Sorour Literature Review

Review
World Journal of
Cancer Research
Copyright 2014 American Scientific Publishers

All rights reserved
Printed in the United States of America
Vol. 1, 121, 2014

www.aspbs.com/wjcr
Application of Iron Oxide Nanoparticles in Sarcoma

Sorour Shahbazi1 , Xuchuan Jiang1! , Jia-Lin Yang2 , and Aibing Yu1
1
Faculty of Science, SIMPAS-Nanotechnology Research Group, School of Materials Science and Engineering,
The University of New South Wales, Sydney, NSW 2052, Australia
2
Faculty of Medicine, Sarcoma and Nanotechnology Group, Adult Cancer Program, Prince of Wales Clinical School and Lowy Cancer
Research Centre, The University of New South Wales, Sydney, NSW 2052, Australia
Nowadays, struggling with different kinds of sarcomas as a rare but malignant cancer is leading at many prestigious institutions around the world. Surgical techniques, chemotherapy, and radiotherapy as conventional methods have improved
the treatment of sarcoma. However, half of the sarcoma patients die at 5 years of the disease. There are still aspects that
need to be improved including early diagnosis, residue tumor cells after surgery, micrometastasis, lymph node metastasis, local recurrence and distant metastasis. Current chemotherapy and radiotherapy are effective, but often face tumor
resistance. It is difficult to overcome the problems through increasing treatment doses since these therapies are not
tumour specific and increasing dose may lead to cytotoxicity to normal tissues and organs. Recently, the application of
nanotechnology in oncology provides potential in problem solving in sarcoma. For examples, administrating a nanoparticle
based therapeutic/diagnostic agent for enhancing early and surgical margin diagnosis, sarcoma tumour cells targeting, as
well as gene and drug delivery has been reported in literature. In particular multifunctional and multimodal magnetic iron
oxide nanoparticles can offer solutions in diverse areas of sarcoma, as one of the most desirable noninvasive magnetic
resonance imaging (MRI) contrast agents, as well as drug, ligand and gene nanocarrier. It is also an outstanding hyperthermia agent via generating local heat under an alternative magnetic field. Although iron oxide nanoparticles have been
presented with noticeable results in preclinical phase, considerable accomplishments have not been reported in clinical
stage, indicating more efforts should be made to apply iron oxide nanoparticles in sarcoma. This review aims to discuss
the promising impact of iron oxide nanoparticles on sarcoma diagnosis and treatment.
KEYWORDS: Cancer, Sarcoma, Magnetic Iron Oxide Nanoparticles, Diagnosis, Hyperthermia.
CONTENTS
Introduction . . . . . . . . . . . . . . . . . . .
Synthesis of IONPs . . . . . . . . . . . . . .
Surface Modifications . . . . . . . . . . . . .
IONPs Against Sarcoma . . . . . . . . . . .
IONPs as a Sarcoma Diagnosis Agent .
Sarcoma Treatment with Drug Delivery
Sarcoma Treatment with Gene Therapy
Sarcoma Treatment with Hyperthermia .
Conclusions and Outlook . . . . . . . . . .
References . . . . . . . . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
1
4
5
6
8
12
12
13
14
14
INTRODUCTION
Cancer has been a serious global health problem, and
numerous cancers have been disclosed currently. Sarcoma
Author to whom correspondence should be addressed.

Email: xcjiang@unsw.edu.au
Received: 11 January 2014
Accepted: 16 February 2014
World J. Cancer Res. 2014, Vol. 1, No. 2
has emerged as one of the most critical cancers. In fact,

according to Cancer Facts and Figures 2013 report published by the American cancer Society annually, sarcoma is estimated to be diagnosed about 11,410 cases
(6,290 males and 5,120 females) and brings about death
of 4,390 (2,500 males and 1,890 females) patients in the
United States in 2013.
In general, there are two main kinds of sarcoma:
osteosarcomas (bone and joint sarcomas) and soft tissue
sarcomas (STS). The soft tissue sarcomas are more popular, which mainly grow from the soft tissues like fat,
muscle, nerves, fibrous tissues, blood vessels, or deep skin
tissues. They can also be found in the trunk, head and neck
area, internal organs, and in the back of the abdominal
cavity. As shown in Table I, Around 50 different types of
STS are classified by their tissues of origin.1 The tumor
heterogeneity brings more problems to the human health
since there are significant differences in clinical behavior, prognosis, and treatment and this obviously makes
2165-6304/2014/1/001/021
doi:10.1166/wjcr.2014.1020
utilizing one method overcome different types of sarcomas

very challenging. A few challenges in this area could be
demonstrated as following.
First challenge is the sarcoma diagnosis at an early stage
(absolutely localized and smaller tumor), which can lead
to simpler and more effective surgical removal. Needle
biopsy is one of the early diagnosis methods, however, the
needle not only is associated with pain and bleeding, but
Shahbazi et al.
also can miss the sarcoma and take a sample of normal

tissue instead.2 Noninvasive imaging tests, such as computed tomography (CT), positron emission tomography
(PET) and magnetic resonance imaging (MRI) are other
commonly used methods offer early diagnosis. Among
them, MRI seems to be more enhancive because of superior spatial resolution and contrast, unlimited penetrating
into tissues and being unharmed to the patient since not
Sorour Shahbazi is studying as a Ph.D. student of materials science at the University

of New South Wales, Australia. Her research interest is in nanotechnology specially bioapplication of iron oxide nanoparticles. She received her M.Sc. and B.Sc. from School
of Materials Engineering at the University of Tehran, Iran and she has professional
experience as a laboratory technical expert before applying for Ph.D. position.
Xuchuan Jiang has fully devoted to the study on synthesis, self-assembly and functional applications of nanoparticles since the award of his Ph.D. in 2001. Dr. Jiang has
been working in various academic research environments, including the University of
Washington (USA), the University of Paris (France) and the University of New South
Wales (Australia) respectively. He has published over 90 papers with SCI citations over
3500 times, leading him to H -index 28. He has been awarded ARC future fellow and
QEII fellow in 2009. He has also been nominated as an OZreader for assessing Australia Research Council (ARC) projects/grants, and as a reviewer for many nanoscience
journals.
Jia-Lin Yang is currently an Associate Professor and a team leader of the Sarcoma and
Nanooncology Group in the Adult Cancer Program of the Lowy Cancer Research Centre
and the Prince of Wales Clinical School, University of New South Wales (UNSW). He
was a clinician scientist 20 years ago and is a teaching and research academic now.
Over the last 22 years he has been prolific with basic and clinical cancer research,
alongside teaching at the Prince of Wales Hospital and UNSW.
Aibing Yu specialized in process metallurgy, obtained B.Eng. in 1982 and M.Eng.

in 1985 from Northeastern University (China), Ph.D. in 1990 from the University of
Wollongong (Australia). Since 1992, he has been with the University of New South
Wales. Currently he is a Scientia Professor. His research is mainly in particle science
and technology, process and materials engineering. He has published over 700 papers
in various international journals and conference proceedings. He is an elected Fellow
of the Australian Academy of Technological Sciences and Engineering, and Australian
Academy of Science.
World J. Cancer Res. 1, 121, 2014
Shahbazi et al.
Table I. Common kinds of STS.
Cancer
Tissue of origin
Special development areas
Patients
Liposarcomas
Fat
Adults (5065)
Leiomyosarcomas
Smooth muscle
Rhabdomyosarcomas
Skeletal muscle
Neurofibrosarcomas
Neurilemmomas
Neurogenic arcomas
Gastrointestinal stromal
tumor (GIST)
Synovial sarcoma
Nerve
Thigh and behind the knee

Inside the back of the abdomen
Retroperitoneum (area in back of the
abdominal cavity)
Internal organs
Blood vessels
Arms or legs
Head and neck
Urinary organs (like vagina or bladder)
Brain and spinal cord
Nerves that run throughout the body
Upper arms or neck (have very large nerves)
In digestive tract (muscles lining the
stomach and intestine)
Knee and ankle
Shoulder
Hip
Parts of the body that have been treated
with radiation
Limbs that are chronically swollen because
lymph circulation is blocked
On the skin
On mucosal surfaces such as inside the
mouth
In the lymph nodes
Digestive tract
Legs and arms
Trunk
Under the skin of hands and forearms
Under the skin of feet and lower legs
Legs and arms
Inside the back of the abdomen
Nerve
Joint
Angiosarcoma
Blood and
lymph vessels
Kaposi sarcoma
Blood and
lymph vessels
Fibrosarcoma
Fibrous
epithelioid sarcoma
Uncertain
malignant fibrous
histiocytoma (MFH)
Uncertain
The elderly
Children
People with an inherited

condition called
neurofibromatosis
Adults older then 50
Children and young adults
People who are treated with

radiation
Older people and

people with suppressed immune
systems (from HIV infection
and in organ transplant
patients)
Adults (2060)
Adolescents and young adults
Older adults
Note: Data were adapted from American Cancer Society website (http://www.cancer.org) with modification.
using ionizing radiation. contrast and resolution of MRI

equipment, to clearly observe and find smaller tumours
(diameter less 2 cm) is still difficult.
Second challenging is to identify surgical margin of sarcoma through accurate distinction of cancer cells from
normal ones, and to distinguish the margin of the tumor
area, which is also important in surgical removal of tumor
cells. Now MRI has been a common detective method
in clinics and the MRI quality can be improved by contrast agent administrated. One of the MRI contrast agents
is iron oxide nanoparticle (IONP), especially superparamagnetic iron oxide nanoparticles (SPIONs) with low
cytotoxicity as a result of high magnetic signal strength.
The IONPs/SPIONs enhanced MRI sensitivity and signal lasting time, superior to other contrast agents such
as gadolinium that suffers from issues of timing, dose
and surgically induced contrast enhancement. In addition,
IONPs present multimodal imaging capability via carrying contrast agents of other imaging modalities such
as optical imaging, CT, PET, and single-photon emission computed tomography (SPECT), however, the size
and surface modification of IONPs should be carefully
controlled.
Variation in drug distribution and absorption and difficulty in drug accessibility to sarcoma cells are some of
challenges faced by chemotherapy.6 Sarcoma multidrug
resistance as a result of p-glycoprotein overexpression is
another complexity hindering adequate drug delivery.7 In
identifying new sarcoma treatment, gene therapy by means
of oligonucleotides such as Dz13 DNA8 and ONYX0115.9 has been trialled. However, poor stability and
low intracellular penetration of oligonucleotides decrease
its therapeutic potential. Engineered IONPs with suitable
coatings as nanocarriers for targeting ligands and oligonucleotides are capable of overcoming these problems. It is
also noticeable that using IONPs could be more affordable
diagnosis and treatment of some kinds of sarcoma.
As the last but not the least, hyperthermia has been
a common method to abolish sarcoma cells. Radio frequency and microwave thermal therapy as two most ordinary hyperthermia techniques have difficulties such as not
uniform heating of only the tumor region and noticeable
injury to the patient in treating large tumors.10 IONPs and
especially SPIONs selectively generate local hyperthermia
in sarcoma area under an alternative external magnetic
field, providing a favourable alternative treatment option.
3
Shahbazi et al.
time, tumor volume and location, vascular content of

tumor and blood flow in tumor are fundamental.23
This review aimed to summarise recent progress in
the literature on IONPs studies, specifically on sarcoma
diagnosis and treatment. It focuses on IONPs synthesis, characterizations, surface modification of IONPs, and
applications of IONPs in sarcoma. It tries to answer the
question whether the IONPs would be a general, desirable and promising solution to conquer heterogeneous
sarcomas.
SYNTHESIS OF IONPs
Figure 1. A schematic of IONPs as multifunctional and multimodal imaging NPs against cancer.
By applying an external magnetic field in sarcoma

region, IONPs pass through blood vessels and leak into
tumor cells by way of damaged and leaky vasculature of
tumor. This property is called the enhanced permeability
and retention (EPR) effect.11 In this situation, rapid clearance of narrow IONPs via renal system during circulation
time is a critical issue. In this case, surface modification
of IONPs with hydrophilic coatings considerably extends
circulating time. Moreover, IONPs could be functionalized with targeting ligands, which conduct IONPs directly
toward intra or extracellular sarcoma biomarkers such as
kinase receptor and transferring receptor.
Among different types of nanoparticles (NPs) used in
sarcoma therapy such as noble metals, semiconductors,
magnetic compounds, and their combinations, IONPs have
been substantially remarked specially due to their theranostic approach.3 Theranostic is defined as the combination of therapy and diagnosis within a single platform.12! 13
Theranostic specification of IONPs is owing to their
multifunctional and multimodal imaging characterizations
(Fig. 1). Freeman et al.14 firstly introduced the concept
of use of magnetism in medicine in the 1970s. Widder
et al.1517 in 1983 utilized IONPs to deliver doxorubicin
to sarcoma tumors implanted in rat tails for the first time.
After that, in vitro and in vivo (with sarcoma diameter
even less than 10 mm) diagnosis and treatment investigations have been carried out in which IONPs were applied
against different types of sarcomas and fulfilling results
have been reported.1822
It is also noticeable that in order to achieve more
enhancive therapeutic effect of IONPs against sarcoma,
considering both physiological characteristics of IONPs
such as size, morphology, surface characteristics, amount
of administration, reversibility and strength of binding
between therapeutic agent and magnetic NPs as well as
the most favorable magnetic field characteristics consist of
geometry, strength and duration and biological properties
including size, weight and body surface, blood volume,
cardiac output and systemic vascular resistance, circulation
4
In the synthesis of IONPs, two mechanisms of nucleation and growth are applied. When a solution reaches
its critical supersaturation, a single short burst of nucleation happens and monodispersed NPs can be produced.
As a result of diffusion of solute particles from the solution onto the surface of the nuclei, NPs with a suitable
size are obtained.24 There are several types of IONPs synthesis methods such as co-precipitation,2528 hydrothermal
synthesis,2932 micro-emulsion,3336 polyol,37 microwave
assisted synthesis,38 electrochemical deposition of metal
on a cathode,39 spray and laser pyrolysis,40! 41 flame
synthesis42 and sonochemical procedures.43! 44 Characteristics and advantages and disadvantages of co-precipitation,
thermal decomposition and micro-emulsion as the three
most common synthesis methods of IONPs are depicted
in Table II.3! 45! 46 Wahajuddin et al.46 published a review
article (2012) in which they explain comprehensively
diverse synthesis methods, and characteristics associated
with advantages and disadvantages.
The size of IONPs plays very key rule in IONPs bioapplication. Determination of residual time in blood (i.e.,
half-life in the circulation) is one of the most important effect of the size of NPs since particles with sizes
smaller than 10 nm are mainly removed by renal clearance and particles larger than 200 nm become concentrated in the spleen or are absorbed by phagocytic cells
of the body and in both leading to decreased plasma
concentrations.4749 Secondly, magnetic property of IONPs
(using in MRI and hyperthermia) is substantially influenced by the size.50 Additionally, potential of IONPs with
a particle size smaller than 2 nm increases and leads
to diffuse through cell membranes, damaging intracellular organelles and thus exhibiting potentially toxic effects;
hence they are not suitable for medical application.46
Also NPs with size more than 150 nm are not able to
pass across the endothelial cells of blood vessels and be
engulfed by tumor cells.51! 52 Kuhn et al.53 studied the
velocity of IONPs with 135 nm and 400 nm in diameters through extracellular matrix from Murine sarcoma,
and they achieved more than 100 times in velocity with
135-nm particles but 400-nm ones. There are considerable pervious investigations42! 50! 5456 to claim that the size
range of 10100 nm is more suitable for bioapplications.
Shahbazi et al.
Table II.
Common synthesis methods of IONPs.3! 45! 46
Method
Coprecipitation
Thermal decomposition
Microemulsion
Reaction
temperature (" C)
Reaction
rate
2090
Size (nm)
Pros
Cons
Fast
15200
Oxidation
Aggregation
100320
Slow
320
2050
Fast
412
Simple method
Rapid synthesis
High yield
Good control of size
Good control of size and shape
Narrow size
High yield
Good control of agglomeration
Good control of size
Homogenous NPs
Adequate and versatile
Simple method
Moreover, the phenomenon of Superparamagnetism in

IONPs is one of the most promising characteristics with
the size of 1020 nm, which could be attributed to the single domain nature of them, leading to exhibiting no residual magnetic interaction and less chances of aggregation
after removal of the magnetic field.45! 46! 57
Morphology of IONPs is another important factor against sarcoma since it affects biodistribution of
themeselves. For example, the phagocytic activity of
macrophages is moved to a minor extent by rod-shaped
particles compared to spherical ones. The rod-shaped
and nonspherical NPs show a longer blood circulation time compared with spherical particles.58 The morphology of NPs also influences cell toxicity. In Zhang
et al.s study, nanobead-shaped, nanoworm-shaped, and
nanosphere-shaped SPIONs showed greater cellular toxicity in comparison with nanorods and colloidal nanocrystal clusters.59 The reaction conditions and chemicals
involved considerably affect the shape of NPs. For example, in the presence of surfactant with bulky hydrocarbon
chain structures (e.g., oleylamine and adamantane amine)
the steric hindrance exerted by surfactants has been shown
to affect the shape of growing crystals of iron oxide during
synthesis.60
The oxidation state of the iron ions can also have
a potential effect on the morphology of NPs prepared.
In fact, iron ions in the trivalent state (Fe3+ ) favor formation of spherical NPs; whereas, ions in the divalent state
(Fe2+ ) prefer to develop nanorods. The oxidation state of
the iron ion on the surface of the nanoparticle is susceptible to its nearby environment, particularly to surfactant
exposure. Analysis of the oxidation state of iron ions on
the surface of NPs can assist in recognizing their structure and chemical environment.61 It is also noticeable that
spherical magnetite and maghemite particles offer a uniform surface area for coating and conjugating of targeting
ligands or therapeutic agents.46
Finally, the surface characteristics of IONPs as the most
important specification necessitate more extensive study.
One of the surface characteristics is its charge determining
Long reaction time

Oxidation
Poor yield
Large amount of solvents
colloidal stability which is related to zeta potential of NPs.

High zeta potential will give stability (i.e., dispersion will
resist aggregation); when the potential is low, as a result
of Van Der Waal interparticle attractions, affinity exceeds
repulsion and the dispersion will break and flocculate.62
Therefore, colloids with high zeta potential (negative or
positive) are electrically stabilized while colloids with low
zeta potentials tend to coagulate or thicken.63! 64 Surface
charge also affects being engulfed of IONPs by target
cells. IONPs having a positive charge are better internalized by breast cancer cells than are negatively charged
ones.65 Surface charge higher than + 25 mV and less than
25 mV have been reported considerable stability.62 In
general, Hydrophilic surfaces are more desirable since they
diminish opsonization and clearance as a result of the least
interacting with blood components.55! 56
SURFACE MODIFICATIONS
Biocompatibility (reduction toxicity), bioavailability, multifunctionality and multimodality of IONPs are substantially enhanced by various types of coatings. Also, coating
of IONPs keeps the surface from oxidation and increases
internalization efficiency by target cells.66 Furthermore,
coating enhances colloidal stability of IONPs via diminishing their tendency to aggregation; in fact, coating material
could be added during the synthesizing process (one-pot
method) in order to prevent the agglomeration of the iron
oxides.48! 67! 68
The most common coatings for biocompatible IONPs
are polymers. Three-dimensional polymer molecules such
as dendrimers, hyperbranched and star polymers have been
engrossed study attractions owing to their unique structures and properties68 dextran69! 70 alginate,71 starch72 and
chitosan73 as some types of polysaccharides are among
the most commonly used coating for the stabilization of
IONPs. Polyethylene glycol (PEG) is another popular biocompatible coating easily conjugates with antibodies or
peptides and improves drug delivery of IONPs.67 Polymer
coatings, also, have been widely used for carrying drugs
5
showing side effects such as nephrotoxicity, cumulative

neurotoxicity or ototoxicity. Fatty acids, dicarboxylic or
tricarboxylic acids and phosphonates and phosphates, silica, carbon, precious metals such as gold (Au) and metal
oxides are other coatings of IONPs.
In fact, surface modification agents convey drugs,
genes and other targeting and therapeutic agents via
encapsulating or conjugating to them. For instance,
Lipoproteins as endogenous nanocarriers have been used
to transform Arginylglycylaspartic acid (RGD) peptides
towards sarcoma cells.74 Because of their compatibility with immune systems they have stealth characteristics and are able to escape from elimination by
renal system. Also, in sarcoma gene therapy encapsulating genes in cationic lipids improves their stability in biological environments and therefore enhances
in vivo intracellular gene delivery to cancer cells; however, lipids aggregation as a result of their cationic nature
is a problem.75 In this case, applying cationic polymers
such as poly(isobutylcyanoacrylate),7577 polyethyleneimine (PEI) and polyallylamine hydrochloride (PAH)78 and
cyclodextrin79 demonstrated considerable in vivo sarcoma
treatment and inhibition of cancer growth. Tracking sarcoma therapeutic process with polymeric nanocapsules is
hard and therefore polymers are mostly applied in association with a traceable agent such as rhodamine (as a
fluorine dye)75 or nanodiamonds (intrinsic fluorescence).78
Obviously, coupling IONPs with appropriate polymers
makes nanocapsules directly traceable and in some cases
increases their stability. Since magnetic property of lipids
is used for MRI, encapsulating IONPs in lipids as
enhancive MRI agents is able to considerably increase
MRI quality and sensitivity. Most recently Muthiah et al.80
published an inclusive review about surface modification
of IONPs and Wahajuddin et al. in another review article
summarized diverse most common coating materials.
IONPs AGAINST SARCOMA

Despite many efforts made in this area, some current
limitations on sarcoma diagnosis and treatment still exist
including:
(1) Early diagnosis and complete surgical removal (avoiding residual) of sarcoma before tumor grow to 5 cm since
probability of metastasis-free survival in soft tissue sarcoma in stage I (in which size of the tumor is not larger
than 5 cm and it generally has not spread to lymph nodes
or more distant sites) is more than 95%;81
(2) Accurate discrimination between sarcoma and normal
tissues which helps determining surgical margin before
surgery and subsequently cause decreasing normal tissues
removal and residual tumor cells because of STS has
asymmetrical and infiltrating growth pattern;82! 83
(3) Identify lymph node metastasis and micrometastases;
taking Ewing sarcoma as an example according to historical data only less than 5% of treated patients with
6
Shahbazi et al.
localized tumour are survived and the others die as a result

of cancer metastases; therefore development of new mothods for treating metastases seems crucial;79! 84
(4) Improve specificity and effect of chemotherapy and
radiotherapy;85! 86
(5) Personalized sarcoma therapy, which will tailor optimized treatment to each patient.
Recently, nanotechnology offers solution in diverse
areas of sarcoma diagnosis and treatment. Table III demonstrates some of the carried out research on sarcoma therapy
by NPs.
In recent decades, functionalized and modified IONPs
have been engrossed attentions due to their bioavailability, biocompatibility, degradability, multimodality imaging
ability, enhancive drug delivery and gene therapy capability, and healing hyperthermia effect. Nowadays considerable research activities are carried out regarding IONPs
cancer therapeutic effect in order to optimize IONPs properties such as increasing magnetic nanoparticle concentration in blood vessels, reducing early clearance from the
body, minimizing nonspecific cell interactions and thus
minimizing side effects and increasing their internalization
efficiency within target cells, thus reducing the total dose
required. Table IV is a summary of mostly recent investigations on theranostic application of IONPs against most
common cancers.
IONPs as contrast agents for MRI and carrying
other imaging modalities (multimodality) can considerably enhance sarcoma diagnosis. They also could be utilized as nanocarriers for targeting agent to genetic changes
and overexpression of certain proteins specifying some
groups of sarcoma. Chemotherapeutic drugs and other
antitumor medicines could be conveyed by modified and
functionalized IONPs. IONPs are also able to produce
local hyperthermia in sarcoma tumor regions via an alternative magnetic field. Moreover, using IONPs could be
more affordable diagnosis and treatment of some kinds
of sarcoma. To our knowledge, in 1996 Lubbe et al.87! 88
for the first time carried out successful phase I clinical
trial with directing ferrofluid to the patients with advanced
sarcomas. The results showed that ferrofluid administration was well accepted in the majority of patients studied,
and the ferrofluid was successfully directed to cancer cells
without cytotoxicity. In 2004 Lemke et al.89 in a phase I
study tracked by MRI, the effect of ferrofluid consists of
epirubicin as a chemotherapeutic drug on sarcomas in different parts of body of 5 patients. Table V shows that
changes in tumors sizes situated in different parts of body
are traceable and assessable by MRI. In fact, they were
able to observe that except sarcoma in right shoulder, the
effect of epirubicin on other types of sarcomas was not
satisfying by MRI in the short period (210 days). In 2006
in a Phase I trial, Wust et al.90 applied thermal therapy
by magnetic fluid on STS patients and achieved desirable
heal without or with only moderate side effects. In 2010,
Shahbazi et al.
Table III.
Item
Nanooncological investigations of diverse types of sarcoma.
Type of
sarcoma
Cancer
cells
Ewings
sarcoma
A673
TC71
EW7
Primary
STS
LSL-Kras
G12D
P53
CD31
FL/FL
Rhabdomyo- R1 H
sarcoma
Uterine sar- MES-SA
coma
Nanoparticle
DNA NPs
Polyisobutylcyanoacrylate NPs
Fluorescent
nanodiamonds
Polycathionscyclodextrins-PEG
NPs
IONPs
Liposomes
encapsulating
iodine and AuNPs
PEG NPs
Au Nanorods
IONPs
Polymeric (PLGA)
Nanocarriers
Nanoplexes
Fibrosarcoma
HT 1080
FsaR
BP6
BFS-1
AuNPs
V2 O5 NPs
La0"7 Sr0"3 MnO3
NPs doped with
cerium
Copolymer NPs
IONPs
Chitosan NPs
Liposomes NPs
IONPs
Murine
sarcoma
S-180
NIH/3T3
J744A.1
Oridonin
nanosuspension
Polyisobutylcyanoacrylate NPs
Ploy-iso-hexylcyanoacrylate
(PIHCA) NPs
Chitosan NPs
Lipid NPs
IONPs
Gliosarcoma 9L
U87
IONPs
Gd NPs
Poly(cyanoacrylate) NPs
Lipid
Nanocapsules
Osteogenic
sarcoma
Chitosan NPs
Silica NPs
Magnetic
orcinol-imprinted
poly(ehylen-covinyl alcohol)
AuNPs
Liposom NPs
SaOS-2
SJSA-1
MES-SA
HOS
KHOS
MNNGHOS
Os515
Size
(nm)
8130
Therapeutic
approach
Targeting
method
Gene Therapy
Active/
(shRNA/siRNA)
Passive
Diagnosis
(MRI/Fluorescence
imaging)
15130 Dual Energy

micro-CT
diagnosis
Gene therapy
(sunitinib) and
Radiotherapy
Photothermal
therapy
256
Drug delivery
(Mitoxantrone)
50135 Drug delivery
(Doxorubicin)
Hyperthermia
Diagnosis
(Thermal-optical
agent)
2250 Photodynamic
therapy and
diagnosis
V2 O5 NPs act as
poisoning material
Hyperthermia
Drug delivery
(Cisplatin)
Optical imaging
MRI
Oleic Acid as
Antitumor
30897 Oridonin as
antitumor
Drug delivery
(Paclitaxel,
Hydroxycamptothecin,
Dihydroartemisinin,
Doxorubicin)
Gene therapy
(AS-ON)
Hyperthermia
3161 Radiotherapy
Diagnosis
(Chlorotexin peptid
/MRI/NIR/NMR)
Drug delivery
(Paclitaxel)
Gene therapy
(9LGFP)
20300 Gene Therapy
(Dz13 DNA)
Drug delivery
(Doxorubicin,
resveratrol)
Hyperthermia
Diagnosis
Passive/
Active
Passive
Biomarkers
Reference
Cell membrane
Glycoprotein
Anti-CD99
Antibodies
EWS-Fli-0
EWS-Fli-1
[19, 23, 7479,

89, 92, 93]
VEGF and
PDGF-R
[86, 9496]
[18, 20, 97]
Active/
Passive
P-Glycoprotein
antibody
[98, 99]
Active/
Passive
Protoporphyrin IX
[21, 22,
100105]
Active/
Passive
Hyaluronic acid
(HA)
EWS-Fli-1
EFT protein
[6, 53,
106115]
Active/
Passive
Transferrin
receptor (ETR)
[11, 116124]
Active/
Passive
C-Jun
ALCAM
[8, 125129]

Table III.
Item
Shahbazi et al.
Continued.
Type of
sarcoma
Cancer
cells
Nanoparticle
Size
(nm)
Therapeutic
approach
Diagnosis (/MRI/
Fluorochrome/
Cholorimetric)
Diagnosis
Kaposis
Sarcoma
KS
Au and Ag NPs
SPIONs
1520
10
Neuroblastoma
Gastric
sarcoma
Neuro2A
AuNPs
144
AGS
Polyethylene
glycol-modified
gelatin
(PEG-GEL) and
polylactic acid
(PLA) NPs
190
11
the first randomized clinical phase III trial performed by

Issels et al.91 applied chemotherapy alone and/or along
with regional hyperthermia on 341 STS patients.
(with tumor size more than 5 cm in diameter), suggesting regional heperthermia increase the benefit of
chemotherapy.
Although, it should be considered that in spite of
fascinating IONPs characteristics regarding therapeutic
approach, their ability to induce cellular toxicity and
nephrotoxicity is concerned as a challenge up till now.
In fact, as a result of their ultrafine size (diameter
< 100 nm), they are readily internalized within cells,
including the vascular endothelium. After internalization
IONPs are able to origin catalytic generation of free radicals through Fenton chemistry and causes oxidative stress.
In other words, IONPs form wide range of reactive oxygen
species, which can cause severe DNA, protein, and lipid
damage leading to cellular dysfunction and death.178 However, it is still blurred what the precise effect on cell viability due to their defence mechanisms which allow them to
deal with certain levels of oxidative stress,179 and several
investigations have been carried out regarding toxicological effect of IONPs.178! 180183
IONPs as a Sarcoma Diagnosis Agent
IONPs have been in the focus of intensive research activities because of their current potential as contrast agents for
MRI as an in vivo noninvasive sarcoma diagnosis method.
MRI as a medical imaging technique is utilized in radiology to imagine internal parts of the body in details. To
improve the appearance of sarcoma as cancer tissues by
MRI, contrast agents can be employed. IONPs as contrast agent of T2 relaxation time (spinspin relaxation time)
significantly enhance MRI quality and sensitivity.184! 185
In fact, IONPs cause high magnetic signal strength,186
relatively low cytotoxicity,187190 longer lasting contrast
enhancement,5! 186! 187! 191! 192 improved delineation of tumor
margins191! 192 and low sensitivity to the number of water
molecules around them.193 On a T2 -weighted scan, waterand fluid-containing tissues are bright and fat-containing
tissues are dark and cancer tissue tends to develop edema
8
Photodynamic
therapy with
CHA2HB
Targeting
method
Biomarkers
Reference
Active
KSHV(vCyclin
RNA)
[130, 131]
Active
Transferrin
Passive
[132]
[133]
(as abnormal collection of fluid in a body cavity) which

makes a T2 -weighted sequence sensitive for pathology.
Khakoo et al.131 labeled human mesenchymal stem cells
(MSCs) with superparamagnetic iron NPs in order to study
the effect of injected MSCs on Kaposis sarcoma growth
via MRI. In 2010 Lemke et al.89 in a phase I clinical trial
tracked the impact of epirubicin as a chemotherapeutic
drug with ferrofluids on different kinds of sarcoma including cystosarcoma, chondrosarcoma and Ewing sarcoma via
MRI.
Combination of MRI with other functional imaging
techniques provides complementary information and thus
offers synergistic advantages over any single imaging
modality alone and leads to save time and decreasing the
number of imaging sessions. In fact, transporting more
than two imaging agents via functionalized IONPs as multimodal imaging probes conquer the limitations of a single
imaging modality.194 Some of these imaging techniques
are CT, PET, SPECT, and optical (or fluorescence) imaging. Medarova et al.122 conjugated Cy5.5 dye as nearinfrared optical imaging contrast agent linking to siRNAs
molecules with IONPs as MRI contrast agent and tracked
gliosarcoma tumor cell uptake of these probes. The combination of the favorable biodistribution of these nanoparticles to tumors and their imaging properties represents
an exciting possibility for the simultaneous delivery and
detection of siRNA-based therapeutic agents in vivo.122
IONPs are concentrated at the sarcomas with the aid
of an external magnetic field applied at the affected zone
(Fig. 2). In fact, IONPs via external magnetic field and
EPR effect penetrate into sarcoma cells, enhance MRI
characteristics and carry and monitor drug and gene delivery. However, as mentioned before toxicological effects of
overloaded IONPs in tissues and elimination of IONPs by
renal system should be considered.18 In order to overcome
these issues and improve therapeutic efficiency, the surface characteristics of IONPs can be also modified and
functionalized by sarcoma cells biomarkers to target sarcoma abnormal tissues. Generally, different types of delivery methods could be categorized in two groups as passive
and active delivery.
Shahbazi et al.
Table IV.
Item
Recent studies on bioapplication of IONPs against common cancers.
Cancer
Cancer
cells
Diagnosis
agent
Size of
IONPs core
range (nm)
Reference
Anti-CD79b
1054
[134, 135]
Drug delivery
Hyperthermia
Cisplatin and
Doxorubicin as an
anti-cancer drug
Mitoxantrone and
Doxorubicin as
anti-cancer drugs
VEGF 121/rGel
protein
Anti-synthetic
peptide antibody
(EGFRvIIIAb) for
the deletion mutant
EGFR
Paclitaxel,
Rapamycin, and
Doxorubicin as
drugs alone or
combination
Antibiotic
Violamycine B1
Luteinizing hormone
releasing hormone
(LHRH)
Doxorubicin,
Daunorubicin, and
Abraxane1 as
anti-cancer drugs
Bombesin (BBN)
1014
[136139]
10110
[121,
140144]
314
[40, 145149]
1025
[150154]
Doxorubicin as an
anti-cancer drugs
Curcumin as an
anti-cancer drugs
810
[10, 155157]
Blood cancer EL4

(lymphoma) C57BL/6-B
Bladder
cancer
UMUC3
MGH-U1
Brain tumor
(Glioma)
9L
RG-2
U87MG
Breast cancer HER-2

MCF-7
SK-BR-3
IONPs for MRI

HER2 antibody
Prostate
cancer
Skin cancer
B16
(Melanoma) SK-MEL-37
B16F10
Me300
Drug delivery
IONPs for MRI
Targeting ligands such
as RGD (prostate
cancer-specific R11
peptides) and folic acid
Endogenous riboflavin
carrier protein RCP
ligand flavin
mononucleotide (FMN)
Targeting
gastric-releasing
peptide receptors
Near-infrared (NIR)
fluorophore Cy5.5
Horseradish peroxidase
enzyme
Drug delivery
IONPs for MRI
Hyperthermia
Anti-S-100 protein
targeting
lanocyte-specific
markers such as
HMB-45 and Melan
GlyArgGlyAspSer
(GRGDS) peptides that
specifically bind to the
#5$3 receptors of
melanoma cells
Therapeutic
agent
Gene therapy
PC3
LNCaP
CT1258
IONPs for MRI

Glutathione
S-Transferase (GST)
fusion protein for
targeting EL4,
Fluorescein
isothiocyanate (FITC)
Propidium iodide
Near infrared (NIR)
fluorescent dyes
(CellVue NIR 815
(NIR815))
IONPs for MRI
Therapeutic
method
Drug delivery
IONPs for MRI
Antiangiogenic
Chlorotoxin (CTX) as
therapy
targeting ligand
RGD peptides targeting
#v$3 endothelial cells
Drug delivery
X-ray
irradiation
Gene therapy

Table IV.
Item
Continued.
Cancer
Cancer
cells
Liver cancer
KB
Hep3B
VX2
SMMC-7721
Lung cancer
Cervical
cancer
A549
LLC cells
H2009
HeLa
10
Colorectal
cancer
LS174T
SW480
SW1222
HT29
HCT 116
SW620
C26
11
Pancreatic
cancer
BxPC-3
Panc-1
Panc-2
Diagnosis
agent
Therapeutic
method
Therapeutic
agent
Size of
IONPs core
range (nm)
Reference
IONPs for MRI

Folic acid for targeting
folate receptor (FR1)
SP5.2/tTF (SP5.2: a
peptide binding to
VEGFR-1; tTF:
truncated tissue factor)
IONPs for MRI
Drug delivery
Doxorubicin as an
anti-cancer drug
510
[158160]
Hyperthermia
Drug delivery
Doxorubicin as an
anti-cancer drug
614
[161165]
IONPs for MRI

MAGCNTSPSS-6diamidino-2phenylindole
(DAPI)
IONPs for MRI
Human serum albumin
near-infrared fluorescen
Anticarcinoembryonic
antigen antibodies
(#CEA)
Peanut agglutinin
Single-chain antibody
conjugates (A33scFv)
that target A33 antigen
Cetuximab as an EGFR
inhibitor
5TR1 aptamer
IONPs for MRI
Antisense
oligodeoxynu-cleotide
of survivin (BIRC5)
gene to active targeting
Antibody epithelial cell
adhesion molecule
Green fluorescent dye
(FITC-IgG)
Urokinase plasminogen
activator receptor
Drug delivery
Folic acid (FA)

targeting Folate
receptors
Methotrexate as
anti-cancer drug
Epirubicin as an
anti-cancer drug
716
[166169]
79
[170173]
412
[174177]
Passive Delivery
Passive delivery methods mostly refer to the EPR effect
on solid tumors,11! 195! 196 and relies on the fact that the
anatomical and physiological irregularities of tumor tissues distinguishing from the healthy tissues of the body.
In the EPR effect because of leaky and damaged vasculature of tumor due to the rapid angiogenesis associated
with tumor growth, NPs can make a way from bloodstream
into tumors more easily rather than healthy tissues.197! 198
Figure 3 demonstrates EPR effect of IONPs on sarcomas.
After penetration into tumor cells, as the weakly developed lymphatic drainage system of most tumors, NPs are
not able to come back to the systemic circulation. To
retention of IONPs inside sarcoma environment leads to
amplify contrast between the sarcoma and the surrounding
healthy tissue which significantly improves diagnosis by
MRI.
10
Shahbazi et al.
Laser-assisted
therapy
Hyperthermia
Drug delivery
Hyperthermia
Krukemeyer et al.18! 20 investigated the EPR effect of

mitoxantrone (as a chemotherapeutic drug) with IONPs
regarding drug delivery to R1 H Rhabdomyosarcoma cell
lines. For comparison they applied mitoxantrone-iron
oxide with and without an extracorporeal magnet and
mitoxantrone without IONPs in normal and tumor tissue.
They observed mitoxantrone-iron oxide concentration was
substantially decreased by removal magnet or administrating mitoxantrone alone. They also histologically studied liver and spleen samples seven days after the trial.
Liver and spleen had detectable iron depositions but no
necrosis seven days after treatment and no allergies or
toxic reactions were observed. In fact, rapid clearance
of IONPs via macrophage phagocytosis in the organs of
the mononuclear phagocyte system such as the liver and
spleen is a challenge. This leads to less absorption of the
conjugated drug at other tumor sites and diminish in the
Shahbazi et al.
Table V. Clinical MRI tracing of change in tumor size after administration of IONPs and drug.89
Types of
sarcoma
Sarcoma
Cystosarcoma
Chondrosarcoma
Ewing sarcoma
Chondrosarcoma
Tumor
location
T2-WI (MRI)
after 210 days
Tumor
size
Right shoulder
Right breast
Right thigh
Left shoulder
Right shoulder
PR
PD
SD
PD
PD
Notes: Moderate signal decrease; Partial response (PR): At least a 30%

decrease of the largest diameter of the tumor; Progressive disease (PD): At
least a 20% increase of the largest diameter of the tumor; Stable disease
(SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD.
contrast-to-noise ratio of the tumor and then a negative

effect on tumor diagnosis. To face these challenges, modification of the IONPs surface with polymer coating such
as hydrophilic stealth polymers (e.g., polyethyleneimine)
could be really helpful to provide a longer circulation
half-life. In fact passive delivery can be achieved by engineering IONPs that is capable of prolonged circulation
times..199
Active Delivery
Active delivery of IONPs are realized by conjugating or
encapsulating with specific targeting ligands that specifically target different kinds of intra or extracellular sarcoma biomarkers or receptors. It considerably helps that
more IONPs accumulate in the cancer cells and provide
much more contrast between the tumor and healthy tissues on an MRI.47 When cancer cell biomarkers or receptors distinguish and bind targeting ligands, the particles
undergo receptor-mediated endocytosis and are engulfed
by the cancer cell. There are several types of receptors,
antibodies, transferrins and peptids which could be conjugated to IONPs in order to tailor specific engineered
therapeutic agent for diverse kinds of sarcomas.
Figure 2. Accumulation of IONPs in targeted zone with an external magnetic field.

Figure 3. EPR effect of IONPs on sarcoma.
One of the most well studied areas in sarcoma treatment

has come from targeting tyrosine kinases. This enzyme
facilitate a wide variety of cellular functions, including
proliferation, migration, and apoptosis. Protein kinase as
an enzyme adds a phosphate group to a protein or other
organic molecule; these phosphorylated groups can turn
a protein on or off. Kinase receptor could be barren by
certain agents to stop cellular survival signaling pathways,
leading to growth arrest or apoptosis.85 Furthermore, the
insulin-like growth factor 1 receptor (IGF 1R) pathway
has been concerned in osteosarcoma,200 Ewing sarcoma,201
and rhabdomyosarcoma.202 Other targets are including the
ERBB family, Met, Src, the MAPK cascade, Raf, c-KIT,
PDGFR, AKT, and signaling pathways including WNT/"catenin, Hedgehog, and Notch. PLK1 and MIRK have
been recognized as potential targets for osteosarcoma. The
PLK1 inhibitor induced apoptosis while MIRK siRNA
inhibited cell growth via inducing apoptosis.85
P-glycoprotein is overexpressed in multidrug-resistant
sarcomas and could be targeted with lentiviral vectors
linked to an anti-P-glycoprotein monoclonal antibody,85! 76
but it is also a fundamental component of various normal tissues such as peripheral blood cells and hematopoietic progenitors found in normal human bone marrow
and the blood brain barrier.94! 100 Consequently, treatmentrelated morbidity, mortality, and increased marrow toxicity
associated with chemotherapeutics and biological agents
that target P-glycoprotein have to be considered carefully. Murthy and Shah7 published a review paper and
discuss strategies for overcoming p-glycoprotein effect.
In fact, p-glycoprotein actively pumps the drug out of cells
and therefore reduces intracellular drug concentration and
diminish therapeutic efficacy. Hung et al.125 applied the
endosomal pH-sensitive mesoporous silica NPs with doxorubicin to improve drug delivery system to human uterine
sarcoma. They perceived their engineered nanocarrier substantially bypassed p-glycoprotein efflux pump and overcame tumor cells drug resistance.125
Although, conjugating antibodies has noticeably developed in recent years, there are still a number of challenges
11
regards to monoclonal antibodies as targeting agents such

as their large hydrodynamic size, being very fragile
molecules.203
Transferrin as iron-binding blood plasma glycoprotein
organizes the level of free iron in biological fluids.204
In fact, it is a vibrant protein involved in iron homeostasis and the regulation of cell growth.205 Human transferrin is encoded by the TF gene.206 The transferrin receptor
(also known as CD71) consists of two identical monomers
joined by disulfide bonds. When a transferrin protein
loaded with iron runs into a transferrin receptor on the
surface of a cell, it binds to receptor and consequently by
receptor-mediated endocytosis is transported into the cell
in a vesicle. The pH of the vesicle is reduced by hydrogen
ion pumps (H+ ATPases) to about 5.5, causing transferrin
to release its iron ions. The receptor is then transported
through the endocytic cycle back to the cell surface, ready
for another round of iron uptake. This process provides
considerable intracellular IONPs accumulation in lysosomes as a favorable environment for ensuring iron stability which decreases early intracellular degradation of
IONPs and thus extending the contrast enhancing effect.13
The whole transferrin internalization cycle takes typically
less than 5 minutes, which yields with a near turnover rate
of 20,000 transferrin molecules per cell per minute. This
leads a larger number of IONPs to be engulfed by the cells,
leading to higher MRI contrast.116 Transferrin receptor is
overexpressed on the surfaces of sarcoma and other cancer
cells such as neuroblastoma and gliosarcoma because of
their increased iron requirements.132! 116! 124! 207 Transferrin
is expressed at low levels in many normal tissues.207! 208
The transferrin receptor can be targeted by direct interaction with conjugates of its ligand transferrin or by monoclonal antibodies specific for the transferrin receptor.205
One of the challenges of utilizing transferrin as conjugating ligand of MRI contrast agent is its high
endogenous plasma concentration under physiological
conditions.209
Chlorotoxin as a 36-amino acid peptide binding preferentially to gliosarcoma cells has been used for active
targeting. In 2009, Veiseh et al.123 created a nanoprobe
containing IONPs coated with biocompatible polyethylene glycol-grafted chitosan copolymer conjugating with
tumor-targeting agent, chlorotoxin, and near-infrared fluorophore. Relying on their observations, they introduced
the nanoprobe as a diagnostic and therapeutic agent for
gliosarcoma which is able to overcome blood brain barriers (BBB).
Radiotherapy (RT) as one of the conventional methods
of sarcoma therapy suffers from tumor resistance and significant risk of local recurrence. An anti-VEGF antibody is
able to conjugate to IONPs and be utilized to target tumor
cells and specify tumor location for RT. Preclinical and
clinical investigations presented that anti-vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors (PDGF-R) antibodies are able to enhance RT
12
Shahbazi et al.
efficiency.86 VEGF over expressed by most of cancer cells

is a key regulator of new blood vessel formation (angiogenesis) that is a fundamental process in tumor growth.210
The VEGF proteins are also expressed in the premalignant stages of tumor providing an opportunity for designing VEGF-targeted approaches for cancer diagnosis and
treatment.211213 VEGF receptors can also be used to target the niche where soft tissue sarcoma grow by sunitinib combined with radiotherapy.86! 214! 215 In other words
soft tissue sarcomas require angiogenesis to grow and survive, for example, PDGFR-alpha expression was sevenfold greater in the STSs than in the normal tissues.216
The inhibitor sunitinib targets receptors including VEGFRs and PDGFRs critical to endothelial cell growth and
tumor angiogenesis and control tumour growth.
Sarcoma Treatment with Drug Delivery
Drugs are released in the tumor region as a dynamically
response of carriers to changes in the environmental conditions such as temperature, light, pH, ultrasound, and magnetic fields. long circulation time, high
levels of bioavailability and specific targeting, intracellular/organelle delivery, reporting/imaging and high
biodegradation are the crucial criteria for powerful
drug delivery systems.45 Doxorubicin,217 paclitaxel,119
mitoxantrone,18 cisplatin,21 hydroxycamptothecin,6 and
dihydroartemisinin110 are the chemotherapeutic drugs
which have been carried by nanomateials in order to treat
several kinds of sarcoma. Additionally, oridonin as a traditional drug,106 V2 O5 ,101 oleic acid104 and resveratrol126 in
nano-scales have been used as antitumor drugs to eliminate
diverse types of sarcoma cancer cells.
Drug delivery to sarcoma cells the same as other
cancers face challenges such as variations in drugs biodistribution, absorption and metabolism, difficulty in drugs
accessibility to cancer cells, increasing tissue hydrostatic
pressure and altering tumor vasculature to protect tumors
by their local microenvironment and finally drugs side
effects. In this case IONPs could be functioned as nanocarries for nanomedicins and deliver them to tumor regions.
Surface modified IONPs by possessing all the characterizations make possibility of administering lower but more
accurately targeted doses of drugs to cancer cells. In fact,
by either external magnetic field or conjugating with targeting ligands they are able to target specific sites of cancer cells in the body and act as promising therapeutic drug
carriers.
Sarcoma Treatment with Gene Therapy
Genetic materials such as small interfered RNA (siRNA)
and DNA are other therapeutic groups enhanced IONPs
as a therapeutic agent. The efficiency of this technique
is called magnetofection or transfection. The technique is
established on the combination of genetic material to magnetic nano particles in order to deliver therapeutic group
to cancer cell region.218
Shahbazi et al.
Sarcomas show two kinds of genetic variations.

One group includes Chromosomal reciprocal translocation resulting in fusion genes and oncogene or tumorsuppressor mutations such as c-kit and p53 and could
be cured by gene therapy methods.85 For example,
ONYX-0115 as a chimeric adenovirus is modified by the
E1B gene and has been used in clinical trials to treat
advanced sarcomas.9! 75 On the other hand, another group
of sarcomas which are specified by considerable genetic
heterogeneity are unfeasible to treat by gene therapy
alone.
In RNA interference (RNAi) as a biological process,
siRNA molecules typically by destruction of specific messenger RNA (mRNA) molecules hinder gene expression in
eukaryotic cells.219 In other words, the strategy is identifying the sequence of the gene responsible for the cancer
and administering a complementary short synthetic double
stranded RNA. This siRNA targets and binds the identified
gene and inhibiting its function. This leads to control of
cancer progression.220
SiRNA has been attractive research area because of its
high specificity, high efficiency, and low toxicity.85 However, siRNAs have poor stability in biological fluids and
low intracellular penetration, which causes reduction in
the biological efficacy.221 Therefore we need suitable carriers to facile formation of a complex with siRNAs and
to help them in stably crossing the cell membrane. The
complex must be released in the cytoplasm from endosomes. After releasing of its siRNA cargo, the carrier
must be nontoxic.222 In order to overcome this challenge,
the surface-modified IONPs carrying functional siRNAs
have represented a desirable option to advance the in vivo
intracellular delivery of these nucleic acid-base therapeutic
agents.223226
Using modified magnetic NPs considerably enhances
transfection efficiency via lowering the diffusion barriers and makes the possibility of site-specific delivery via an external magnetic field. IONPs coated with
cathionic polymers such as polyallylamine hydrocholoride
seem desirable carriers for anionic siRNA. In fact,
polyallylamine hydrocholoride as a cationic polymer is
capable of interacting with anionic siRNA, forming a
reproducible complex which is stable aqueous suspension and has low cell toxicity. For instance, nanodiamonds coated with polyallylamine hydrocholoride utilized
by Alhaddad et al.78 to delivery siRNA to Ewings sarcoma cells. In another investigation Medarova et al.122
combined siRNA (9L-GFP) silencing therapeutic method
with MRI and and near-infrared optical imaging together
via functionalized IONPs and tracked gliosarcoma tumor
cell uptake of these probes. As other nucleotides applied
with nanomaterials in order to perform gene therapy of
diverse sarcoma cancers are shRNA as a recent patent
for Ewings sarcoma,92 and antisense oligonucleotide
(AS-ON).77! 93! 227
Sarcoma Treatment with Hyperthermia

Hyperthermia which leads to cancer cells death by increasing temperature is another way to abolish sarcoma cells.
Tumor tissues have less vasculature endurance rather than
normal tissues. There are some difficulties in hyperthrmal
therapy including uniform heating of only the tumor region
without damaging normal tissue, variation in heating ability because of tumor size,228 the position of the electrodes,
adhesion of the electrodes at uneven sites in radiofrequency thermal therapy, and considerably injury to the
patient in treating large tumors by microwave thermal therapy. These problems could be substantially diminished by
applying nanomaterials to generate local heat in tumor
region or carrying thermal agents towards tumor cells. As
an instance, Tang et al.98 conveyed indocyanine green as
thermal-Optical agents by polymeric nanocarrier to uterine
sarcoma cells to generate heat for hyperthermia.
Magnetic NPs which are able to produce local hyperthermia in tumor regions via an alternative magnetic field
seem promising therapeutic method. Figure 4 shows the
hyperthermia effect of IONPs under fluctuating external
electromagnetic field. For example Babincova et al.22 utilized magnetic NPs hyperthermia (4244 " C was achieved
after 710 minutes of exposure) in vivo and in vitro to
abolish BP-6 rat sarcoma cells. In a recent study magnetic heating effect of Fe3 O4 ferrofluids (48.6 " C57 " C)
were applied in ex vivo condition on sarcoma 180 cells by
Luong et al.112 which caused elimination of 50% of cancer cells after 45 minutes. There are many similar other
Figure 4. Hyperthermia effect of IONPs under fluctuating external

electromagnetic field.
13
researches113115 which have used hyperthermia against

sarcoma 180 cells.
Moreover hyperthermia could be applied along with
drug delivery to increase permeability of nanocrriers of
drugs into sarcoma cells. Issels et al.91 ran a clinical investigation including 341 STS patients and studied the applying chemotherapy (consisting of etoposide, ifosfamide,
and doxorubicin) together with regional hyperthermia or
alone. They found chemotherapy with local hyperthermia enhances local control compared with chemotherapy
alone. In fact, drug delivery based on nanocarriers permeability into tumor vasculature could be limited due to
nanocarries size, compact nature of the interstitial matrix
in tumors and being permeable in only a fraction of the
tumor vessel. In order to overcome these challenges Li
et al.105 in a recent investigation utilized local mild hyperthermia in fibrosarcoma to increase permeability of drug
carried by liposome NPs. In other words, hyperthermia
increased the pore size in tumor vasculature (about 30%),
whilst decreased steric and hydrodynamic hindrances. Li
et al. also applied optimized thermo sensitive liposome
as nanocarrier to enable a triggered drug release upon
mild hyperthermia. Also, Hyperthermia healing effect of
IONPs has been used along with other therapeutic methods in order to treat sarcoma. For example, Brusentsov
et al.229 applied heat generated from different kinds of ferromagnetic fluids and radiotherapy singly or together to
eliminate MX11 sarcoma cells. They observed the elimination of MX11 cells using both ferrofluids hyperthermia
and radiofrequency was much more effective than with
radiofrequency alone.
CONCLUSIONS AND OUTLOOK

In summary, IONPs (alone and engineered) have shown
promising features in application of sarcoma diagnosis
and treatment, such as being an effective magnetic resonance imaging contrast agent, and a versatile vehicle
for genetic materials, small drug molecules, targeting ligands or all of them together, as well as hyperthermia
effect. The IONPs are able to produce local hyperthermia in sarcoma regions via an alternative magnetic field.
Also, using IONPs could be more affordable diagnosis.
Therefore, establishing new modified and functionalized
IONPs to diagnosis and treatment of sarcoma could be still
attractive future investigations. However, to our knowledge
just a few preclinical and clinical investigations regarding applying IONPs against sarcoma have been reported
which presents some major issues that need to be carefully considered. These include, development of novel
surface modified IONPs that are able to carry target agents
against the targets overexpressed by sarcoma cells, as well
as special drugs and genes, and bring about improvement of diagnosis and treatment efficiency. Therefore, it
is highly demanded to crate magnetic nanoparticels with
14
Shahbazi et al.
optimum physiochemical properties, including size, morphology, surface characteristics, amount of administration,
reversibility and strength of binding between therapeutic agent and magnetic NPs as well as most favorable
magnetic field characteristics consist of geometry, strength
and duration. Moreover, understanding mechanism beyond
physical experiments or tests for finding the principles
governing diagnosis, treatment and safety assessment are
also demanding research areas.
REFERENCES
1. Davicioni, E., Anderson, M. J., Finckenstein, F. G., Lynch, J. C.,
Qualman, S. J., Shimada, H., Schofield, D. E., Buckley, J. D.,
Meyer, W. H., Sorensen, P. H . B., and Triche, T. J. (2009). Molecular classification of rhabdomyosarcoma-genotypic and phenotypic
determinants of diagnosis: A report from the childrens oncology
group. Am. J. Pathol. 174, 550564.
2. Heslin, M., Lewis, J., Woodruff, J., and Brennan, M. (1997). Core
needle biopsy for diagnosis of extremity soft tissue sarcoma. Annals
of Surgical Oncology 4, 425431.
3. Thomas, R., Park, I. K., and Jeong, Y. (2013). Magnetic iron oxide
nanoparticles for multimodal imaging and therapy of cancer. Int. J.
Mol. Sci. 14, 1591015930.
4. Misri, R., Meier, D., Yung, A. C., Kozlowski, P., and Hafeli,
U. O. (2012). Development and evaluation of a dual-modality
(MRI/SPECT). molecular imaging bioprobe. Nanomedicine
8, 10071016.
5. Heidt, T., and Nahrendorf, M. (2013). Multimodal iron oxide
nanoparticles for hybrid biomedical imaging. NMR Biomed.
26, 756765.
6. Hou, Z., Han, J., Zhan, C., Zhou, C., Hu, Q., and Zhang, Q.
(2010). Synthesis and evaluation of N-succinyl-chitosan nanoparticles toward local hydroxycamptothecin delivery. Carbohydr. Polym.
81, 765768.
7. Murthy, R. S. R., and Shah, N. M. (2007). Strategies for inhibition
of P-glycoproteins for effective treatment of multidrug resistance
tumors. J. Biomed. Nanotechnol. 3, 117.
8. Tan, M. L., Dunstan, D. E., Friedhuber, A. M., Choong, P. F. M.,
and Dass, C. R. (2010). A nanoparticulate system that enhances the
efficacy of the tumoricide Dz13 when administered proximal to the
lesion site. J. Control. Release 144, 196202.
9. Galanis, E., Okuno, S. H., Nascimento, A. G., Lewis, B. D., Lee,
R. A., Oliveira, A. M., Sloan, J. A., Atherton, P., Edmonson,
J. H., Erlichman, C., Randlev, B., Wang, Q., Freeman, S., and
Rubin, J. (2005). Phase I-II trial of ONYX-015 in combination
with MAP chemotherapy in patients with advanced sarcomas. Gene
Ther. 12, 437445
10. Suzuki, M., Shinkai, M., Honda, H., and Kobayashi, T. (2003).
Anticancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes. Melanoma
Research 13, 129135.
11. Moore, A., Marecos, E., Bogdanov, A., Jr., and Weissleder, R.
(2000). Tumoral distribution of long-circulating dextran-coated iron
oxide nanoparticles in a rodent model. Radiology 214, 568574.
12. Yoo, D., Lee, J. H., Shin, T. H., and Cheon, J. (2011). Theranostic
magnetic nanoparticles. Accounts, Chem. Res. 44, 863874.
13. Rosen, J. E., Chan, L., Shieh, D. B., and Gu, F. X. (2012). Iron
oxide nanoparticles for targeted cancer imaging and diagnostics.
Nanomedicine 8, 275290.
14. Freeman, M. W., Arrott, A., and Watson, J. H. L. (1960). Magnetism in medicine. J. Appl. Phys. 31, 404405.
15. Widder, K. J., Morris, R. M., Poore, G. A., Howard, D. P.,
and Senyei, A. E. (1983). Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin: Total remission
Shahbazi et al.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
in Yoshida sarcoma-bearing rats. Eur. J. Cancer. Clin. Oncol.

19, 135139.
Widder, K. J., Marino, P. A., Morris, R. M., Howard, D. P., Poore,
G. A., and Senyei, A. E. (1983). Selective targeting of magnetic
albumin microspheres to the Yoshida sarcoma: Ultrastructural evaluation of microsphere disposition. European Journal of Cancer and
Clinical Oncology 19, 141147.
Widder, K. J. and Senyei, A. E. (1983). Magnetic microspheres:
A vehicle for selective targeting of drugs. Pharmacology and Therapeutics 20, 377395.
Krukemeyer, M. G., Krenn, V., Jakobs, M., and Wagner, W. (2012).
mitoxantrone-iron oxide biodistribution in blood, tumor, spleen, and
livermagnetic nanoparticles in cancer treatment. J. Surg. Res.
175, 3543.
Jarzyna, P. A., Skajaa, T., Gianella, A., Cormode, D. P., Samber,
D. D., Dickson, S. D., Chen, W., Griffioen, A. W., Fayad, Z. A., and
Mulder, W. J. M. (2009). Iron oxide core oil-in-water emulsions
as a multifunctional nanoparticle platform for tumor targeting and
imaging. Biomaterials 30, 69476954.
Krukemeyer, M. G., Krenn, V., Jakobs, M., and Wagner, W. (2012).
Magnetic drug targeting in a rhabdomyosarcoma rat model using
magnetite-dextran composite nanoparticle-bound mitoxantrone and
0.6 tesla extracorporeal magnetssarcoma treatment in progress.
J. Drug Target. 20, 185193.
Babincova, M., Altanerova, V., Altaner, C., Bergemann, C., and
Babinec, P. (2008). In vitro analysis of cisplatin functionalized magnetic nanoparticles in combined cancer chemotherapy and electromagnetic hyperthermia. IEEE Trans. Nanobioscience 7, 1519.
Ci
cmanec, P., and
Babincov M., Altanerov, V., Altaner, C,
Babinec, P. (2004). In vivo heating of magnetic nanoparticles in
alternating magnetic field. Med. Phys. 31, 22192221.
Lbbe A. S., Bergemann, C., Brock, J., and McClure, D. G. (1999).
Physiological aspects in magnetic drug-targeting. J. Magn. Magn.
Mater. 194, 149155.
Richards, R., and Bnnemann, H., (2005). Nanofabrication Towards
Biomedical Applications, edited by Kumar, C. S. S. R., Hormes
J., and Leuschner, C., Wiley-VCH Verlag GmbH & Co. KGaA.,
Australia, pp.132.
Pislaru-Danescu L. A. M., Telipana, G., and Stoica, V. (2010).
Nanoparticles of ferrofluid Fe3 O4 synthetised by coprecipitation
method used in microactuation process. Optoelectronicns and
Advannced MaterialsRapid Communications 4, 11821186.
Hribernik, S., Sfiligoj-Smole, M., Bele, M., Gyergyek, S.,
Jamnik, J., and Stana-Kleinschek, K. (2012). Synthesis of magnetic
iron oxide particles: Development of an in situ coating procedure
for fibrous materials. Colloids Surf., A 400, 5866.
Meng, H., Zhang, Z., Zhao, F., Qiu, T., and Yang, J. (2013). Orthogonal optimization design for preparation of Fe3 O4 nanoparticles via
chemical coprecipitation. Appl. Surf. Sci. 280, 679685.
Gyergyek, S., Drofenik, M., and Makovec, D. (2012). Oleic-acidcoated CoFe2O4 nanoparticles synthesized by co-precipitation and
hydrothermal synthesis. Mater. Chem. Phys. 133, 515522.
Maity, D., Kale, S. N., Kaul-Ghanekar, R., Xue, J-M., and Ding, J.
(2009). Studies of magnetite nanoparticles synthesized by thermal
decomposition of iron (III). acetylacetonate in tri(ethylene glycol).
J. Magn. Magn. Mater. 321, 30933098.
Angermann, A. and Tpfer, J. (2008). Synthesis of magnetite
nanoparticles by thermal decomposition of ferrous oxalate dihydrate. J. Mater. Sci. 43, 51235130.
Amara, D., Felner, I., Nowik, I., and Margel, S. (2009). Synthesis and characterization of Fe and Fe3 O4 nanoparticles by thermal decomposition of triiron dodecacarbonyl. Colloids Surf., A
339, 106110.
Tu, Z., Zhang, B., Yang, G., Wang, M., Zhao, F., Sheng, D.,
and Wang, J. (2013). Synthesis of poly(ethylene glycol). and
poly(vinyl pyrrolidone). co-coated superparamagnetic iron oxide
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
nanoparticle as a pH-sensitive release drug carrier. Colloids Surf., A

436, 854861.
Sanchez-Dominguez M., Boutonnet, M., and Solans, C. (2009).
A novel approach to metal and metal oxide nanoparticle synthesis:
the oil-in-water microemulsion reaction method. J. Nanopart. Res.
11, 18231829.
Lu, T., Wang, J., Yin, J., Wang, A., Wang, X., and Zhang, T. (2013).
Surfactant effects on the microstructures of Fe3 O4 nanoparticles,
synthesized by microemulsion method. Colloids Surf., A 436, 675
683.
Zhou, Z., Jiang, F., Lee, T-C., and Yue, T. (2013). Two-step preparation of nano-scaled magnetic chitosan particles using Triton X100 reversed-phase water-in-oil microemulsion system. J. Alloys
Compd. 581, 843848.
Singh, M., Ulbrich, P., Prokopec, V., Svoboda, P., Santava, E., and
Stepanek, F. (2013). Effect of hydrophobic coating on the magnetic
anisotropy and radiofrequency heating of #-Fe2 O3 nanoparticles.
J. Magn. Magn. Mater. 339, 106113.
Zhang, B., Tu, Z., Zhao, F., and Wang, J. (2013). Superparamagnetic iron oxide nanoparticles prepared by using an improved
polyol method. Appl. Surf. Sci. 266, 375379.
Xiao, W., Gu, H., Li, D., Chen, D., Deng, X., Jiao, Z., and
Lin, J. (2012). Microwave-assisted synthesis of magnetite nanoparticles for MR blood pool contrast agents. J. Magn. Magn. Mater.
324, 488494.
Tartaj, P., Morales, M. P., Gonzlez-Carreo, T., VeintemillasVerdaguer, S., and Serna, C. J. (2005). Advances in magnetic
nanoparticles for biotechnology applications. J. Magn. Magn.
Mater. 290291, 2834.
Marcu, A., Pop, S., Dumitrache, F., Mocanu, M., Niculite, C. M.,
Gherghiceanu, M., Lungu, C. P., Fleaca, C., Ianchis, R., Barbut, A.,
Grigoriu, C., and Morjan, I. (2013). Magnetic iron oxide nanoparticles as drug delivery system in breast cancer. Appl. Surf. Sci.
281, 6065.
Harra, J., Nikkanen, J. P., Aromaa, M., Suhonen, H., Honkanen,
M., Salminen, T., Heinonen, S., Levnen, E., and Mkel, J. M.
(2013). Gas phase synthesis of encapsulated iron oxidetitanium
dioxide composite nanoparticles by spray pyrolysis. Powder Technol. 243, 4652.
Perrault, S. D., Walkey, C., Jennings, T., Fischer, H. C., and
Chan, W. C. W. (2009). Mediating tumor targeting efficiency of
nanoparticles through design. Nano Lett. 9, 19091915.
Vijayakumar, R., Koltypin, Y., Felner, I., and Gedanken, A. (2000).
Sonochemical synthesis and characterization of pure nanometersized Fe3 O4 particles. Materials Science and Engineering: A
286, 101105.
Dang, F., Enomoto, N., Hojo, J., and Enpuku, K. (2009). Sonochemical synthesis of monodispersed magnetite nanoparticles
by using an ethanolwater mixed solvent. Ultrason. Sonochem.
16, 649654.
Laurent, S. and Mahmoudi, M. (2011). Superparamagnetic iron
oxide nanoparticles: promises for diagnosis and treatment of cancer.
Int. J. Mol. Epidemiol. Genet. 2, 367390.
Wahajuddin and Sumit, A. (2012). Superparamagnetic iron oxide
nanoparticles: Magnetic nanoplatforms as drug carriers. Int. J.
Nanomedicine 7.
Thorek, D. J., Chen, A., Czupryna, J., and Tsourkas, A. (2006).
Superparamagnetic iron oxide nanoparticle probes for molecular
imaging. Ann. Biomed. Eng. 34, 2338.
Gupta, A. K., and Gupta, M. (2005). Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications.
Biomaterials 26, 39954021.
Laurent, S., Forge, D., Port, M., Roch, A., Robic, C.,
Vander Elst, L., and Muller, R. N. (2008). Magnetic iron oxide
nanoparticles: Synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev.
108, 20642110.
15

50. C. Chouly, D. Pouliquen, I. Lucet, Jeune, J. J., and Jallet, P.
(1996). Development of superparamagnetic nanoparticles for MRI:
Effect of particle size, charge and surface nature on biodistribution.
J. Microencapsul. 13, 245255.
51. Garnett, M. C. and Kallinteri, P. (2006). Nanomedicines and
nanotoxicology: Some physiological principles. Occup. Med.
56, 307311.
52. Berry, C. C., Charles, S., Wells, S., Dalby, M. J., and Curtis, A.
S. G. (2004). The influence of transferrin stabilised magnetic
nanoparticles on human dermal fibroblasts in culture. Int. J. Pharm.
269, 211225.
53. Kuhn, S., Hallahan, D., and Giorgio, T. (2006). Characterization
of superparamagnetic nanoparticle interactions with extracellular
matrix in an in vitro System. Ann. Biomed. Eng. 34, 5158.
54. Gupta, A. K. and Wells, S. (2004). Surface-modified superparamagnetic nanoparticles for drug delivery: preparation, characterization,
and cytotoxicity studies. IEEE Trans. Nanobioscience 3, 6673.
55. Neuberger, T., Schpf, B., Hofmann, H., Hofmann, M., and
von Rechenberg, B. (2005). Superparamagnetic nanoparticles for
biomedical applications: Possibilities and limitations of a new drug
delivery system. J. Magn. Magn. Mater. 293, 483496.
56. Brannon-Peppas L., and Blanchette, J. O. (2012). Nanoparticle
and targeted systems for cancer therapy. Adv. Drug Deliver. Rev.
64, 206212.
57. Pedro, T., Mara del Puerto, M., Sabino, V.-V., Teresita, G.-C., and
Carlos, J. S. (2003). The preparation of magnetic nanoparticles for
applications in biomedicine. J. Phys. D: Appl. Phys. 36, R182.
58. Huang, X., Li, L., Liu, T., Hao, N., Liu, H., Chen, D., and Tang, F.
(2011). The shape effect of mesoporous silica nanoparticles on
biodistribution, clearance, and biocompatibility in vivo. ACS Nano.
5, 53905399.
59. Zhang, L., Dou, Y.-H., and Gu, H-C. (2006). Sterically induced
shape control of magnetite nanoparticles. J. Cryst. Growth
296, 221226.
60. Mahmoudi, M., Simchi, A., Milani, A. S., and Stroeve, P. (2009).
Cell toxicity of superparamagnetic iron oxide nanoparticles. J. Colloid Interface Sci. 336, 510518.
61. Ganguly, A., Kundu, R., Ramanujachary, K., Lofland, S., Das, D.,
Vasanthacharya, N. Y., Ahmad, T., and Ganguli, A. (2008). Role of
carboxylate ion and metal oxidation state on the morphology and
magnetic properties of nanostructured metal carboxylates and their
decomposition products. J. Chem. Sci. 120, 521528.
62. Palchoudhury, S., Xu, Y., Rushdi, A., Holler, R. A., and Bao, Y.
(2012). controlled synthesis of iron oxide nanoplates and nanoflowers. Chem. Commun. 48, 1049910501.
63. Greenwood, R., and Kendall, K. (1999). Selection of suitable dispersants for aqueous suspensions of zirconia and titania powders
using acoustophoresis. J. Eur. Ceram. Soc. 19, 479488.
64. Hanaor, D., Michelazzi, M., Leonelli, C., and Sorrell, C. C. (2012).
The effects of carboxylic acids on the aqueous dispersion and electrophoretic deposition of ZrO2 . J. Eur. Ceram. Soc. 32, 235244.
65. Veiseh, O., Gunn, J. W., and Zhang, M. (2010). Design and fabrication of magnetic nanoparticles for targeted drug delivery and
imaging. Adv. Drug Deliver. Rev. 62, 284304.
66. Petri, Fink A., Chastellain, M., Juillerat Jeanneret, L., Ferrari, A.,
and Hofmann, H. (2005). Development of functionalized superparamagnetic iron oxide nanoparticles for interaction with human
cancer cells. Biomaterials 26, 26852694.
67. Li, Z., Wei, L., Gao, M. Y., and Lei, H. (2005). One-pot reaction
to synthesize biocompatible magnetite nanoparticles. Adv. Mater.
17, 10011005.
68. Sun, C., Du, K., Fang, C., Bhattarai, N., Veiseh, O., Kievit, F.,
Stephen, Z., Lee, D., Ellenbogen, R. G., Ratner, B., and Zhang,
M. (2010). PEG-Mediated synthesis of highly dispersive multifunctional superparamagnetic nanoparticles: Their physicochemical
properties and function in vivo. ACS Nano 4, 24022410.
16
Shahbazi et al.
69. Lunov, O., Syrovets, T., Bchele, B., Jiang, X., Rcker, C.,
Tron, K., Nienhaus, G. U., Walther, P., Mailnder, V., Landfester,
K., and Simmet, T. (2010). The effect of carboxydextran-coated
superparamagnetic iron oxide nanoparticles on c-Jun N -terminal
kinase-mediated apoptosis in human macrophages. Biomaterials
31, 50635071.
70. Mouaziz, H., Veyret, R., Theretz, A., Ginot, F., and Elaissari, A.
(2009). Aminodextran containing magnetite nanoparticles for
molecular biology applications: preparation and evaluation.
J. Biomed. Nanotechnol. 5, 172181.
71. Mahmoudi, M., Simchi, A., and Imani, M. (2010). Recent advances
in surface engineering of superparamagnetic iron oxide nanoparticles for biomedical applications. J. Iran. Chem. Soc. 7, S1S27.
72. Kim, D. K., Mikhaylova, M., Wang, F. H., Kehr, J., Bjelke, B.,
Zhang, Y., Tsakalakos, T., and Muhammed, M. (2003). Starchcoated superparamagnetic nanoparticles as MR contrast agents.
Chem. Mater. 15, 43434351.
73. Huang, H.-Y., Shieh, Y.-T., Shih, C.-M., and Twu, Y.-K. (2010).
Magnetic chitosan/iron (II., III). oxide nanoparticles prepared by
spray-drying. Carbohydr. Polym. 81, 906910.
74. Chen, W., Jarzyna, P. A., van Tilborg, G. A. F., Nguyen, V. A.,
Cormode, D. P., Klink, A., Griffioen, A. W., Randolph, G. J., Fisher,
E. A., Mulder, W. J. M., and Fayad, Z. A. (2010). RGD peptide
functionalized and reconstituted high-density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe. FASEB J. 24, 16891699.
75. Toub, N., Bertrand, J-R., Tamaddon, A., Elhamess, H., Hillaireau,
H., Maksimenko, A., Maccario, J., Malvy, C., Fattal, E., and
Couvreur, P. (2006). efficacy of siRNA nanocapsules targeted
against the EWSFli1 oncogene in Ewing Sarcoma. Pharm. Res.
23, 892900.
76. Ramon, A. L., Bertrand, J. R., de Martimprey, H., Bernard, G.,
Ponchel, G., Malvy, C., and Vauthier, C. (2013). siRNA associated
with immunonanoparticles directed against cd99 antigen improves
gene expression inhibition in vivo in Ewings sarcoma. J. Mol.
Recognit. 26, 318329.
77. Lambert, G., Bertrand, J. R., Fattal, E., Subra, F., Pinto Alphandary,
H., Malvy, C., Auclair, C., and Couvreur, P. (2000). EWS Fli-1
Antisense nanocapsules inhibits ewing sarcoma-related tumor in
mice. Biochem. Cell. Biol. 279, 401406.
78. Alhaddad, A., Adam, M-P., Botsoa, J., Dantelle, G., Perruchas, S.,
Gacoin, T., Mansuy, C., Lavielle, S., Malvy, C., Treussart, F., and
Bertrand, J.-R. (2011). Nanodiamond as a vector for siRNA delivery to ewing sarcoma cells. Small 7, 30873095.
79. Hu-Lieskovan S., Heidel, J. D., Bartlett, D. W., Davis, M. E., and
Triche, T. J. (2005). Sequence-specific knockdown of EWS-FLI1 by
targeted, nonviral delivery of small interfering RNA inhibits tumor
growth in a murine model of metastatic ewings sarcoma. Cancer
Res. 65, 89848992.
80. Muthiah, M., Park, I. K., and Cho, C. S. (2013). Surface modification of iron oxide nanoparticles by biocompatible polymers for
tissue imaging and targeting. Biotechnol Adv.
81. Yang, J. C. (2009). Surgical Pitfalls, edited by S. R. T. Evans, W. B.
Saunders, Philadelphia 489496.
82. Sadoski, C., Suit, H. D., Rosenberg, A., Mankin, H., and Efird, J.
(1993). Preoperative radiation, surgical margins, and local control
of extremity sarcomas of soft tissues. Journal of Surgical Oncology
52, 223230.
83. Giudice, C., Stefanello, D., Sala, M., Cantatore, M., Russo, F.,
Romussi, S., Travetti, O., Giancamillo, M. D., and Grieco, V.
(2010). Feline injection-site sarcoma: Recurrence, tumour grading
and surgical margin status evaluated using the three-dimensional
histological technique. The Veterinary Journal 186, 8488.
84. Smith, V. A., Overton, L. J., and Lentsch, E. J. (2012). Head
and neck soft tissue sarcomas: Unique lack of significance
of synchronous node metastases. Journal of Surgical Oncology
106, 837843.
Shahbazi et al.
85. Susa, M., Milane, L., Amiji, M., Hornicek, F., and Duan, Z. (2011).
Nanoparticles: A promising modality in the treatment of sarcomas.
Pharm. Res. 28, 260272.
86. Yoon, S. S., Stangenberg, L., Lee, Y-J., Rothrock, C., Dreyfuss,
J. M., Baek, K-H., Waterman, P. R., Nielsen, G. P., Weissleder,
R., Mahmood, U., Park, P. J., Jacks, T., Dodd, R. D., Fisher,
C. J., Ryeom, S., and Kirsch, D. G. (2009). Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of
soft-tissue sarcoma. International Journal of Radiation Oncology*Biology*Physics 74, 12071216.
87. Lbbe A. S., Bergemann, C., Riess, H., Schriever, F., Reichardt,
P., Possinger, K., Matthias, M., Drken, B., Herrmann, F., Grtler,
R., Hohenberger, P., Haas, N., Sohr, R., Sander, B., Lemke, A.-J.,
Ohlendorf, D., Huhnt, W., and Huhn, D. (1996). Clinical experiences with magnetic drug targeting: A phase I study with 4 epidoxorubicin in 14 patients, with advanced solid tumors. Cancer
Res. 56, 46864693.
88. Lbbe A. S., Bergemann, C., Huhnt, W., Fricke, T., Riess, H.,
Brock, J. W., and Huhn, D. (1996). Preclinical experiences with
magnetic drug targeting: tolerance and efficacy. Cancer Res.
56, 46944701.
89. Lemke, A. J., Senfft von Pilsach, M. I., Lbbe, A., Bergemann, C.,
Riess, H., and Felix, R. (2004). MRI after magnetic drug targeting in patients with advanced solid malignant tumors. Eur. Radiol.
14, 19491955.
90. Wust, P., Gneveckow, U., Wust, P., Gneveckow, U., Johannsen,
M., Bhmer, D., Henkel, T., Kahmann, F., Sehouli, J., Felix, R.,
Ricke, J., and Jordan, A. (2006). Magnetic nanoparticles for interstitial thermotherapyfeasibility, tolerance and achieved temperatures. Int. J. Hyperthermia 22, 673685.
91. Issels, R. D., Lindner, L. H., Verweij, J., Wust, P., Reichardt,
P., Schem, B.-C., Abdel-Rahman, S., Daugaard, S., Salat, C.,
Wendtner, C.-M., Vujaskovic, Z., Wessalowski, R., Jauch, K.-W.,
Drr, H. R., Ploner, F., Baur-Melnyk, A., Mansmann, U., Hiddemann, W., Blay, J.-Y., and Hohenberger, P. (2010). Neo-adjuvant
chemotherapy alone or with regional hyperthermia for localised
high-risk soft-tissue sarcoma: A randomised phase3 multicentre
study. Lancet Oncol. 11, 561570.
92. Nemunaitis, J. J., Rao, D., and Senzer, N., (2013). Ewings sarcoma
bifunctional shRNA design.
93. Maksimenko, A., Malvy, C., Lambert, G., Bertrand, J.-R., Fattal,
E., Maccario, J., and Couvreur, P. (2003). Oligonucleotides targeted
against a junction oncogene are made efficient by nanotechnologies.
Pharm. Res. 20, 15651567.
94. Darin, P. C., Ketan, G., Everett, J. M., David, G. K., and Cristian,
T. B. (2013). In vivo characterization of tumor vasculature using
iodine and gold nanoparticles and dual energy micro-CT. Phys.
Med. Biol. 58, 1683.
95. Moding, E. J., Clark, D. P., Qi, Y., Li, Y., Ma, Y., Ghaghada, K.,
Johnson, G. A., Kirsch, D. G., and Badea, C. T. (2013). Dualenergy micro-computed tomography imaging of radiation-induced
vascular changes in primary mouse sarcomas. International Journal
of Radiation Oncology*Biology*Physics 85, 13531359.
96. Lin, K. Y., Bagley, A. F., Zhang, A. Y., Karl, D. L., Yoon, S. S.,
and Bhatia, S. N. (2010). Gold nanorod photothermal therapy in a
genetically engineered mouse model of saft tissue sarcoma. Nano
Life 01, 277287.
97. Krukemeyer, M. G. and Wagner, W. (2013). Nanomedicine in cancer treatment. J. Nanomed. Nanotechnol. 4, 21577439.
98. Tang, Y., Lei, T., Manchanda, R., Nagesetti, A., FernandezFernandez, A., Srinivasan, S., and McGoron, A. (2010). Simultaneous Delivery of Chemotherapeutic and Thermal-Optical Agents
to Cancer Cells by a Polymeric (PLGA). Nanocarrier: An in vitro
study. Pharm Res 27, 22422253.

99. Manchanda, R., Fernandez-Fernandez, A., Carvajal, D. A., Lei, T.,
Tang, Y., and McGoron, A. J. (2012). Nanoplexes for cell imaging and hyperthermia: In vitro studies. J. Biomed. Nanotechnol.
8, 686694.
100. Khaing, Oo M. K., Yang, X., Du, H., and Wang, H. (2008).
5aminolevulinic acid-conjugated gold nanoparticles for photodynamic therapy of cancer. Nanomedicine 3, 777786.
101. Ivankovic, S., Music, S., Gotic, M., and Ljubesic, N. (2006). Cytotoxicity of nanosize V2O5 particles to selected fibroblast and tumor
cells. Toxicol. In Vitro 20, 286294.
102. Kale, S. N., Arora, S., Bhayani, K. R., Paknikar, K. M., Jani,
M., Wagh, U. V., Kulkarni, S. D., and Ogale, S. B. (2006).
Cerium doping and stoichiometry control for biomedical use of
La0$7 Sr0$3 MnO3 nanoparticles: Microwave absorption and cytotoxicity study. Nanomedicine 2, 217221.
103. Naeini, A. T., Adeli, M., and Vossoughi, M. (2010). Poly(citric
acid).-block-poly(ethylene glycol). copolymersnew biocompatible hybrid materials for nanomedicine. Nanomedicine 6, 556562.
104. Zablotskaya, A., Segal, I., Lukevics, E., Maiorov, M., Zablotsky,
D., Blums, E., Shestakova, I., and Domracheva, I. (2009). Watersoluble magnetic nanoparticles with biologically active stabilizers.
J. Magn. Magn. Mater. 321, 14281432.
105. Li, L., ten Hagen, T. L. M., Bolkestein, M., Gasselhuber, A., Yatvin,
J., van Rhoon, G. C., Eggermont, A. M. M., Haemmerich, D., and
Koning, G. A. (2013). Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia. J. Control. Release
167, 130137.
106. Lou, H., Zhang, X., Gao, L., Feng, F., Wang, J., Wei, X., Yu, Z.,
Zhang, D., and Zhang, Q. (2009). In vitro and in vivo antitumor
activity of oridonin nanosuspension. Int. J. Pharm. 379, 181186.
107. He, M., Zhao, Z., Yin, L., Tang, C., and Yin, C. (2009). Hyaluronic
acid coated poly(butyl cyanoacrylate). Nanoparticles as anticancer
drug carriers. Int. J. Pharm. 373, 165173.
108. Qi, L., and Xu, Z. (2006). In vivo antitumor activity of chitosan
nanoparticles. Bioorg. Med. Chem. Lett. 16, 42434245.
109. Elhamess, H., Bertrand, J. R., Maccario, J., Maksimenko, A., and
Malvy, C. (2009). Antitumor vectorized oligonucleotides in a model
of ewing sarcoma: Unexpected role of nanoparticles. Oligonucleotides 19, 255264.
110. Zhang, X., Qiao, H., Zhao, P., Ni, J., and Shi, Y. (2013). Antitumor
activity and biodistribution of DHA-NLC formulation in sarcoma
180bearing mice. J. Chinese Pharm. Sci. 22, 348354.
111. Rogers, W. J., and Basu, P. (2005). Factors regulating macrophage
endocytosis of nanoparticles: implications for targeted magnetic
resonance plaque imaging. Atherosclerosis 178, 6773.
112. Luong, T. T., Ha, T. P., Tran, L. D., Do, M. H., Mai, T. T.,
Pham, N. H., Phan, H. B. T., Pham, G. H. T., Hoang, N. M. T.,
Nguyen, Q. T., and Nguyen, P. X. (2011). Design of carboxylated Fe3 O4 /poly(styrene-co-acrylic acid). ferrofluids with highly
efficient magnetic heating effect. Colloids Surf., A 384, 2330.
113. Xuan, Phuc N., Dai Lam, T., Phuong Thu, H., Hong Nam, P., Thu
Trang, M., Hoai Linh, P., Van Hong, L., Hung Manh, D., Thi Bich
Hoa, P., Thi Ha Giang, P., Dac Tu, N., Thi My Nhung, H., Khanh,
L., and Thi Quy, N. (2012). Iron oxide-based conjugates for cancer
theragnostics. Adv. Nat. Sci.: Nanosci. Nanotechnol. 3, 033001.
114. Pham, Hoai L., Nguyen Chi, T., Nguyen Anh, T., Pham Van, T.,
Tran Cong, Y., Nguyen Thi, Q., Hoang Thi My, N., Phi Thi, X.,
Nguyen Xuan, P., and Le Van, H. (2009). In vitro toxicity test and
searching the possibility of cancer cell line extermination by magnetic heating with using Fe3 O4 magnetic fluid. J. Phys.: Conference
Series 187, 012008.
115. Linh, P. H., Manh, D. H., Lam, T. D., Hong, L. V., Phuc, N.,
Tuan, N., Ngoc, N., and Tuan, V. (2011). Magnetic nanoparticles:
study of magnetic heating and adsorption and #47; desorption for
biomedical and environmental applications. International Journal
of Nanotechnology 8, 399413.
17

116. Hogemann-Savellano D., Bos, E., Blondet, C., Sato, F., Abe, T.,
Josephson, L., Weissleder, R., Gaudet, J., Sgroi, D., Peters, P. J.,
and Basilion, J. P. (2003). The transferrin receptor: A potential molecular imaging marker for human cancer. Neoplasia
5, 495506.
117. Rima, W., Sancey, L., Aloy, M-T., Armandy, E., Alcantara, G. B.,
Epicier, T., Malchre, A., Joly-Pottuz, L., Mowat, P., Lux, F., Tillement, O., Burdin, B., Rivoire, A., Boul, C., Anselme-Bertrand,
I., Pourchez, J., Cottier, M., Roux, S., Rodriguez-Lafrasse, C.,
and Perriat, P. (2013). Internalization pathways into cancer cells
of gadolinium-based radiosensitizing nanoparticles. Biomaterials
34, 181195.
118. Brigger, I., Morizet, J., Aubert, G., Chacun, H., Terrier-Lacombe,
M-J., Couvreur, P., and Vassal, G. (2002). Poly(ethylene glycol).coated hexadecylcyanoacrylate nanospheres display a combined
effect for brain tumor targeting. J. Pharm. Exp. Ther. 303, 928936.
119. Vinchon-Petit S., Jarnet, D., Paillard, A., Benoit, J.-P., Garcion, E.,
and Menei, P. (2010). In vivo evaluation of intracellular drugnanocarriers infused into intracranial tumours by convectionenhanced delivery: distribution and radiosensitisation efficacy.
J. Neurooncol. 97, 195205.
120. Kircher, M. F., Mahmood, U., King, R. S., Weissleder, R., and
Josephson, L. (2003). A multimodal nanoparticle for preoperative
magnetic resonance imaging and intraoperative optical brain tumor
delineation. Cancer Res. 63, 81228125.
121. Sun, C., Veiseh, O., Gunn, J., Fang, C., Hansen, S., Lee, D., Sze, R.,
Ellenbogen, R. G., Olson, J., and Zhang, M. (2008). In vivo MRI
detection of gliomas by chlorotoxin-conjugated superparamagnetic
nanoprobes. Small 4, 372379.
122. Medarova, Z., Pham, W., Farrar, C., Petkova, V., and Moore, A.
(2007). In vivo imaging of siRNA delivery and silencing in tumors.
Nature Medicine 13, 372377.
123. Veiseh, O., Sun, C., Fang, C., Bhattarai, N., Gunn, J., Kievit, F.,
Du, K., Pullar, B., Lee, D., Ellenbogen, R. G., Olson, J., and
Zhang, M. (2009). Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain
barrier. Cancer Res. 69, 62006207.
124. Moore, A., Basilion, J. P., Chiocca, E. A., and Weissleder, R.
(1998). Measuring transferrin receptor gene expression by NMR
imaging. Biochimica et Biophysica Acta (BBA)Molecular Cell
Research 1402, 239249.
125. Huang, I. P., Sun, S. P., Cheng, S. H., Lee, C. H., Wu, C. Y., Yang,
C. S., Lo, L. W., and Lai, Y. K. (2011). Enhanced chemotherapy of
cancer using pH-sensitive mesoporous silica nanoparticles to antagonize P-glycoproteinmediated drug resistance. Mol. Cancer Ther.
10, 761769.
126. Lee, M.-H., Thomas, J. L., Wang, H.-Y., Chang, C.-C., Lin,
C.-C., and Lin, H.-Y. (2012). Extraction of resveratrol from polygonum cuspidatum with magnetic orcinol-imprinted poly(ethyleneco-vinyl alcohol). composite particles and their in vitro suppression
of human osteogenic sarcoma (HOS). cell line. J. Mater. Chem.
22, 2464424651.
127. Ghahramani, F. H., Sazgarnia, A., Bahreini-Toosi, M. H.,
Rajabi, O., and Aledavood, A. (2011). Efficacy of microwave
hyperthermia and chemotherapy in the presence of gold nanoparticles: An in vitro study on osteosarcoma. Int. J. Hyperthermia
27, 625636.
128. Federman, N., Chan, J., Nagy, J. O., Landaw, E. M., McCabe, K.,
Wu, A. M., Triche, T., Kang, H., Liu, B., Marks, J. D., and Denny,
C. T. (2012). Enhanced growth inhibition of osteosarcoma by cytotoxic polymerized liposomal nanoparticles targeting the alcam cell
surface receptor. Sarcoma 2012, 126906.
129. Kubo, T., Sugita, T., Shimose, S., Nitta, Y., Ikuta, Y., and
Murakami, T. (2000). Targeted delivery of anticancer drugs with
intravenously administered magnetic liposomes in osteosarcomabearing hamsters. Int. J. Oncol. 17, 309315.
18
Shahbazi et al.
130. Mancuso, M., Jiang, L., Cesarman, E., and Erickson, D. (2013).
Multiplexed colorimetric detection of Kaposis sarcoma associated
herpesvirus and Bartonella DNA using gold and silver nanoparticles. Nanoscale 5, 16781686.
131. Khakoo, A. Y., Pati, S., Anderson, S. A., Reid, W., Elshal, M. F.,
Rovira, I. I., Nguyen, A. T., Malide, D., Combs, C. A., Hall, G.,
Zhang, J., Raffeld, M., Rogers, T. B., Stetler-Stevenson, W., Frank,
J. A., Reitz, M., and Finkel, T. (2006). Human mesenchymal stem
cells exert potent antitumorigenic effects in a model of Kaposis
sarcoma. J. Exp. Med. 203, 12351247.
132. Choi, C. H. J., Alabi, C. A., Webster, P., and Davis, M. E.
(2010). Mechanism of active targeting in solid tumors with
transferrin-containing gold nanoparticles. Proc. Natl. Acad. Sci.
USA 107, 12351240.
133. Babu, A., Periasamy, J., Gunasekaran, A., Kumaresan, G.,
Naicker, S., Gunasekaran, P., and Murugesan, R. (2013). Polyethylene glycol-modified gelatin/polylactic acid nanoparticles for
enhanced photodynamic efficacy of a hypocrellin derivative in vitro.
J. Biomed. Nanotechnol. 9, 177192.
134. Zhao, M., Beauregard, D. A., Loizou, L., Davletov, B., and Brindle,
K. M. (2001). Non-invasive detection of apoptosis using magnetic
resonance imaging and a targeted contrast agent. Nature Medicine
7, 1241244.
135. Thorek, D. L. J., Tsao, P. Y., Arora, V., Zhou, L., Eisenberg, R. A.,
and Tsourkas, A. (2010). In vivo, multimodal imaging of B cell
distribution and response to antibody immunotherapy in mice. PLoS
One 5, e10655.
136. Huang, C., Neoh, K. G., Xu, L., Kang, E. T., and Chiong, E. (2012).
Polymeric nanoparticles with encapsulated superparamagnetic iron
oxide and conjugated cisplatin for potential bladder cancer therapy.
Biomacromolecules 13, 25132520.
137. Hua, M. Y., Yang, H. W., Liu, H. L., Tsai, R. Y., Pang, S. T.,
Chuang, K. L., Chang, Y. S., Hwang, T. L., Chang, Y. H.,
Chuang, H. C., and Chuang, C. K. (2011). Superhigh-magnetization
nanocarrier as a doxorubicin delivery platform for magnetic targeting therapy. Biomaterials 32, 89999010.
138. Deserno, W. ML. L. G., Harisinghani, M. G., Taupitz, M., Jager,
G. J., Witjes, J. A., Mulders, P. F., Hulsbergen van de Kaa, C. A.,
Kaufmann, D., and Barentsz, J. O. (2004). Urinary Bladder Cancer:
Preoperative Nodal Staging with Ferumoxtran-10enhanced MR
Imaging1. Radiology 233, 449456.
139. Kaufman, D. S., Shipley, W. U., and Feldman, A. S. (2009). Bladder cancer. The Lancet 374, 239249.
140. Cole, A. J., David, A. E., Wang, J., Galbn, C. J., Hill, H. L.,
and Yang, V. C. (2011). Polyethylene glycol modified, cross-linked
starch-coated iron oxide nanoparticles for enhanced magnetic tumor
targeting. Biomaterials 32, 21832193.
141. Zhang, F., Huang, X., Zhu, L., Guo, N., Niu, G., Swierczewska,
M., Lee, S., Xu, H., Wang, A. Y., Mohamedali, K. A., Rosenblum,
M. G., Lu, G., and Chen, X. (2012). Noninvasive monitoring of
orthotopic glioblastoma therapy response using RGD-conjugated
iron oxide nanoparticles. Biomaterials 33, 54145422.
142. Chertok, B., Moffat, B. A., David, A. E., Yu, F., Bergemann, C.,
Ross, B. D., and Yang, V. C. (2008). Iron oxide nanoparticles as
a drug delivery vehicle for MRI monitored magnetic targeting of
brain tumors. Biomaterials 29, 487496.
143. Chertok, B., David, A. E., and Yang, V. C. (2010).
Polyethyleneimine-modified iron oxide nanoparticles for brain
tumor drug delivery using magnetic targeting and intra-carotid
administration. Biomaterials 31, 63176324.
144. Hadjipanayis, C. G., Machaidze, R., Kaluzova, M., Wang, L.,
Schuette, A. J., Chen, H., Wu, X., and Mao, H. (2010). EGFRvIII
antibodyconjugated iron oxide nanoparticles for magnetic resonance imagingguided convection-enhanced delivery and targeted
therapy of glioblastoma. Cancer Res. 70, 63036312.
145. Klein, S., Sommer, A., Distel, L. V. R., Neuhuber, W., and
Kryschi, C. (2012). Superparamagnetic iron oxide nanoparticles
Shahbazi et al.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
as radiosensitizer via enhanced reactive oxygen species formation.

Biochem. Cell. Biol. 425, 393397.
Dilnawaz, F., Singh, A., Mohanty, C., and Sahoo, S. K. (2010).
Dual drug loaded superparamagnetic iron oxide nanoparticles for
targeted cancer therapy. Biomaterials 31, 36943706.
Yang, H. M., Park, C. W., Woo, M. A., Kim, M. I., Jo, Y. M.,
Park, H. G., and Kim, J. D. (2010). HER2/neu antibody conjugated
poly(amino acid).-coated iron oxide nanoparticles for breast cancer
MR imaging. Biomacromolecules 11, 28662872.
Yang, J., Lee, C. H., Ko, H. J., Suh, J.-S., Yoon, H. G., Lee,
K., Huh, Y. M., and Haam, S. (2007). Multifunctional magnetopolymeric nanohybrids for targeted detection and synergistic therapeutic effects on breast cancer. Angew. Chem. Int. Ed. Engl.
46, 88368839.
Su, H., Liu, Y., Wang, D., Wu, C., Xia, C., Gong, Q., Song, B.,
and Ai, H. (2013). Amphiphilic starlike dextran wrapped superparamagnetic iron oxide nanoparticle clsuters as effective magnetic
resonance imaging probes. Biomaterials 34, 11931203.
Wadajkar, A. S., Menon, J. U., Tsai, Y. S., Gore, C., Dobin, T.,
Gandee, L., Kangasniemi, K., Takahashi, M., Manandhar, B., Ahn,
J. M., Hsieh, J.-T., and Nguyen, K. T. (2013). Prostate cancerspecific thermo-responsive polymer-coated iron oxide nanoparticles. Biomaterials 34, 36183625.
Jayapaul, J., Hodenius, M., Arns, S., Lederle, W., Lammers, T.,
Comba, P., Kiessling, F., and Gaetjens, J. (2011). FMN-coated fluorescent iron oxide nanoparticles for RCP-mediated targeting and
labeling of metabolically active cancer and endothelial cells. Biomaterials 32, 58635871.
Lee, C. M., Jeong, H. J., Cheong, S. J., Kim, Ei, Kim, D.,
Lim, S., and Sohn, M. H. (2010). Prostate cancer-targeted imaging using magnetofluorescent polymeric nanoparticles functionalized with bombesin. Pharm. Res. 27, 712721.
Li, H., Wei, Q., Wang, G., Yang, M., Qu, F., and Qian, Z. (2011).
Sensitive electrochemical immunosensor for cancer biomarker with
signal enhancement based on nitrodopamine-functionalized iron
oxide nanoparticles. Biosens. Bioelectron. 26, 30443049.
Sterenczak, K. A., Meier, M., Glage, S., Meyer, M.,
Willenbrock, S., Wefstaedt, P., Dorsch, M., Bullerdiek, J., Murua
Escobar, H., Hedrich, H., and Nolte, I. (2012). Longitudinal MRI
contrast enhanced monitoring of early tumour development with
manganese chloride (MnCl2) and superparamagnetic iron oxide
nanoparticles (SPIOs) in a CT1258 based in vivo model of prostate
cancer. BMC Cancer 12, 284.
De, Souza F. F., Dos Santos, M. C., Dos Passos, D. C. S., De
Oliveira Lima, E. C., and Guillo, L. A. (2011). Curcumin associated magnetite nanoparticles inhibit in vitro melanoma cell growth.
J. Nanosci. Nanotechnol. 11, 76037610.
Wadajkar, A. S., Bhavsar, Z., Ko, C. Y., Koppolu, B., Cui,
W., Tang, L., and Nguyen, K. T. (2012). Multifunctional particles for melanoma-targeted drug delivery. Acta Biomaterialia
8, 29963004.
Cengelli, F., Voinesco, F., and Juillerat-Jeanneret, L. (2010). Interaction of cationic ultrasmall superparamagnetic iron oxide nanoparticles with human melanoma cells. Nanomedicine 5, 10751087.
Maeng, J. H., Lee, D. H., Jung, K. H., Bae, Y. H., Park, I. S., Jeong,
S., Jeon, Y. S., Shim, C. K., Kim, W., Kim, J., Lee, J., Lee, Y. M.,
Kim, J. H., Kim, W. H., and Hong, S. S. (2010). Multifunctional
doxorubicin loaded superparamagnetic iron oxide nanoparticles for
chemotherapy and magnetic resonance imaging in liver cancer. Biomaterials 31, 49955006.
Ma, H. L., Xu, Y. F., Qi, X. R., Maitani, Y., and Nagai, T. (2008).
Superparamagnetic iron oxide nanoparticles stabilized by alginate:
Pharmacokinetics, tissue distribution, and applications in detecting
liver cancers. Int. J. Pharm. 354, 217226.
Chen, X., Lv, H., Ye, M., Wang, S., Ni, E., Zeng, F., Cao, C.,
Luo, F., and Yan, J. (2012). Novel superparamagnetic iron oxide
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
nanoparticles for tumor embolization application: Preparation, characterization and double targeting. Int. J. Pharm. 426, 248255.
Schweiger, C., Pietzonka, C., Heverhagen, J., and Kissel, T. (2011).
Novel magnetic iron oxide nanoparticles coated with poly(ethylene
imine)-g-poly(ethylene glycol) for potential biomedical application:
Synthesis, stability, cytotoxicity and MR imaging. Int. J. Pharm.
408, 130137.
Sadhukha, T., Wiedmann, T. S., and Panyam, J. (2013). Inhalable
magnetic nanoparticles for targeted hyperthermia in lung cancer
therapy. Biomaterials 34, 51635171.
Yu, M. K., Jeong, Y. Y., Park, J., Park, S., Kim, J. W., Min,
J. J., Kim, K., and Jon, S. (2008). Drug-loaded superparamagnetic
iron oxide nanoparticles for combined cancer imaging and therapy
in vivo. Angew. Chem. Int. Ed. Engl. 47, 53625365.
Huang, G., Zhang, C., Li, S., Khemtong, C., Yang, S. G., Tian, R.,
Minna, J. D., Brown, K. C., and Gao, J. (2009). A novel strategy for
surface modification of superparamagnetic iron oxide nanoparticles
for lung cancer imaging. J. Mater. Chem. 19, 63676372.
Choi, H., Choi, S. R., Zhou, R., Kung, H. F., and Chen, I. W.
(2004). Iron oxide nanoparticles as magnetic resonance contrast
agent for tumor imaging via folate receptor-targeted delivery1.
Acad. Radiol. 11, 9961004.
Yin, M., Wang, M., Miao, F., Ji, Y., Tian, Z., Shen, H., and Jia, N.
(2012). Water-dispersible multiwalled carbon nanotube/iron oxide
hybrids as contrast agents for cellular magnetic resonance imaging.
Carbon 50, 21622170.
Bhattacharya, D., Sahu, S., Banerjee, I., Das, M., Mishra, D.,
Maiti, T., and Pramanik, P. (2011). Synthesis, characterization, and
in vitro biological evaluation of highly stable diversely functionalized superparamagnetic iron oxide nanoparticles. J. Nanopart. Res.
13, 41734188.
Kohler, N., Sun, C., Wang, J., and Zhang, M. (2005). Methotrexatemodified superparamagnetic nanoparticles and their intracellular
uptake into human cancer cells. Langmuir 21, 88588864.
Giri, S., Trewyn, B. G., Stellmaker, M. P., and Lin, V. S. Y.
(2005). Stimuli-responsive controlled-release delivery system based
on mesoporous silica nanorods capped with magnetic nanoparticles.
Angew. Chem. Int. Ed. Engl. 44, 50385044.
Corem-Salkmon E., Perlstein, B., and Margel, S. (2012). Design
of near-infrared fluorescent bioactive conjugated functional iron
oxide nanoparticles for optical detection of colon cancer. Int. J.
Kirui, D. K., Khalidov, I., Wang, Y., and Batt, C. A. (2013). Targeted near-IR hybrid magnetic nanoparticles for in vivo cancer therapy and imaging. Nanomedicine 9, 702711.
Cho, Y. S., Yoon, T. J., Jang, E. S., Soo Hong, K., Young Lee,
S., Ran Kim, O., Park, C., Kim, Y. J., Yi, G. C., and Chang, K.
(2010). Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging. Cancer Lett.
299, 6371.
Jalalian, S. H., Taghdisi, S. M., Shahidi Hamedani, N., Kalat,
S. A. M., Lavaee, P., ZandKarimi, M., Ghows, N., Jaafari, M. R.,
Naghibi, S., Danesh, N. M., Ramezani, M., and Abnous, K. (2013).
Epirubicin loaded super paramagnetic iron oxide nanoparticleaptamer bioconjugate for combined colon cancer therapy and imaging in vivo. Eur. J. Pharm. Sci. 50, 191197.
Tong, M., Xiong, F., Shi, Y., Luo, S., Liu, Z., Wu, Z., and Wang,
Z. (2013). In vitro study of SPIO-labeled human pancreatic cancer
cell line BxPC-3. Contrast Media Mol. 8, 101107.
Olariu, C. I., Yiu, H. H. P., Bouffier, L., Nedjadi, T., Costello, E.,
Williams, S. R., Halloran, C. M., and Rosseinsky, M. J. (2011).
Multifunctional Fe3 O4 nanoparticles, for targeted bi-modal imaging
of pancreatic cancer. J. Mater. Chem. 21, 1265012659.
Basel, M. T., Balivada, S., Wang, H., Shrestha, T. B., Seo, G. M.,
Pyle, M., Abayaweera, G., Dani, R., Koper, O. B., Tamura, M.,
Chikan, V., Bossmann, S. H., and Troyer, D. L. (2012). Celldelivered magnetic nanoparticles caused hyperthermia-mediated
19
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
20
increased survival in a murine pancreatic cancer model. Int. J.

Yang, L., Mao, H., Cao, Z., Wang, Y. A., Peng, X., Wang, X., Sajja,
H. K., Wang, L., Duan, H., Ni, C., Staley, C. A., Wood, W. C., Gao,
X., and Nie, S. (2009). Molecular imaging of pancreatic cancer
in an animal model using targeted multifunctional nanoparticles.
Gastroenterology 136, 15141525.e1512.
Cochran, D. B., Wattamwar, P. P., Wydra, R., Hilt, J. Z., Anderson,
K. W., Eitel, R. E., and Dziubla, T. D. (2013). Suppressing iron
oxide nanoparticle toxicity by vascular targeted antioxidant polymer nanoparticles. Biomaterials 34, 96159622.
Soenen, S. J. H., Himmelreich, U., Nuytten, N., and De Cuyper, M.
(2011). Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling. Biomaterials 32, 195205.
Zhu, M. T., Wang, B., Wang, Y., Yuan, L., Wang, H. J., Wang,
M., Ouyang, H., Chai, Z. F., Feng, W. Y., and Zhao, Y. L. (2011).
Endothelial dysfunction and inflammation induced by iron oxide
nanoparticle exposure: Risk factors for early atherosclerosis. Toxicol. Lett. 203, 162171.
Wilson, M. R., Lightbody, J. H., Donaldson, K., Sales, J., and
Stone, V. (2002). Interactions between ultrafine particles and transition metals in vivo and in vitro. Toxicol. Appl. Pharmacol.
184, 172179.
Mahmoudi, M., Shokrgozar, M. A., Simchi, A., Imani, M., Milani,
A. S., Stroeve, P., Vali, H., Hafeli, U. O., and Bonakdar, S. (2009).
Multiphysics flow modeling and in vitro toxicity of iron oxide
nanoparticles coated with poly(vinyl alcohol). The Journal of Physical Chemistry C 113, 23222331.
Singh, N., Jenkins, G. J. S., Asadi, R., and Doak, S. H. (2010).
Potential toxicity of superparamagnetic iron oxide nanoparticles
(SPION). Nano Rev.
M. A. Oghabian, Guiti M., Haddad P., Gharehaghaji N., Saber
R., Alam N. R., Malekpour M., and Rafie B., M. A. Oghabian,
Guiti M., Haddad P., Gharehaghaji N., Saber R., Alam N. R.,
Malekpour M., and Rafie B. S. (2006). Detection Sensitivity of
MRI Using Ultra-Small Super Paramagnetic Iron Oxide NanoParticles (USPIO). Biological tissues. Engineering in Medicine
and Biology Society, 2006. EMBS 06. 28th Annual International Conference of the IEE. E. New York, AugustSeptember,
Vols. 56255626.
Yang, L., Peng, X-H., Wang, Y. A., Wang, X., Cao, Z., Ni, C.,
Karna, P., Zhang, X., Wood, W. C., Gao, X., Nie, S., and Mao,
H. (2009). Receptor-Targeted Nanoparticles for In vivo Imaging of
Breast cancer. Clin. Cancer. Res. 15, 47224732.
Wang, Y. X., Hussain, S. M., and Krestin, G. P. (2001). Superparamagnetic iron oxide contrast agents: Physicochemical characteristics and applications in MR imaging. Eur. Radiol. 11, 23192331.
Corot, C., Robert, P., Ide, J.-M., and Port, M. (2006). Recent
advances in iron oxide nanocrystal technology for medical imaging.
Adv. Drug Deliver. Rev. 58, 14711504.
Jeng, H. A., and Swanson, J. (2006). Toxicity of metal oxide
nanoparticles in mammalian cells. Journal of Environmental Science and Health, Part A 41, 26992711.
Karlsson, H. L., Gustafsson, J., Cronholm, P., and Mller, L.
(2009). Size-dependent toxicity of metal oxide particlesA
comparison between nano- and micrometer size. Toxicol. Lett.
188, 112118.
Kim, J. S., Yoon, T-J., Yu, K. N., Kim, B. G., Park, S. J., Kim,
H. W., Lee, K. H., Park, S. B., Lee, J.-K., and Cho, M. H.
(2006). Toxicity and Tissue Distribution of Magnetic Nanoparticles
in Mice. Toxicological Sciences 89, 338347.
Enochs, W. S., Harsh, G., Hochberg, F., and Weissleder, R. (1999).
Improved delineation of human brain tumors on MR images using
a long-circulating, superparamagnetic iron oxide agent. J. Magn.
Reson. Imaging 9, 228232.
Varallyay, P., Nesbit, G., Muldoon, L. L., Nixon, R. R., Delashaw,
J., Cohen, J. I., Petrillo, A., Rink, D., and Neuwelt, E. A. (2002).
Shahbazi et al.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in
imaging intracranial tumors. AJNR. American Journal of Neuroradiology 23, 510519.
Landmark, K. J., Dimaggio, S., Ward, J., Kelly, C., Vogt, S., Hong,
S., Kotlyar, A., Myc, A., Thomas, T. P., Penner-Hahn, J. E., Baker,
J. R., Holl, M. M., and Orr, B. G. (2008). Synthesis, characterization, and in vitro testing of superparamagnetic iron oxide nanoparticles targeted using folic Acid-conjugated dendrimers. ACS Nano.
2, 773783.
Cai, W., and Chen, X. (2008). Multimodality molecular imaging of
tumor angiogenesis. J. Nucl. Med. 2, 113s128s.
Moore, A., Weissleder, R., and Bogdanov, A. (1997). Uptake of
dextran-coated monocrystalline iron oxides in tumor cells and
macrophages. J. Magn. Reson. Imaging 7, 11401145.
Clement, O., Frija, G., Chambon, C., Schouman-Clayes, E.,
Mosnier, J. F., Poupon, M. F., and Balkau, B. (1991). Liver tumors
in cirrhosis: Experimental study with SPIO-enhanced MR imaging.
Radiology 180, 3136.
Brannon-Peppas L. and Blanchette, J. O. (2004). Nanoparticle
and targeted systems for cancer therapy. Adv. Drug Deliver. Rev.
56, 16491659.
Cho, K., Wang, X., Nie, S., Chen, Z., and Shin, D. M. (2008).
Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer.
Res. 14, 13101316.
Sykes, P. D., Neoptolemos, J. P., Costello, E., and Halloran,
C. M. (2012). Nanotechnology advances in upper gastrointestinal,
liver and pancreatic cancer. Expert. Rev. Gastroenterol. Hepatol.
6, 343356.
Duan, Z., Choy, E., Harmon, D., Yang, C., Ryu, K., Schwab, J.,
Mankin, H., and Hornicek, F. J. (2009). Insulin-like growth factorI receptor tyrosine kinase inhibitor cyclolignan picropodophyllin
inhibits proliferation and induces apoptosis in multidrug resistant
osteosarcoma cell lines. Mol. Cancer Ther. 8, 21222130.
Kolb, E. A., Gorlick, R., Houghton, P. J., Morton, C. L., Lock, R.,
Carol, H., Reynolds, C. P., Maris, J. M., Keir, S. T., Billups, C. A.,
and Smith, M. A. (2008). Initial testing (stage 1) of a monoclonal
antibody (SCH 717454) against the IGF-1 receptor, by the pediatric
preclinical testing program Pediatr. Blood Cancer 50, 11901197.
Scotlandi, K., Manara, M. C., Nicoletti, G., Lollini, P. L., Lukas, S.,
Benini, S., Croci, S., Perdichizzi, S., Zambelli, D., Serra, M.,
Garca-Echeverra, C., Hofmann, F., and Picci, P. (2005). Antitumor activity of the insulin-like growth factor-i receptor kinase
inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res.
65, 38683876.
Hynes, N. E. and Lane, H. A. (2005). ERBB receptors and cancer:
The complexity of targeted inhibitors. Nat. Rev. Cancer 5, 341354.
Crichton, R. R. and Charloteaux-Wauters, M. (1987). Iron transport
and storage. Eur. J. Biochem. 164, 485506.
Pasqualini, R., Koivunen, E., and Ruoslahti, E. (1997). Alpha v
integrins as receptors for tumor targeting by circulating ligands.
Nature Biotechnology 15, 542546.
Yang, F., Lum, J. B., McGill, J. R., Moore, C. M., Naylor, S. L., van
Bragt, P. H., Baldwin, W. D., and Bowman, B. H. (1984). Human
transferrin: cDNA characterization and chromosomal localization,
Proceedings of the National Academy of Sciences of the United
States of America 81, 27522756.
Islam, T. and Josephson, L. (2009). Current state and future applications of active targeting in malignancies using superparamagnetic
iron oxide nanoparticles. Cancer Biomarkers: Section A of Disease
Markers 5, 99107.
Kresse, M., Wagner, S., Pfefferer, D., Lawaczeck, R., Elste, V.,
and Semmler, W. (1998). Targeting of ultrasmall superparamagnetic iron oxide (USPIO). particles to tumor cells in Vivo by using
transferrin receptor pathways. Magn. Reson. Med. 40, 236242.
Shahbazi et al.
209. Huang, R., Ke, W., Liu, Y., Jiang, C., and Pei, Y. (2008). The use
of lactoferrin as a ligand for targeting the polyamidoamine-based
gene delivery system to the brain. Biomaterials 29, 238246.
210. Ferrara, N. (2004). Vascular endothelial growth factor: Basic science and clinical progress. Endocr. Rev. 25, 581611.
211. Tugues, S., Koch, S., Gualandi, L., Li, X., and Claesson-Welsh,
L. (2011). Vascular endothelial growth factors and receptors: Antiangiogenic therapy in the treatment of cancer. Mol. Aspects Med.
32, 88111.
212. Hicklin, D. J. and Ellis, L. M. (2005). Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.
J. Clin. Oncol. 23, 10111027.
213. Guba, M., Seeliger, H., Kleespies, A., Jauch, K.-W., and Bruns, C.
(2004). Vascular endothelial growth factor in colorectal cancer. Int.
J. Colorectal Dis. 19, 510517.
214. Zhou, Z., Bolontrade, M. F., Reddy, K., Duan, X., Guan, H.,
Yu, L., Hicklin, D. J., and Kleinerman, E. S. (2007). Suppression
of ewings sarcoma tumor growth, tumor vessel formation, and
vasculogenesis following antivascular endothelial growth factor
receptor-2 therapy. Clin. Cancer. Res. 13, 48674873.
215. Maris, J. M., Courtright, J., Houghton, P. J., Morton, C. L.,
Gorlick, R., Kolb, E. A., Lock, R., Tajbakhsh, M., Reynolds, C. P.,
Keir, S. T., Wu, J., and Smith, M. A. (2008). Initial testing of the
V. EGFR inhibitor AZD2171 by the pediatric preclinical testing
program. Pediatr. Blood Cancer 50, 581587.
216. Yoon, S. S., Segal, N. H., Park, P. J., Detwiller, K. Y., Fernando,
N. T., Ryeom, S. W., Brennan, M. F., and Singer, S. (2006). Angiogenic profile of soft tissue sarcomas based on analysis of circulating
factors and microarray gene expression. J. Surg. Res. 135, 282290.
217. Wang, Y., Xu, H., Liu, H., Wang, Y., Sun, J., and He, Z. (2012).
Efficacy and biodistribution of tocopheryl polyethylene glycol succinate noncovalent functionalized single walled nanotubes loading
doxorubicin in sarcoma bearing mouse model. J. Biomed. Nanotechnol. 8, 450457.
218. Dobson, J. (2006). Gene therapy progress and prospects: magnetic
nanoparticle-based gene delivery. Gene Ther. 13, 283287.
219. Pal-Bhadra M., Bhadra, U., and Birchler, J. A. (2002). RNAi
related mechanisms affect both transcriptional and posttranscriptional transgene silencing in drosophila. Mol. Cell 9, 315327.

220. Dykxhoorn, D. M., and Lieberman, J. (2006). Knocking down disease with siRNAs. Cell 126, 231235.
221. Brummelkamp, T. R., Bernards, R., and Agami, R. (2002). A system for stable expression of short interfering RNAs in mammalian
cells. Science 296, 550553.
222. Guo, J., Bourre, L., Soden, D. M., OSullivan, G. C., and
ODriscoll, C. (2011). Can non-viral technologies knockdown the
barriers to siRNA delivery and achieve the next generation of cancer therapeutics? Biotechnol. Adv. 29, 402417.
223. Kievit, F. M., Veiseh, O., Fang, C., Bhattarai, N., Lee, D.,
Ellenbogen, R. G., and Zhang, M. (2010). Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma. ACS Nano
4, 45874594.
224. Mikhaylova, M., Stasinopoulos, I., Kato, Y., Artemov, D., and
Bhujwalla, Z. M. (2009). Imaging of cationic multifunctional
liposome-mediated delivery of COX-2 siRNA. Cancer Gene Ther.
16, 217226.
225. Agrawal, A., Min, D. H., Singh, N., Zhu, H., Birjiniuk, A., von
Maltzahn, G., Harris, T. J., Xing, D., Woolfenden, S. D., Sharp,
P. A., Charest, A., and Bhatia, S. (2009). Functional delivery of
siRNA in mice using dendriworms. ACS Nano 3, 24952504.
226. Mykhaylyk, O., Vlaskou, D., Tresilwised, N., Pithayanukul, P.,
Mller, W., and Plank, C. (2007). Magnetic nanoparticle formulations for DNA and siRNA delivery. J. Magn. Magn. Mater.
311, 275281.
227. Tanaka, K., Iwakuma, T., Harimaya, K., Sato, H., and Iwamoto, Y.
(1997). EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewings sarcoma and primitive neuroectodermal
tumor cells. The Journal of Clinical Investigation 99, 239247.
228. Castillo, B., Bromberg, L., pez, X., Badillo, V., Gonz, lez Feliciano,
J. A., Gonz, lez, C. I., Hatton, T. A., and Barletta, G. (2012).
Intracellular delivery of siRNA by polycationic superparamagnetic
nanoparticles. J. Drug Deliv. 2012, 12.
229. Brusentsov, N. A., Gogosov, V. V., Brusentsova, T. N., Sergeev,
A. V., Jurchenko, N. Y., Kuznetsov, A. A., Kuznetsov, O. A.,
and Shumakov, L. I. (2001). Evaluation of ferromagnetic fluids
and suspensions for the site-specific radiofrequency-induced hyperthermia of MX11 sarcoma cells in vitro. J. Magn. Magn. Mater.
225, 113117.
21

Sorour Literature Review

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Sorour Literature Review

Uploaded by

Copyright:

Available Formats

Review

Copyright 2014 American Scientific Publishers

Vol. 1, 121, 2014

Application of Iron Oxide Nanoparticles in Sarcoma

KEYWORDS: Cancer, Sarcoma, Magnetic Iron Oxide Nanoparticles, Diagnosis, Hyperthermia.

Author to whom correspondence should be addressed.

World J. Cancer Res. 2014, Vol. 1, No. 2

has emerged as one of the most critical cancers. In fact,

Application of Iron Oxide Nanoparticles in Sarcoma

utilizing one method overcome different types of sarcomas

also can miss the sarcoma and take a sample of normal

Sorour Shahbazi is studying as a Ph.D. student of materials science at the University

Aibing Yu specialized in process metallurgy, obtained B.Eng. in 1982 and M.Eng.

World J. Cancer Res. 1, 121, 2014

Application of Iron Oxide Nanoparticles in Sarcoma

Special development areas

Thigh and behind the knee

People with an inherited

People who are treated with

Older people and

using ionizing radiation. contrast and resolution of MRI

Application of Iron Oxide Nanoparticles in Sarcoma

time, tumor volume and location, vascular content of

By applying an external magnetic field in sarcoma

Application of Iron Oxide Nanoparticles in Sarcoma

Common synthesis methods of IONPs.3! 45! 46

Moreover, the phenomenon of Superparamagnetism in

Long reaction time

colloidal stability which is related to zeta potential of NPs.

Application of Iron Oxide Nanoparticles in Sarcoma

showing side effects such as nephrotoxicity, cumulative

IONPs AGAINST SARCOMA

localized tumour are survived and the others die as a result

Application of Iron Oxide Nanoparticles in Sarcoma

Nanooncological investigations of diverse types of sarcoma.

World J. Cancer Res. 1, 121, 2014

15130 Dual Energy

[19, 23, 7479,

[18, 20, 97]

Application of Iron Oxide Nanoparticles in Sarcoma

the first randomized clinical phase III trial performed by

(as abnormal collection of fluid in a body cavity) which

Application of Iron Oxide Nanoparticles in Sarcoma

Recent studies on bioapplication of IONPs against common cancers.

Blood cancer EL4

Breast cancer HER-2

IONPs for MRI

World J. Cancer Res. 1, 121, 2014

IONPs for MRI

Application of Iron Oxide Nanoparticles in Sarcoma

IONPs for MRI

IONPs for MRI

Folic acid (FA)

Krukemeyer et al.18! 20 investigated the EPR effect of

Application of Iron Oxide Nanoparticles in Sarcoma

Notes: Moderate signal decrease; Partial response (PR): At least a 30%

contrast-to-noise ratio of the tumor and then a negative

Figure 2. Accumulation of IONPs in targeted zone with an external magnetic field.

Figure 3. EPR effect of IONPs on sarcoma.

One of the most well studied areas in sarcoma treatment

Application of Iron Oxide Nanoparticles in Sarcoma

regards to monoclonal antibodies as targeting agents such

efficiency.86 VEGF over expressed by most of cancer cells

Sarcomas show two kinds of genetic variations.