D, Wu C, Li X, Jiang H, Wang X, Chen B. In vitro cellular
uptake and cytotoxic effect of functionalized nickel nanoparticles
on leukemia cancer cells. J Nanosci Nanotechnol 2008; 8: 2301-07.
[6] Zeisberger M, Dutz S, Müller R, Hergt R, Matoussevitch N, Bön-
nemann H. Metallic cobalt nanoparticles for heating applications. J
Magn Magn Mater 2007; 311: 224-7.
[7] Latorre M, Rinaldi C. Applications of magnetic nanoparticles in
medicine: magnetic fluid hyperthermia. P R Health Sci J 2009;
28(3): 227–38.
[8] Jain P, Lee K, El-Sayed I, El-Sayed M. Calculated absorption and
scattering properties of gold nanoparticles of different size, shape,
and composition: applications in biological imaging and biomedi-
cine. J Phys Chem B 2006; 110(14): 7238-48.
[9] Merritt WM, Lin YG, Spannuth WA, et al. Effect of interleukin-8
gene silencing with liposome-encapsulated small interfering RNA
on ovarian cancer cell growth. J Nat Cancer Inst 2008; 100(5): 359-
72.
[10] Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy
and diagnosis. Adv Drug Deliv Rev 2002; 54(5): 631-51.
[11] Ferrari M. Cancer nanotechnology: opportunities and challenges.
Nat Rev Cancer 2005; 5(3): 161-71.
[12] Gupta A, Gupta M. Synthesis and surface engineering of iron oxide
nanoparticles for biomedical applications. Biomateri-
als.2005:26:3995-4021.
[13] Torchilin VP. Targeted pharmaceutical nanocarriers for cancer
therapy and imaging. AAPS J. 2007; 9(2): E128-47.
[14] Yokoyama M, Okano T. Introduction: targetable drug carriers:
present status and a future perspective. Adv Drug Deliver Rev
1996; 21(2): 77-80.
[15] Montet X, Figueiredo JL, Alencar H, et al. Tomographic fluores-
cence imaging of tumor vascular volume in mice. Radiol 2007;
242(3): 751-8.
[16] Bremer C, Ntziachristos V, Weitkamp B, et al. Optical imaging of
spontaneous breast tumors using protease sensing ‘smart’ optical
probes. Invest Radiol 2005; 40(6): 321-7.
[17] Shukla R, Thomas TP, Peters JL, et al. HER2 specific tumor target-
ing with dendrimer conjugated anti-HER2 mAb. Bioconjug Chem
2006; 17(5): 1109-15.
[18] Yousefpour P, Atyabi F, Vasheghani-Farahani E, et al. Targeted
delivery of doxorubicin-utilizing chitosan nanoparticles surface
functionalized with anti-Her2 trastuzumab. Int J Nanomedicine
2011; 6: 1977–90.
[19] Mahmoudi M, Sant S, Wang B, et al. Superparamagnetic iron
oxide nanoparticles (SPIONs): Development, surface modification
and applications in chemotherapy. Adv Drug Deliv Rev 2011; 63:
24-46.
[20] Laurent S, Bridot JL, Elst LV, Muller RN. Magnetic iron oxide
nanoparticles for biomedical applications. Future Med Chem 2010;
2: 427-49.
[21] Means GE, Feeney RE. Chemical modifications of proteins: His-
tory and applications. Bioconjugate Chem 1990; 1: 2-12.
[22] Chau Y, Dang NM, Tan FE, Langer R. Investigation of targeting
mechanism of new dextranpeptide-methotrexate conjugates using
biodistribution study in matrix-metalloproteinase overexpressing
tumor xenograft model. J Pharm Sci 2006; 95: 542-51.
[23] Gregoriadis G. Engineering liposomes for drug delivery: Progress
and problems. Trends Biotechnol 1995; 13: 527-37.
[24] Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copoly-
mers for drug delivery. J Pharm Sci 2003; 92: 1343-55.
[25] Rosler A, Vandermeulen GWM, Klok HA. Advanced drug delivery
devices via self-assembly of amphiphilic block copolymers. Adv
Drug Deliv Rev 2001; 53: 95-108.
[26] Wu GH, Milkhailovsky A, Khant HA, Fu C, Chiu W, Zasadzinski
JA. Remotely triggered liposome release by near-infrared light ab-
sorption via hollow gold nanoshells. J Am Chem Soc 2008; 130:
8175-7.
[27] Son SJ, Bai X, Lee SB. Inorganic hollow nanoparticles and nano-
tubes in nanomedicine. Part 1. Drug/gene delivery applications.
Drug Discov Today 2007; 12: 650-6.
Current Drug Targets, 2018, Vol. 19, No. 3 245
[28] Akerman ME, Chan WCW, Laakkonen P, Bhatia SN, Ruoslahti E.
Nanocrystal targeting in vivo. Proc Natl Acad Sci USA 2002; 99:
12617-21.
[29] Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polym-
eric systems for controlled drug release. Chem Rev 1999; 99: 3181-
98.
[30] Veronese FM, Pasut G. PEGylation, successful approach to drug
delivery. Drug Discov Today 2005; 10: 1451-8.
[31] Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric
system for dual growth factor delivery. Nat Biotechnol 2001; 19:
1029-34.
[32] Vinogradov SV, Bronich TK, Kabanov AV. Nanosized cationic
hydrogels for drug delivery: preparation, properties and interactions
with cells. Adv Drug Deliv Rev 2002; 54: 135-47.
[33] Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to
pH-responsive drug delivery. Drug Discov Today 2002; 7: 569-79.
[34] Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery.
Adv Drug Deliv Rev 2001; 53: 321-39.
[35] Teodor E, Litescu SC, Lazar V, Somoghi R. Hydrogel-magnetic
nanoparticles with immobilized L-Asparaginase for biomedical ap-
plications, J Mat Sci Mat Med 2009; 20: 1307-14.
[36] Santini JT, Cima MJ, Langer R. A controlled release microchip.
Nature 1999; 397:335-8.
[37] LaVan DA, McGuire T, Langer R. Small-scale systems for in vivo
drug delivery. Nat Biotechnol 2003; 21: 1184-91.
[38] Grayson ACR, Choi IS, Tyler BM, Wang PP, Brem H, Cima MJ,
Langer R. Multi-pulse drug delivery from a resorbable polymeric
microchip device. Nat Mater 2003; 2: 767- 72.
[39] Razzacki SZ, Thwar PK, Yang M, Ugaz VM, Burns MA. Inte-
grated microsystems for controlled drug delivery. Adv Drug Deliv
Rev 2004; 56: 185-98.
[40] Collins JM. Pharmacologic rationale for regional drug delivery. J
Clin Oncol 1984; 2: 498-504.
[41] Egan TD. Intravenous drug delivery systems: Toward an intrave-
nous ''vaporizer''. J Clin Anesthesia 1996; 8: S8-S14.
[42] Markman M. Intraperitoneal antineoplastic drug delivery: rationale
and results. Lancet Oncol 2003; 4: 277-83.
[43] Edwards DA, Hanes J, Caponetti G, et al. Large porous particles
for pulmonary drug delivery. Science 1997; 276: 1868-71.
[44] Prausnitz MR, Bose VG, Langer R, Weaver JC. Electroporation of
mammalian skin – a Mechanism to enhance transdermal drug-
delivery. Proc Natl Acad Sci USA 1993; 90: 10504-8.
[45] Henry S, McAllister DV, Allen MG, Prausnitz MR. Microfabri-
cated microneedles: A novel approach to transdermal drug deliv-
ery. J Pharm Sci 1998; 87: 922-5.
[46] Prausnitz MR, Mitragotri S, Langer R. Current status and future
potential of transdermal drug delivery. Nature Rev Drug Discov
2004; 3: 115-24.
[47] Illum L. Nasal drug delivery: new developments and strategies.
Drug Discovery Today 2002; 7: 1184-9.
[48] Illum L. Nasal drug delivery - possibilities, problems and solutions.
J Control Release 2003; 87: 187-98.
[49] Brannonpeppas L. Novel vaginal drugrelease applications. Adv
Drug Deliv Rev 1993; 11: 169-77.
[50] Loftssona T, Jarvinen T. Cyclodextrins in ophthalmic drug deliv-
ery. Adv Drug Deliv Rev 1999; 36: 59-79.
[51] Le Bourlais C, Acar L, Zia H, Sado PA, Needham T, Leverge R.
Ophthalmic drug delivery systems - Recent advances. Progress
Retin Eye Res 1998; 17: 33-58.
[52] Liu F, Laurent S, Fattahi H, Elst LV, Muller RN. Superparamag-
netic nanosystems based on iron oxide nanoparticles for biomedical
imaging. Nanomed (Lond) 2011; 6: 519-28.
[53] Santhosh P.B., Ulrih N.P., Multifunctional superparamagnetic iron
oxide nanoparticles: Promising tools in cancer theranostics, Cancer
Lett 2013; 336: 8-17.
[54] Tietze R, Zaloga J, Unterweger H, et al. Magnetic nanoparticle-
based drug delivery for cancer therapy. Biochem Biophys Res
Commun 2015; 468: 463-70.
[55] Whajuddin, Arora S. Superparamagnetic iron oxide nanoparticles:
magnetic nanoplatforms as drug carriers. Int J Nanomed 2012; 7:
3445–71.
[56] Akbarzadeh A, Mikaeili H, Zarghami N, Mohammad R, Barkhord-
ari A, Davaran S. Preparation and in vitro evaluation of doxorubi-
cinloaded Fe3O4 magnetic nanoparticles modified with biocom-
patible copolymers, Int J Nanomed 2012; 7: 511-26.
246 Current Drug Targets, 2018, Vol. 19, No. 3
[57] Singh A, Dilnawaz F, Sahoo SK. Long circulating lectin conju-
gated paclitaxel loaded magnetic nanoparticles: A new theranostic
avenue for leukemia therapy. PLoS ONE 2011; 6(11): e26803
[58] Dilnawaz F, Singh A, Mohanty C, Sahoo SK. Dual drug loaded
superparamagnetic iron oxide nanoparticles for targeted cancer
therapy. Biomaterials 2010; 31: 3694–706.
[59] Singh A, Dilnawaz F, Mewar S, et al. Composite polymeric mag-
netic nanoparticles for co-delivery of hydrophobic and hydrophilic
anticancer drugs and MRI imaging for cancer therapy. ACS Appl
Mater Interfaces 2011; 3: 842-56.
[60] Wang J, Chen B, Chen J, et al. Synthesis and antitumor efficacy of
daunorubicin-loaded magnetic nanoparticles. Int J Nanomed 2011;
6: 203-11.
[61] Bell GI, Burant CF, Takeda J, Gould GW. Structure and function
of mammalian facilitative sugar transporters. J Biol Chem. 1993;
268:19161–4.
[62] Gold J. Inhibition of Walker 256 intramuscular carcinoma in rats
by administration of hydrazine sulfate. Oncology 1971; 25: 66-71.
[63] Fanciulli M, Valentini A, Bruno T, Citro G, Zupi G, Floridi A.
Effect of the antitumor drug lonidamine on glucose metabolism of
adriamycin-sensitive and -resistant human breast cancer cells. On-
col Res 1996; 8: 111–20.
[64] Shan XH, Hu H, Xiong F, et al. Targeting Glut1-overexpressing
MDA-MB-231 cells with 2-deoxy-D-g1ucose modified SPIOs. Eur
J Radiol. 2012; 81(1): 95-9.
[65] Xiong F, Zhu ZY, Xiong C, Hua XQ, Shan XH, Zhang Y, Gu N.
Preparation, characterization of 2-deoxy-D-glucose functionalized
dimercaptosuccinic acid-coated maghemite nanoparticles for tar-
geting tumor cells. Pharm Res 2012; 29(4): 1087-97.
[66] Rouhollah K, Pelin M, Serap Y, Gozde U, Ufuk G. Doxorubicin
loading, release, and stability of polyamidoamine dendrimer-coated
magnetic nanoparticles. J Pharm Sci 2013; 102(6): 1825-35.
[67] Unterweger H, Tietze R, Janko C, et al. Development and charac-
terization of magnetic iron oxide nanoparticles with a cisplatin-
bearing polymer coating for targeted drug delivery. Int J Nanomed
2014; 9: 3659-76.
[68] Zaloga J, Janko C, Nowak J, et al. Development of a lauric
acid/albumin hybrid iron oxide nanoparticle system with improved
biocompatibility. Int J Nanomed 2014; 9: 4847-66.
[69] Zaloga J, Janko C, Agarwal R, et al. Different storage conditions
influence biocompatibility and physicochemical properties of iron
oxide nanoparticles. Int J Mol Sci 2015; 16(5): 9368-84.
[70] Gu L, X He, Z Wu. Mesoporous Fe3O4/hydroxyapatite composite
for targeted drug delivery. Mat Res Bull 2014; 59: 65-8.
[71] Wu J, Wang Y, Jiang W, Xu S, Tian R. Synthesis and characteriza-
tion of recyclable clusters of magnetic nanoparticles as doxorubicin
carriers for cancer therapy. Appl Surf Sci 2014; 321: 43-9.
[72] Zou Y, Liu P, Liu C-H, Zhi X-T. Doxorubicin-loaded mesoporous
magnetic nanoparticles to induce apoptosis in breast cancer cells.
Biomed Pharmacother 2015; 69: 355-60.
[73] Elbialy NS, Fathy MM, Khalil WM. Doxorubicin loaded magnetic
gold nanoparticles for in vivo targeted drug delivery. Int J Pharma-
ceutics 2015; 490: 190-9.
[74] Jia L, Patwari Y, Kelsey SM, Newland AC. Trail-induced apopto-
sis in Type I leukemic cells is not enhanced by overexpression of
bax. Biochem Biophys Res Commun 2001; 283: 1037-45.
[75] Teodor E, Truica G, Lupescu I. The release of L-asparaginase from
hydrogel-magnetic nanoparticles. Roum Biotechnol Lett 2008; 13:
3907-13.
[76] Chen B, Liang Y, Wu W, et al. Synergistic effect of magnetic
nanoparticles of Fe3O4 with gambogic acid on apoptosis of K562
leukemia cells, Int J Nanomed 2009; 4: 251-9.
[77] Wang C, Zhang H, Chen B, Yin H, Wang W. Study of the en-
hanced anticancer efficacy of gambogic acid on Capan-1 pancreatic
cancer cells when mediated via magnetic Fe3O4 nanoparticles. Int J
Nanomed 2011; 6: 1921-35.
[78] Yallapu MM, Ebeling MC, Khan S, et al. Novel curcumin loaded
magnetic nanoparticles for pancreatic cancer treatment. Mol Cancer
Ther 2013; 12: 1471-80.
[79] Sundar S, Mariappan R, Piraman S. Synthesis and characterization
of amine modified magnetite nanoparticles as carriers of curcumin-
anticancer drug. Powder Technol 2014; 266: 321-8.
[80] Zhu X-M, Yuan J, Leung K C-F, et al. Hollow superparamagnetic
iron oxide nanoshells as a hydrophobic anticancer drug carrier: in-
tracelluar pH-dependent drug release and enhanced cytotoxicity.
Nanoscale 2012; 4: 5744-54.
Teodor et al.
[81] Semple SC, Akinc A, Chen J, et al. Rational design of cationic
lipids for siRNA delivery. Nat Biotechnol 2010; 28: 172-6.
[82] Scherer LJ, Rossi JJ. Approaches for the sequence-specific knock-
down of mRNA. Nat Biotechnol 2003; 21: 1457-65.
[83] Hannon GJ. RNA interference. Nature 2002; 418: 244-51.
[84] Dykxhoorn DM, Chowdhury D, Lieberman J. RNA interference
and cancer: endogenous pathways and therapeutic approaches. Adv
Exp Med Biol 2008; 615: 299-329.
[85] Oh YK, Park TG. siRNA delivery systems for cancer treatment.
Adv Drug Deliv Rev 2009; 61: 850-62.
[86] Whitehead KA, Langer R, Anderson DG. Knocking down barriers:
advances in siRNA delivery. Nat Rev Drug Discov 2009; 8: 129-
38.
[87] Tseng YC, Mozumdar S, Huang L. Lipid-based systemic delivery
of siRNA. Adv Drug Deliv Rev 2009; 61: 721-31.
[88] Howard KA. Delivery of RNA interference therapeutics using
polycation-based nanoparticles. Adv Drug Deliv Rev 2009; 61:
710-20.
[89] Mok H, Lee SH, Park JW, Park TG. Multimeric small interfering
ribonucleic acid for highly efficient sequence-specific gene silenc-
ing. Nat Mater 2010; 9: 272-8.
[90] Yezhelyev MV, Qi L, O’Regan RM, Nie S, Gao X. Proton-sponge
coated quantum dots for siRNA delivery and intracellular imaging.
J Am Chem Soc 2008; 130: 9006-12.
[91] Lee JS, Green JJ, Love KT, Sunshine J, Langer R, Anderson DG.
Gold, poly(beta-amino ester) nanoparticles for small interfering
RNA delivery. Nano Lett 2009; 9: 2402-6.
[92] Giljohann DA, Seferos DS, Prigodich AE, Patel PC, Mirkin CA.
Gene regulation with polyvalent siRNA-nanoparticle conjugates. J
Am Chem Soc 2009; 131: 2072-73.
[93] Veiseh O, Kievit FM, Fang C, et al. Chlorotoxin Bound Magnetic
Nanovector Tailored for Cancer Cell Targeting, Imaging, and
siRNA. Deliv Biomat 2010; 31(31): 8032–42
[94] Zhao P, Wang HY, Gao H, Li CZ, Zhang YZ. Reversal of
multidrug resistance by magnetic chitosan-Fe3O4 nanoparticle-
encapsulated MDR1 siRNA in glioblastoma cell line. J Neurol Res
2013; 35: 821-8
[95] Jin Y, Jia C, Huang SW, O’Donnell M, Gao X. Multifunctional
nanoparticles as coupled contrast agents. Nat Commun 2010; 1: 41.
[96] Fattahi H, Laurent S, Liu F, Arsalani N, Elst LV, Muller RN. Mag-
netoliposomes as multimodal contrast agents for molecular imaging
and cancer nanotheragnostics. Nanomedicine (Lond) 2011; 6: 529-
44.
[97] Issadore D, Shao H, Chung J, et al. Self-assembled magnetic filter
for highly efficient immunomagnetic separation. Lab Chip 2011;
11: 147-51.
[98] Das M, Dhak P, Gupta S, et al. Highly biocompatible and water-
dispersible, amine functionalized magnetite nanoparticles, prepared
by a low temperature, air-assisted polyol process: a new platform
for bio-separation and diagnostics. Nanotechnology 2010; 21:
125103.
[99] Yang X, Hong H, Grailer JJ, et al. cRGD-functionalized, DOX -
conjugated, and 64Cu - labeled superparamagnetic iron oxide
nanoparticles for targeted anticancer drug delivery and PET/MR
imaging. Biomaterials 2011; 32: 4151-60.
[100] Yallapu MM, Othman SF, Curtis ET, Gupta BK, Jaggi M, Chauhan
SC. Multi-functional magnetic nanoparticles for magnetic reso-
nance imaging and cancer therapy. Biomaterials 2011; 32: 1890-
905.
[101] Elsherbini AA, Saber M, Aggag M, El-Shahawy A, Shokier HA.
Magnetic nanoparticle-induced hyperthermia treatment under mag-
netic resonance imaging. Magn Reson Imaging 2011; 29: 272-80.
[102] Maity D, Chandrasekharan P, Yang CT, et al. Facile synthesis of
water-stable magnetite nanoparticles for clinical MRI and magnetic
hyperthermia applications. Nanomedicine (Lond) 2010; 5: 1571-84.
[103] Foy SP, Manthe RL, Foy ST, Dimitrijevic S, Krishnamurthy N,
Labhasetwar V. Optical imaging and magnetic field targeting of
magnetic nanoparticles in tumors. ACS Nano 2010; 4(9): 5217-24.
[104] Jain TK, Morales MA, Sahoo SK, Leslie-Pelecky DL, Labhasetwar
V. Iron oxide nanoparticles for sustained delivery of anticancer
agents. Mol Pharmaceutics 2005; 2: 194-205.
[105] Jain TK, Richey J, Strand M, Leslie-Pelecky DL, Flask CA, Lab-
hasetwar V. Magnetic nanoparticles with dual functional proper-
ties: Drug delivery and magnetic resonance imaging. Biomaterials
2008; 29: 4012-21.
Functionalized Magnetic Nanostructures for Anticancer Therapy
[106] Sun P, Zhang H, Liu C, et al. Preparation and characterization of
Fe3O4/CdTe magnetic/fluorescent nanocomposites and their appli-
cations in immunolabeling and fluorescent imaging of cancer cells.
Langmuir 2010; 26(2): 1278-84.
[107] Chen W, Cao Y, Liu M, et al. Rotavirus capsid surface protein
VP4-coated Fe3O4 nanoparticles as a theranostic platform for cel-
lular imaging and drug delivery. Biomaterials 2012; 33: 7895-902.
[108] Ma Y, Tong S, Bao G, Gao C, Dai Z. Indocyanine green loaded
SPIO nanoparticles with phospholipid-PEG coating for dual-modal
imaging and photothermal therapy. Biomaterials 2013; 34: 7706-
14.
[109] Zhang M, Cao Y, Wang L, Ma Y, Tu X, Zhang Z. Manganese
doped iron oxide theranostic nanoparticles for combined T1 mag-
netic resonance imaging and phototherma therapy. ACS Appl Ma-
ter Interfaces 2015; 7(8): 4650-8.
[110] Zhao L, Huo M, Liu J, et al. In vitro investigation on the magnetic
thermochemotherapy mediated by magnetic nanoparticles com-
bined with methotrexate for breast cancer treatment. J Nanosci
Nanotechnol 2013; 13(2): 741-5.
[111] Meenach SA, Shapiro JM, Hilt JZ, Anderson KW. Characterization
of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia
and paclitaxel delivery. J Biomater Sci Polym Ed 2013; 24(9):
1112-26.
[112] Sahoo B, Devi K SP, Dutta S, Maiti TK, Pramanik P, Dhara D,
Biocompatible mesoporous silica-coated superparamagnetic man-
ganese ferrite nanoparticles for targeted drug delivery and MR im-
aging applications, J Colloid Interface Sci 2014; 431: 31-4.
[113] Ye F, Barrefelt Å, Asem H, et al. Biodegradable polymeric vesicles
containing magnetic nanoparticles, quantum dots and anticancer
PMID: 26853321
Current Drug Targets, 2018, Vol. 19, No. 3 247
drugs for drug delivery and imaging. Biomaterials 2014; 35: 3885-
94.
[114] Wang YX, Zhu XM, Liang Q, Cheng CH, Wang W, Leung KC. In
vivo chemoembolization and magnetic resonance imaging of liver
tumors by using iron oxide nanoshell/doxorubicin/poly(vinyl alco-
hol) hybrid composites. Angew Chem Int Ed Engl 2014; 53(19):
4812-5.
[115] Ficai A, Andronescu E, Ghitulica CD, Ficai D, Voicu G, Albu MG.
Process for preparing composite multi-purpose materials with pos-
sible applicability in the treatment of bone cancer; Patent No:
RO127725-A2; RO127725-B1;
[116] Ficai D, Sonmez M, Albu MG, Mihaiescu DE, Ficai A, Bleotu C.
Antitumoral materials with regenerative function obtained using a
layer-by-layer technique. Drug Des Dev Ther 2015; 9: 1269-79.
[117] Patrascu JM, Nedelcu IA, Sonmez M, et al. Composite scaffolds
based on silver nanoparticles for biomedical applications. J Nano-
materials 2015; 1-8.
[118] Nedelcu IA, Ficai A, Sonmez M, Ficai D, Oprea O, Andronescu E.
Silver based materials for biomedical applications. Curr Org Chem
2014; 18(2): 173-84.
[119] Andronescu E, Ficai M, Voicu G, Ficai D, Maganu M, Ficai A.
Synthesis and characterization of collagen/ hydroxyapatite: mag-
netite composite material for bone cancer treatment. J Mater Sci-
Mater M 2010; 21: 2237-42.
[120] Andronescu E, Ficai A, Albu MG, et al. Collagen-
hydroxyapatite/cisplatin drug delivery systems for locoregional
treatment of bone cancer. Technol Cancer Res Treat 2013; 12: 275-
84.