Sorour Literature Review

Copyright 2014 American Scientific PublishersAll rights reservedPrinted in the United States of America

ReviewWorld Journal ofCancer ResearchVol. 1, 121, 2014

www.aspbs.com/wjcr

Application of Iron Oxide Nanoparticles in SarcomaSorour Shahbazi1, Xuchuan Jiang1!, Jia-Lin Yang2, and Aibing Yu11Faculty of Science, SIMPAS-Nanotechnology Research Group, School of Materials Science and Engineering,The University of New South Wales, Sydney, NSW 2052, Australia2Faculty of Medicine, Sarcoma and Nanotechnology Group, Adult Cancer Program, Prince of Wales Clinical School and Lowy CancerResearch 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 insti-tutions around the world. Surgical techniques, chemotherapy, and radiotherapy as conventional methods have improvedthe treatment of sarcoma. However, half of the sarcoma patients die at 5 years of the disease. There are still aspects thatneed to be improved including early diagnosis, residue tumor cells after surgery, micrometastasis, lymph node metasta-sis, local recurrence and distant metastasis. Current chemotherapy and radiotherapy are effective, but often face tumorresistance. It is difficult to overcome the problems through increasing treatment doses since these therapies are nottumour specific and increasing dose may lead to cytotoxicity to normal tissues and organs. Recently, the application ofnanotechnology in oncology provides potential in problem solving in sarcoma. For examples, administrating a nanoparticlebased therapeutic/diagnostic agent for enhancing early and surgical margin diagnosis, sarcoma tumour cells targeting, aswell as gene and drug delivery has been reported in literature. In particular multifunctional and multimodal magnetic ironoxide nanoparticles can offer solutions in diverse areas of sarcoma, as one of the most desirable noninvasive magneticresonance imaging (MRI) contrast agents, as well as drug, ligand and gene nanocarrier. It is also an outstanding hyper-thermia agent via generating local heat under an alternative magnetic field. Although iron oxide nanoparticles have beenpresented with noticeable results in preclinical phase, considerable accomplishments have not been reported in clinicalstage, indicating more efforts should be made to apply iron oxide nanoparticles in sarcoma. This review aims to discussthe promising impact of iron oxide nanoparticles on sarcoma diagnosis and treatment.

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

CONTENTSIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Synthesis of IONPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Surface Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5IONPs Against Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 6IONPs as a Sarcoma Diagnosis Agent . . . . . . . . . . . . . . . . . 8Sarcoma Treatment with Drug Delivery . . . . . . . . . . . . . . . . 12Sarcoma Treatment with Gene Therapy . . . . . . . . . . . . . . . . 12Sarcoma Treatment with Hyperthermia . . . . . . . . . . . . . . . . . 13Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . 14

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

INTRODUCTIONCancer has been a serious global health problem, andnumerous cancers have been disclosed currently. Sarcoma

Author to whom correspondence should be addressed.Email: [email protected]: 11 January 2014Accepted: 16 February 2014

has emerged as one of the most critical cancers. In fact,according to Cancer Facts and Figures 2013 report pub-lished by the American cancer Society annually, sar-coma is estimated to be diagnosed about 11,410 cases(6,290 males and 5,120 females) and brings about deathof 4,390 (2,500 males and 1,890 females) patients in theUnited States in 2013.In general, there are two main kinds of sarcoma:

osteosarcomas (bone and joint sarcomas) and soft tissuesarcomas (STS). The soft tissue sarcomas are more pop-ular, which mainly grow from the soft tissues like fat,muscle, nerves, fibrous tissues, blood vessels, or deep skintissues. They can also be found in the trunk, head and neckarea, internal organs, and in the back of the abdominalcavity. As shown in Table I, Around 50 different types ofSTS are classified by their tissues of origin.1 The tumorheterogeneity brings more problems to the human healthsince there are significant differences in clinical behav-ior, prognosis, and treatment and this obviously makes

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utilizing one method overcome different types of sarcomasvery challenging. A few challenges in this area could bedemonstrated as following.First challenge is the sarcoma diagnosis at an early stage

(absolutely localized and smaller tumor), which can leadto simpler and more effective surgical removal. Needlebiopsy is one of the early diagnosis methods, however, theneedle not only is associated with pain and bleeding, but

Sorour Shahbazi is studying as a Ph.D. student of materials science at the Universityof New South Wales, Australia. Her research interest is in nanotechnology specially bio-application of iron oxide nanoparticles. She received her M.Sc. and B.Sc. from Schoolof Materials Engineering at the University of Tehran, Iran and she has professionalexperience as a laboratory technical expert before applying for Ph.D. position.

Xuchuan Jiang has fully devoted to the study on synthesis, self-assembly and func-tional applications of nanoparticles since the award of his Ph.D. in 2001. Dr. Jiang hasbeen working in various academic research environments, including the University ofWashington (USA), the University of Paris (France) and the University of New SouthWales (Australia) respectively. He has published over 90 papers with SCI citations over3500 times, leading him to H -index 28. He has been awarded ARC future fellow andQEII fellow in 2009. He has also been nominated as an OZreader for assessing Aus-tralia Research Council (ARC) projects/grants, and as a reviewer for many nanosciencejournals.

Jia-Lin Yang is currently an Associate Professor and a team leader of the Sarcoma andNanooncology Group in the Adult Cancer Program of the Lowy Cancer Research Centreand the Prince of Wales Clinical School, University of New South Wales (UNSW). Hewas 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 ofWollongong (Australia). Since 1992, he has been with the University of New SouthWales. Currently he is a Scientia Professor. His research is mainly in particle scienceand technology, process and materials engineering. He has published over 700 papersin various international journals and conference proceedings. He is an elected Fellowof the Australian Academy of Technological Sciences and Engineering, and AustralianAcademy of Science.

also can miss the sarcoma and take a sample of normaltissue instead.2 Noninvasive imaging tests, such as com-puted tomography (CT), positron emission tomography(PET) and magnetic resonance imaging (MRI) are othercommonly used methods offer early diagnosis. Amongthem, MRI seems to be more enhancive because of supe-rior spatial resolution and contrast, unlimited penetratinginto tissues and being unharmed to the patient since not

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Table I. Common kinds of STS.

Cancer Tissue of origin Special development areas Patients

Liposarcomas Fat Thigh and behind the kneeInside the back of the abdomen

Adults (5065)

Leiomyosarcomas Smooth muscle Retroperitoneum (area in back of theabdominal cavity)

Internal organsBlood vessels

The elderly

Rhabdomyosarcomas Skeletal muscle Arms or legsHead and neck Urinary organs (like vagina or bladder)

Children

NeurofibrosarcomasNeurilemmomasNeurogenic arcomas

Nerve Brain and spinal cordNerves that run throughout the bodyUpper arms or neck (have very large nerves)

People with an inheritedcondition calledneurofibromatosis

Gastrointestinal stromaltumor (GIST)

Nerve In digestive tract (muscles lining thestomach and intestine)

Adults older then 50

Synovial sarcoma Joint Knee and ankleShoulderHip

Children and young adults

Angiosarcoma Blood andlymph vessels

Parts of the body that have been treatedwith radiation

Limbs that are chronically swollen becauselymph circulation is blocked

People who are treated withradiation

Kaposi sarcoma Blood andlymph vessels

On the skinOn mucosal surfaces such as inside themouth

In the lymph nodesDigestive tract

Older people andpeople with suppressed immunesystems (from HIV infectionand in organ transplantpatients)

Fibrosarcoma Fibrous Legs and armsTrunk

Adults (2060)

epithelioid sarcoma Uncertain Under the skin of hands and forearmsUnder the skin of feet and lower legs

Adolescents and young adults

malignant fibroushistiocytoma (MFH)

Uncertain Legs and armsInside the back of the abdomen

Older adults

Note: Data were adapted from American Cancer Society website (http://www.cancer.org) with modification.

using ionizing radiation. contrast and resolution of MRIequipment, to clearly observe and find smaller tumours(diameter less 2 cm) is still difficult.Second challenging is to identify surgical margin of sar-

coma through accurate distinction of cancer cells fromnormal ones, and to distinguish the margin of the tumorarea, which is also important in surgical removal of tumorcells. Now MRI has been a common detective methodin clinics and the MRI quality can be improved by con-trast agent administrated. One of the MRI contrast agentsis iron oxide nanoparticle (IONP), especially superpara-magnetic iron oxide nanoparticles (SPIONs) with lowcytotoxicity as a result of high magnetic signal strength.The IONPs/SPIONs enhanced MRI sensitivity and sig-nal lasting time, superior to other contrast agents suchas gadolinium that suffers from issues of timing, doseand surgically induced contrast enhancement. In addition,IONPs present multimodal imaging capability via car-rying contrast agents of other imaging modalities suchas optical imaging, CT, PET, and single-photon emis-sion computed tomography (SPECT), however, the sizeand surface modification of IONPs should be carefullycontrolled.

Variation in drug distribution and absorption and diffi-culty in drug accessibility to sarcoma cells are some ofchallenges faced by chemotherapy.6 Sarcoma multidrugresistance as a result of p-glycoprotein overexpression isanother complexity hindering adequate drug delivery.7 Inidentifying new sarcoma treatment, gene therapy by meansof oligonucleotides such as Dz13 DNA8 and ONYX-0115.9 has been trialled. However, poor stability andlow intracellular penetration of oligonucleotides decreaseits therapeutic potential. Engineered IONPs with suitablecoatings as nanocarriers for targeting ligands and oligonu-cleotides are capable of overcoming these problems. It isalso noticeable that using IONPs could be more affordablediagnosis 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 fre-quency and microwave thermal therapy as two most ordi-nary hyperthermia techniques have difficulties such as notuniform heating of only the tumor region and noticeableinjury to the patient in treating large tumors.10 IONPs andespecially SPIONs selectively generate local hyperthermiain sarcoma area under an alternative external magneticfield, providing a favourable alternative treatment option.

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Figure 1. A schematic of IONPs as multifunctional and multi-modal imaging NPs against cancer.

By applying an external magnetic field in sarcomaregion, IONPs pass through blood vessels and leak intotumor cells by way of damaged and leaky vasculature oftumor. This property is called the enhanced permeabilityand retention (EPR) effect.11 In this situation, rapid clear-ance of narrow IONPs via renal system during circulationtime is a critical issue. In this case, surface modificationof IONPs with hydrophilic coatings considerably extendscirculating time. Moreover, IONPs could be functional-ized with targeting ligands, which conduct IONPs directlytoward intra or extracellular sarcoma biomarkers such askinase 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 havebeen substantially remarked specially due to their thera-nostic approach.3 Theranostic is defined as the combina-tion of therapy and diagnosis within a single platform.12!13

Theranostic specification of IONPs is owing to theirmultifunctional and multimodal imaging characterizations(Fig. 1). Freeman et al.14 firstly introduced the conceptof use of magnetism in medicine in the 1970s. Widderet al.1517 in 1983 utilized IONPs to deliver doxorubicinto sarcoma tumors implanted in rat tails for the first time.After that, in vitro and in vivo (with sarcoma diametereven less than 10 mm) diagnosis and treatment investiga-tions have been carried out in which IONPs were appliedagainst different types of sarcomas and fulfilling resultshave been reported.1822

It is also noticeable that in order to achieve moreenhancive therapeutic effect of IONPs against sarcoma,considering both physiological characteristics of IONPssuch as size, morphology, surface characteristics, amountof administration, reversibility and strength of bindingbetween therapeutic agent and magnetic NPs as well asthe most favorable magnetic field characteristics consist ofgeometry, strength and duration and biological propertiesincluding size, weight and body surface, blood volume,cardiac output and systemic vascular resistance, circulation

time, tumor volume and location, vascular content oftumor and blood flow in tumor are fundamental.23

This review aimed to summarise recent progress inthe literature on IONPs studies, specifically on sarcomadiagnosis and treatment. It focuses on IONPs synthe-sis, characterizations, surface modification of IONPs, andapplications of IONPs in sarcoma. It tries to answer thequestion whether the IONPs would be a general, desir-able and promising solution to conquer heterogeneoussarcomas.

SYNTHESIS OF IONPsIn the synthesis of IONPs, two mechanisms of nucle-ation and growth are applied. When a solution reachesits critical supersaturation, a single short burst of nucle-ation happens and monodispersed NPs can be produced.As a result of diffusion of solute particles from the solu-tion onto the surface of the nuclei, NPs with a suitablesize are obtained.24 There are several types of IONPs syn-thesis methods such as co-precipitation,2528 hydrothermalsynthesis,2932 micro-emulsion,3336 polyol,37 microwaveassisted synthesis,38 electrochemical deposition of metalon a cathode,39 spray and laser pyrolysis,40!41 flamesynthesis42 and sonochemical procedures.43!44 Characteris-tics and advantages and disadvantages of co-precipitation,thermal decomposition and micro-emulsion as the threemost common synthesis methods of IONPs are depictedin Table II.3!45!46 Wahajuddin et al.46 published a reviewarticle (2012) in which they explain comprehensivelydiverse synthesis methods, and characteristics associatedwith advantages and disadvantages.The size of IONPs plays very key rule in IONPs bioap-

plication. Determination of residual time in blood (i.e.,half-life in the circulation) is one of the most impor-tant effect of the size of NPs since particles with sizessmaller than 10 nm are mainly removed by renal clear-ance and particles larger than 200 nm become concen-trated in the spleen or are absorbed by phagocytic cellsof the body and in both leading to decreased plasmaconcentrations.4749 Secondly, magnetic property of IONPs(using in MRI and hyperthermia) is substantially influ-enced by the size.50 Additionally, potential of IONPs witha particle size smaller than 2 nm increases and leadsto diffuse through cell membranes, damaging intracellu-lar 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 topass across the endothelial cells of blood vessels and beengulfed by tumor cells.51!52 Kuhn et al.53 studied thevelocity of IONPs with 135 nm and 400 nm in diam-eters through extracellular matrix from Murine sarcoma,and they achieved more than 100 times in velocity with135-nm particles but 400-nm ones. There are consider-able pervious investigations42!50!5456 to claim that the sizerange of 10100 nm is more suitable for bioapplications.


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Table II. Common synthesis methods of IONPs.3!45!46

Reaction ReactionMethod temperature ("C) rate Size (nm) Pros Cons

Coprecipitation 2090 Fast 15200 Simple methodRapid synthesisHigh yieldGood control of size

OxidationAggregation

Thermal decomposition 100320 Slow 320 Good control of size and shapeNarrow sizeHigh yieldGood control of agglomeration

Long reaction timeOxidation

Microemulsion 2050 Fast 412 Good control of sizeHomogenous NPsAdequate and versatileSimple method

Poor yieldLarge amount of solvents

Moreover, the phenomenon of Superparamagnetism inIONPs is one of the most promising characteristics withthe size of 1020 nm, which could be attributed to the sin-gle domain nature of them, leading to exhibiting no resid-ual magnetic interaction and less chances of aggregationafter removal of the magnetic field.45!46!57

Morphology of IONPs is another important fac-tor against sarcoma since it affects biodistribution ofthemeselves. For example, the phagocytic activity ofmacrophages is moved to a minor extent by rod-shapedparticles compared to spherical ones. The rod-shapedand nonspherical NPs show a longer blood circula-tion time compared with spherical particles.58 The mor-phology of NPs also influences cell toxicity. In Zhanget al.s study, nanobead-shaped, nanoworm-shaped, andnanosphere-shaped SPIONs showed greater cellular tox-icity in comparison with nanorods and colloidal nano-crystal clusters.59 The reaction conditions and chemicalsinvolved considerably affect the shape of NPs. For exam-ple, in the presence of surfactant with bulky hydrocarbonchain structures (e.g., oleylamine and adamantane amine)the steric hindrance exerted by surfactants has been shownto affect the shape of growing crystals of iron oxide duringsynthesis.60

The oxidation state of the iron ions can also havea potential effect on the morphology of NPs prepared.In fact, iron ions in the trivalent state (Fe3+) favor forma-tion of spherical NPs; whereas, ions in the divalent state(Fe2+) prefer to develop nanorods. The oxidation state ofthe iron ion on the surface of the nanoparticle is suscep-tible to its nearby environment, particularly to surfactantexposure. Analysis of the oxidation state of iron ions onthe surface of NPs can assist in recognizing their struc-ture and chemical environment.61 It is also noticeable thatspherical magnetite and maghemite particles offer a uni-form surface area for coating and conjugating of targetingligands or therapeutic agents.46

Finally, the surface characteristics of IONPs as the mostimportant specification necessitate more extensive study.One of the surface characteristics is its charge determining

colloidal stability which is related to zeta potential of NPs.High zeta potential will give stability (i.e., dispersion willresist aggregation); when the potential is low, as a resultof Van Der Waal interparticle attractions, affinity exceedsrepulsion and the dispersion will break and flocculate.62

Therefore, colloids with high zeta potential (negative orpositive) are electrically stabilized while colloids with lowzeta potentials tend to coagulate or thicken.63!64 Surfacecharge also affects being engulfed of IONPs by targetcells. IONPs having a positive charge are better internal-ized by breast cancer cells than are negatively chargedones.65 Surface charge higher than +25 mV and less than25 mV have been reported considerable stability.62 Ingeneral, Hydrophilic surfaces are more desirable since theydiminish opsonization and clearance as a result of the leastinteracting with blood components.55!56

SURFACE MODIFICATIONSBiocompatibility (reduction toxicity), bioavailability, mul-tifunctionality and multimodality of IONPs are substan-tially enhanced by various types of coatings. Also, coatingof IONPs keeps the surface from oxidation and increasesinternalization efficiency by target cells.66 Furthermore,coating enhances colloidal stability of IONPs via diminish-ing their tendency to aggregation; in fact, coating materialcould be added during the synthesizing process (one-potmethod) in order to prevent the agglomeration of the ironoxides.48!67!68

The most common coatings for biocompatible IONPsare polymers. Three-dimensional polymer molecules suchas dendrimers, hyperbranched and star polymers have beenengrossed study attractions owing to their unique struc-tures and properties68 dextran69!70 alginate,71 starch72 andchitosan73 as some types of polysaccharides are amongthe most commonly used coating for the stabilization ofIONPs. Polyethylene glycol (PEG) is another popular bio-compatible coating easily conjugates with antibodies orpeptides and improves drug delivery of IONPs.67 Polymercoatings, also, have been widely used for carrying drugs


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showing side effects such as nephrotoxicity, cumulativeneurotoxicity or ototoxicity. Fatty acids, dicarboxylic ortricarboxylic acids and phosphonates and phosphates, sil-ica, carbon, precious metals such as gold (Au) and metaloxides are other coatings of IONPs.In fact, surface modification agents convey drugs,

genes and other targeting and therapeutic agents viaencapsulating or conjugating to them. For instance,Lipoproteins as endogenous nanocarriers have been usedto transform Arginylglycylaspartic acid (RGD) peptidestowards sarcoma cells.74 Because of their compatibil-ity with immune systems they have stealth charac-teristics and are able to escape from elimination byrenal system. Also, in sarcoma gene therapy encap-sulating genes in cationic lipids improves their stabil-ity in biological environments and therefore enhancesin vivo intracellular gene delivery to cancer cells; how-ever, lipids aggregation as a result of their cationic natureis a problem.75 In this case, applying cationic polymerssuch as poly(isobutylcyanoacrylate),7577 polyethylene-imine (PEI) and polyallylamine hydrochloride (PAH)78 andcyclodextrin79 demonstrated considerable in vivo sarcomatreatment and inhibition of cancer growth. Tracking sar-coma therapeutic process with polymeric nanocapsules ishard and therefore polymers are mostly applied in asso-ciation with a traceable agent such as rhodamine (as afluorine dye)75 or nanodiamonds (intrinsic fluorescence).78

Obviously, coupling IONPs with appropriate polymersmakes nanocapsules directly traceable and in some casesincreases their stability. Since magnetic property of lipidsis used for MRI, encapsulating IONPs in lipids asenhancive MRI agents is able to considerably increaseMRI quality and sensitivity. Most recently Muthiah et al.80

published an inclusive review about surface modificationof IONPs and Wahajuddin et al. in another review articlesummarized diverse most common coating materials.

IONPs AGAINST SARCOMADespite many efforts made in this area, some currentlimitations on sarcoma diagnosis and treatment still existincluding:(1) Early diagnosis and complete surgical removal (avoid-ing residual) of sarcoma before tumor grow to 5 cm sinceprobability of metastasis-free survival in soft tissue sar-coma in stage I (in which size of the tumor is not largerthan 5 cm and it generally has not spread to lymph nodesor more distant sites) is more than 95%;81

(2) Accurate discrimination between sarcoma and normaltissues which helps determining surgical margin beforesurgery and subsequently cause decreasing normal tissuesremoval and residual tumor cells because of STS hasasymmetrical and infiltrating growth pattern;82!83

(3) Identify lymph node metastasis and micrometastases;taking Ewing sarcoma as an example according to his-torical data only less than 5% of treated patients with

localized tumour are survived and the others die as a resultof cancer metastases; therefore development of new moth-ods for treating metastases seems crucial;79!84

(4) Improve specificity and effect of chemotherapy andradiotherapy;85!86

(5) Personalized sarcoma therapy, which will tailor opti-mized treatment to each patient.

Recently, nanotechnology offers solution in diverseareas of sarcoma diagnosis and treatment. Table III demon-strates some of the carried out research on sarcoma therapyby NPs.In recent decades, functionalized and modified IONPs

have been engrossed attentions due to their bioavailabil-ity, biocompatibility, degradability, multimodality imagingability, enhancive drug delivery and gene therapy capabil-ity, and healing hyperthermia effect. Nowadays consider-able research activities are carried out regarding IONPscancer therapeutic effect in order to optimize IONPs prop-erties such as increasing magnetic nanoparticle concentra-tion in blood vessels, reducing early clearance from thebody, minimizing nonspecific cell interactions and thusminimizing side effects and increasing their internalizationefficiency within target cells, thus reducing the total doserequired. Table IV is a summary of mostly recent investi-gations on theranostic application of IONPs against mostcommon cancers.IONPs as contrast agents for MRI and carrying

other imaging modalities (multimodality) can consider-ably enhance sarcoma diagnosis. They also could be uti-lized as nanocarriers for targeting agent to genetic changesand overexpression of certain proteins specifying somegroups of sarcoma. Chemotherapeutic drugs and otherantitumor medicines could be conveyed by modified andfunctionalized IONPs. IONPs are also able to producelocal hyperthermia in sarcoma tumor regions via an alter-native magnetic field. Moreover, using IONPs could bemore affordable diagnosis and treatment of some kindsof sarcoma. To our knowledge, in 1996 Lubbe et al.87!88

for the first time carried out successful phase I clinicaltrial with directing ferrofluid to the patients with advancedsarcomas. The results showed that ferrofluid administra-tion was well accepted in the majority of patients studied,and the ferrofluid was successfully directed to cancer cellswithout cytotoxicity. In 2004 Lemke et al.89 in a phase Istudy tracked by MRI, the effect of ferrofluid consists ofepirubicin as a chemotherapeutic drug on sarcomas in dif-ferent parts of body of 5 patients. Table V shows thatchanges in tumors sizes situated in different parts of bodyare traceable and assessable by MRI. In fact, they wereable to observe that except sarcoma in right shoulder, theeffect of epirubicin on other types of sarcomas was notsatisfying by MRI in the short period (210 days). In 2006in a Phase I trial, Wust et al.90 applied thermal therapyby magnetic fluid on STS patients and achieved desirableheal without or with only moderate side effects. In 2010,


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Table III. Nanooncological investigations of diverse types of sarcoma.

Type of Cancer Size Therapeutic TargetingItem sarcoma cells Nanoparticle (nm) approach method Biomarkers Reference

1 Ewingssarcoma

A673TC71EW7

DNA NPsPolyisobutylcyano-acrylate NPs

Fluorescentnanodiamonds

Polycathions-cyclodextrins-PEGNPs

IONPs

8130 Gene Therapy(shRNA/siRNA)

Diagnosis(MRI/Fluorescenceimaging)

Active/Passive

Cell membraneGlycoprotein

Anti-CD99AntibodiesEWS-Fli-0EWS-Fli-1

[19, 23, 7479,89, 92, 93]

2 PrimarySTS

LSL-KrasG12DP53CD31FL/FL

Liposomesencapsulatingiodine and AuNPs

PEG NPsAu Nanorods

15130 Dual Energymicro-CTdiagnosis

Gene therapy(sunitinib) andRadiotherapy

Photothermaltherapy

Passive/Active

VEGF andPDGF-R

[86, 9496]

3 Rhabdomyo-sarcoma

R1H IONPs 256 Drug delivery(Mitoxantrone)

Passive [18, 20, 97]

4 Uterine sar-coma

MES-SA Polymeric (PLGA)Nanocarriers

Nanoplexes

50135 Drug delivery(Doxorubicin)

HyperthermiaDiagnosis(Thermal-opticalagent)

Active/Passive

P-Glycoproteinantibody

[98, 99]

5 Fibro-sarcoma

HT 1080FsaRBP6BFS-1

AuNPsV2O5 NPsLa0"7Sr0"3MnO3NPs doped withcerium

Copolymer NPsIONPsChitosan NPsLiposomes NPsIONPs

2250 Photodynamictherapy anddiagnosis

V2O5 NPs act aspoisoning material

HyperthermiaDrug delivery(Cisplatin)

Optical imagingMRIOleic Acid asAntitumor

Active/Passive

Protoporphyrin IX [21, 22,100105]

6 Murinesarcoma

S-180NIH/3T3J744A.1

Oridoninnanosuspension

Polyisobutylcyano-acrylate NPs

Ploy-iso-hexyl-cyanoacrylate(PIHCA) NPs

Chitosan NPsLipid NPsIONPs

30897 Oridonin asantitumor

Drug delivery(Paclitaxel,Hydroxycamp-tothecin,Dihy-droartemisinin,Doxorubicin)

Gene therapy(AS-ON)

Hyperthermia

Active/Passive

Hyaluronic acid(HA)

EWS-Fli-1EFT protein

[6, 53,106115]

7 Gliosarcoma 9LU87

IONPsGd NPsPoly(cyano-acrylate) NPs

LipidNanocapsules

3161 RadiotherapyDiagnosis(Chlorotexin peptid/MRI/NIR/NMR)

Drug delivery(Paclitaxel)

Gene therapy(9LGFP)

Active/Passive

Transferrinreceptor (ETR)

[11, 116124]

8 Osteogenicsarcoma

SaOS-2SJSA-1MES-SAHOSKHOSMNNG-HOS

Os515

Chitosan NPsSilica NPsMagneticorcinol-imprintedpoly(ehylen-co-vinyl alcohol)

AuNPsLiposom NPs

20300 Gene Therapy(Dz13 DNA)

Drug delivery(Doxorubicin,resveratrol)

HyperthermiaDiagnosis

Active/Passive

C-JunALCAM

[8, 125129]



Table III. Continued.

Type of Cancer Size Therapeutic TargetingItem sarcoma cells Nanoparticle (nm) approach method Biomarkers Reference

9 KaposisSarcoma

KS Au and Ag NPsSPIONs

1520 Diagnosis (/MRI/Fluorochrome/Cholorimetric)

Active KSHV(vCyclinRNA)

[130, 131]

10 Neuro-blastoma

Neuro2A AuNPs 144 Diagnosis Active Transferrin [132]

11 Gastricsarcoma

AGS Polyethyleneglycol-modifiedgelatin(PEG-GEL) andpolylactic acid(PLA) NPs

190 Photodynamictherapy withCHA2HB

Passive [133]

the first randomized clinical phase III trial performed byIssels et al.91 applied chemotherapy alone and/or alongwith regional hyperthermia on 341 STS patients.(with tumor size more than 5 cm in diameter), sug-

gesting regional heperthermia increase the benefit ofchemotherapy.Although, it should be considered that in spite of

fascinating IONPs characteristics regarding therapeuticapproach, their ability to induce cellular toxicity andnephrotoxicity is concerned as a challenge up till now.In fact, as a result of their ultrafine size (diameter


Table IV. Recent studies on bioapplication of IONPs against common cancers.

Size ofCancer Diagnosis Therapeutic Therapeutic IONPs core

Item Cancer cells agent method agent range (nm) Reference

1 Blood cancer(lymphoma)

EL4C57BL/6-B

IONPs for MRIGlutathioneS-Transferase (GST)fusion protein fortargeting EL4,

Fluoresceinisothiocyanate (FITC)

Propidium iodideNear infrared (NIR)fluorescent dyes(CellVue NIR 815(NIR815))

Gene therapy Anti-CD79b 1054 [134, 135]

2 Bladdercancer

UMUC3MGH-U1

IONPs for MRI Drug deliveryHyperthermia

Cisplatin andDoxorubicin as ananti-cancer drug

1014 [136139]

3 Brain tumor(Glioma)

9LRG-2U87MG

IONPs for MRIChlorotoxin (CTX) astargeting ligand

RGD peptides targeting#v$3 endothelial cells

Drug deliveryAntiangiogenictherapy

Mitoxantrone andDoxorubicin asanti-cancer drugs

VEGF 121/rGelprotein

Anti-syntheticpeptide antibody(EGFRvIIIAb) forthe deletion mutantEGFR

10110 [121,140144]

4 Breast cancer HER-2MCF-7SK-BR-3

IONPs for MRIHER2 antibody

Drug deliveryX-rayirradiation

Gene therapy

Paclitaxel,Rapamycin, andDoxorubicin asdrugs alone orcombination

AntibioticViolamycine B1

Luteinizing hormonereleasing hormone(LHRH)

314 [40, 145149]

5 Prostatecancer

PC3LNCaPCT1258

IONPs for MRITargeting ligands suchas RGD (prostatecancer-specific R11peptides) and folic acid

Endogenous riboflavincarrier protein RCPligand flavinmononucleotide (FMN)

Targetinggastric-releasingpeptide receptors

Near-infrared (NIR)fluorophore Cy5.5

Horseradish peroxidaseenzyme

Drug delivery Doxorubicin,Daunorubicin, andAbraxane1 asanti-cancer drugs

Bombesin (BBN)

1025 [150154]

6 Skin cancer(Melanoma)

B16SK-MEL-37B16F10Me300

IONPs for MRIAnti-S-100 proteintargetinglanocyte-specificmarkers such asHMB-45 and Melan

GlyArgGlyAspSer(GRGDS) peptides thatspecifically bind to the#5$3 receptors ofmelanoma cells

Drug deliveryHyperthermia

Doxorubicin as ananti-cancer drugs

Curcumin as ananti-cancer drugs

810 [10, 155157]



Table IV. Continued.

Size ofCancer Diagnosis Therapeutic Therapeutic IONPs core

Item Cancer cells agent method agent range (nm) Reference

7 Liver cancer KBHep3BVX2SMMC-7721

IONPs for MRIFolic acid for targetingfolate receptor (FR1)

SP5.2/tTF (SP5.2: apeptide binding toVEGFR-1; tTF:truncated tissue factor)

Drug delivery Doxorubicin as ananti-cancer drug

510 [158160]

8 Lung cancer A549LLC cellsH2009

IONPs for MRI HyperthermiaDrug delivery

Doxorubicin as ananti-cancer drug

614 [161165]

9 Cervicalcancer

HeLa IONPs for MRIMAGCNTSPSS-6-diamidino-2-phenylindole(DAPI)

Drug delivery Folic acid (FA)targeting Folatereceptors

Methotrexate asanti-cancer drug

716 [166169]

10 Colorectalcancer

LS174TSW480SW1222HT29HCT 116SW620C26

IONPs for MRIHuman serum albuminnear-infrared fluorescen

Anticarcinoembryonicantigen antibodies(#CEA)

Peanut agglutininSingle-chain antibodyconjugates (A33scFv)that target A33 antigen

Cetuximab as an EGFRinhibitor

5TR1 aptamer

Laser-assistedtherapy

HyperthermiaDrug delivery

Epirubicin as ananti-cancer drug

79 [170173]

11 Pancreaticcancer

BxPC-3Panc-1Panc-2

IONPs for MRIAntisenseoligodeoxynu-cleotideof survivin (BIRC5)gene to active targeting

Antibody epithelial celladhesion molecule

Green fluorescent dye(FITC-IgG)

Urokinase plasminogenactivator receptor

Hyperthermia 412 [174177]

Passive DeliveryPassive delivery methods mostly refer to the EPR effecton solid tumors,11!195!196 and relies on the fact that theanatomical and physiological irregularities of tumor tis-sues distinguishing from the healthy tissues of the body.In the EPR effect because of leaky and damaged vascu-lature of tumor due to the rapid angiogenesis associatedwith tumor growth, NPs can make a way from bloodstreaminto 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 devel-oped lymphatic drainage system of most tumors, NPs arenot able to come back to the systemic circulation. Toretention of IONPs inside sarcoma environment leads toamplify contrast between the sarcoma and the surroundinghealthy tissue which significantly improves diagnosis byMRI.

Krukemeyer et al.18!20 investigated the EPR effect ofmitoxantrone (as a chemotherapeutic drug) with IONPsregarding drug delivery to R1H Rhabdomyosarcoma celllines. For comparison they applied mitoxantrone-ironoxide with and without an extracorporeal magnet andmitoxantrone without IONPs in normal and tumor tissue.They observed mitoxantrone-iron oxide concentration wassubstantially decreased by removal magnet or adminis-trating mitoxantrone alone. They also histologically stud-ied liver and spleen samples seven days after the trial.Liver and spleen had detectable iron depositions but nonecrosis seven days after treatment and no allergies ortoxic reactions were observed. In fact, rapid clearanceof IONPs via macrophage phagocytosis in the organs ofthe mononuclear phagocyte system such as the liver andspleen is a challenge. This leads to less absorption of theconjugated drug at other tumor sites and diminish in the



Table V. Clinical MRI tracing of change in tumor size after admin-istration of IONPs and drug.89

Types of Tumor T2-WI (MRI) Tumorsarcoma location after 210 days size

Sarcoma Right shoulder PRCystosarcoma Right breast PDChondrosarcoma Right thigh SDEwing sarcoma Left shoulder PDChondrosarcoma Right shoulder PDNotes: Moderate signal decrease; Partial response (PR): At least a 30%decrease of the largest diameter of the tumor; Progressive disease (PD): Atleast a 20% increase of the largest diameter of the tumor; Stable disease(SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase toqualify for PD.

contrast-to-noise ratio of the tumor and then a negativeeffect on tumor diagnosis. To face these challenges, mod-ification of the IONPs surface with polymer coating suchas hydrophilic stealth polymers (e.g., polyethyleneimine)could be really helpful to provide a longer circulationhalf-life. In fact passive delivery can be achieved by engi-neering IONPs that is capable of prolonged circulationtimes..199

Active DeliveryActive delivery of IONPs are realized by conjugating orencapsulating with specific targeting ligands that specif-ically target different kinds of intra or extracellular sar-coma biomarkers or receptors. It considerably helps thatmore IONPs accumulate in the cancer cells and providemuch more contrast between the tumor and healthy tis-sues on an MRI.47 When cancer cell biomarkers or recep-tors distinguish and bind targeting ligands, the particlesundergo receptor-mediated endocytosis and are engulfedby the cancer cell. There are several types of receptors,antibodies, transferrins and peptids which could be con-jugated to IONPs in order to tailor specific engineeredtherapeutic agent for diverse kinds of sarcomas.

Figure 2. Accumulation of IONPs in targeted zone with an exter-nal magnetic field.

Figure 3. EPR effect of IONPs on sarcoma.

One of the most well studied areas in sarcoma treatmenthas come from targeting tyrosine kinases. This enzymefacilitate a wide variety of cellular functions, includingproliferation, migration, and apoptosis. Protein kinase asan enzyme adds a phosphate group to a protein or otherorganic molecule; these phosphorylated groups can turna protein on or off. Kinase receptor could be barren bycertain agents to stop cellular survival signaling pathways,leading to growth arrest or apoptosis.85 Furthermore, theinsulin-like growth factor 1 receptor (IGF 1R) pathwayhas been concerned in osteosarcoma,200 Ewing sarcoma,201

and rhabdomyosarcoma.202 Other targets are including theERBB family, Met, Src, the MAPK cascade, Raf, c-KIT,PDGFR, AKT, and signaling pathways including WNT/"-catenin, Hedgehog, and Notch. PLK1 and MIRK havebeen recognized as potential targets for osteosarcoma. ThePLK1 inhibitor induced apoptosis while MIRK siRNAinhibited cell growth via inducing apoptosis.85

P-glycoprotein is overexpressed in multidrug-resistantsarcomas and could be targeted with lentiviral vectorslinked to an anti-P-glycoprotein monoclonal antibody,85!76

but it is also a fundamental component of various nor-mal tissues such as peripheral blood cells and hematopoi-etic progenitors found in normal human bone marrowand the blood brain barrier.94!100 Consequently, treatment-related morbidity, mortality, and increased marrow toxicityassociated with chemotherapeutics and biological agentsthat target P-glycoprotein have to be considered care-fully. Murthy and Shah7 published a review paper anddiscuss strategies for overcoming p-glycoprotein effect.In fact, p-glycoprotein actively pumps the drug out of cellsand therefore reduces intracellular drug concentration anddiminish therapeutic efficacy. Hung et al.125 applied theendosomal pH-sensitive mesoporous silica NPs with dox-orubicin to improve drug delivery system to human uterinesarcoma. They perceived their engineered nanocarrier sub-stantially bypassed p-glycoprotein efflux pump and over-came tumor cells drug resistance.125

Although, conjugating antibodies has noticeably devel-oped in recent years, there are still a number of challenges



regards to monoclonal antibodies as targeting agents suchas their large hydrodynamic size, being very fragilemolecules.203

Transferrin as iron-binding blood plasma glycoproteinorganizes the level of free iron in biological fluids.204

In fact, it is a vibrant protein involved in iron homeosta-sis and the regulation of cell growth.205 Human transfer-rin is encoded by the TF gene.206 The transferrin receptor(also known as CD71) consists of two identical monomersjoined by disulfide bonds. When a transferrin proteinloaded with iron runs into a transferrin receptor on thesurface of a cell, it binds to receptor and consequently byreceptor-mediated endocytosis is transported into the cellin a vesicle. The pH of the vesicle is reduced by hydrogenion pumps (H+ ATPases) to about 5.5, causing transferrinto release its iron ions. The receptor is then transportedthrough the endocytic cycle back to the cell surface, readyfor another round of iron uptake. This process providesconsiderable intracellular IONPs accumulation in lyso-somes as a favorable environment for ensuring iron sta-bility which decreases early intracellular degradation ofIONPs and thus extending the contrast enhancing effect.13

The whole transferrin internalization cycle takes typicallyless than 5 minutes, which yields with a near turnover rateof 20,000 transferrin molecules per cell per minute. Thisleads a larger number of IONPs to be engulfed by the cells,leading to higher MRI contrast.116 Transferrin receptor isoverexpressed on the surfaces of sarcoma and other cancercells such as neuroblastoma and gliosarcoma because oftheir increased iron requirements.132!116!124!207 Transferrinis expressed at low levels in many normal tissues.207!208

The transferrin receptor can be targeted by direct interac-tion with conjugates of its ligand transferrin or by mon-oclonal antibodies specific for the transferrin receptor.205

One of the challenges of utilizing transferrin as con-jugating ligand of MRI contrast agent is its highendogenous plasma concentration under physiologicalconditions.209

Chlorotoxin as a 36-amino acid peptide binding pref-erentially to gliosarcoma cells has been used for activetargeting. In 2009, Veiseh et al.123 created a nanoprobecontaining IONPs coated with biocompatible polyethy-lene glycol-grafted chitosan copolymer conjugating withtumor-targeting agent, chlorotoxin, and near-infrared flu-orophore. Relying on their observations, they introducedthe nanoprobe as a diagnostic and therapeutic agent forgliosarcoma which is able to overcome blood brain barri-ers (BBB).Radiotherapy (RT) as one of the conventional methods

of sarcoma therapy suffers from tumor resistance and sig-nificant risk of local recurrence. An anti-VEGF antibody isable to conjugate to IONPs and be utilized to target tumorcells and specify tumor location for RT. Preclinical andclinical investigations presented that anti-vascular endothe-lial growth factor (VEGF) and platelet-derived growth fac-tor receptors (PDGF-R) antibodies are able to enhance RT

efficiency.86 VEGF over expressed by most of cancer cellsis a key regulator of new blood vessel formation (angio-genesis) that is a fundamental process in tumor growth.210

The VEGF proteins are also expressed in the premalig-nant stages of tumor providing an opportunity for design-ing VEGF-targeted approaches for cancer diagnosis andtreatment.211213 VEGF receptors can also be used to tar-get the niche where soft tissue sarcoma grow by suni-tinib combined with radiotherapy.86!214!215 In other wordssoft tissue sarcomas require angiogenesis to grow and sur-vive, for example, PDGFR-alpha expression was seven-fold greater in the STSs than in the normal tissues.216

The inhibitor sunitinib targets receptors including VEG-FRs and PDGFRs critical to endothelial cell growth andtumor angiogenesis and control tumour growth.

Sarcoma Treatment with Drug DeliveryDrugs are released in the tumor region as a dynamicallyresponse of carriers to changes in the environmen-tal conditions such as temperature, light, pH, ultra-sound, and magnetic fields. long circulation time, highlevels of bioavailability and specific targeting, intra-cellular/organelle delivery, reporting/imaging and highbiodegradation are the crucial criteria for powerfuldrug delivery systems.45 Doxorubicin,217 paclitaxel,119

mitoxantrone,18 cisplatin,21 hydroxycamptothecin,6 anddihydroartemisinin110 are the chemotherapeutic drugswhich have been carried by nanomateials in order to treatseveral kinds of sarcoma. Additionally, oridonin as a tradi-tional drug,106 V2O5,101 oleic acid104 and resveratrol126 innano-scales have been used as antitumor drugs to eliminatediverse types of sarcoma cancer cells.Drug delivery to sarcoma cells the same as other

cancers face challenges such as variations in drugs biodis-tribution, absorption and metabolism, difficulty in drugsaccessibility to cancer cells, increasing tissue hydrostaticpressure and altering tumor vasculature to protect tumorsby their local microenvironment and finally drugs sideeffects. In this case IONPs could be functioned as nanocar-ries for nanomedicins and deliver them to tumor regions.Surface modified IONPs by possessing all the character-

izations make possibility of administering lower but moreaccurately targeted doses of drugs to cancer cells. In fact,by either external magnetic field or conjugating with tar-geting ligands they are able to target specific sites of can-cer cells in the body and act as promising therapeutic drugcarriers.

Sarcoma Treatment with Gene TherapyGenetic materials such as small interfered RNA (siRNA)and DNA are other therapeutic groups enhanced IONPsas a therapeutic agent. The efficiency of this techniqueis called magnetofection or transfection. The technique isestablished on the combination of genetic material to mag-netic nano particles in order to deliver therapeutic groupto cancer cell region.218



Sarcomas show two kinds of genetic variations.One group includes Chromosomal reciprocal transloca-tion resulting in fusion genes and oncogene or tumor-suppressor mutations such as c-kit and p53 and couldbe cured by gene therapy methods.85 For example,ONYX-0115 as a chimeric adenovirus is modified by theE1B gene and has been used in clinical trials to treatadvanced sarcomas.9!75 On the other hand, another groupof sarcomas which are specified by considerable geneticheterogeneity are unfeasible to treat by gene therapyalone.In RNA interference (RNAi) as a biological process,

siRNA molecules typically by destruction of specific mes-senger RNA (mRNA) molecules hinder gene expression ineukaryotic cells.219 In other words, the strategy is identi-fying the sequence of the gene responsible for the cancerand administering a complementary short synthetic doublestranded RNA. This siRNA targets and binds the identifiedgene and inhibiting its function. This leads to control ofcancer progression.220

SiRNA has been attractive research area because of itshigh specificity, high efficiency, and low toxicity.85 How-ever, siRNAs have poor stability in biological fluids andlow intracellular penetration, which causes reduction inthe biological efficacy.221 Therefore we need suitable car-riers to facile formation of a complex with siRNAs andto help them in stably crossing the cell membrane. Thecomplex must be released in the cytoplasm from endo-somes. After releasing of its siRNA cargo, the carriermust be nontoxic.222 In order to overcome this challenge,the surface-modified IONPs carrying functional siRNAshave represented a desirable option to advance the in vivointracellular delivery of these nucleic acid-base therapeuticagents.223226

Using modified magnetic NPs considerably enhancestransfection efficiency via lowering the diffusion bar-riers and makes the possibility of site-specific deliv-ery via an external magnetic field. IONPs coated withcathionic polymers such as polyallylamine hydrocholorideseem desirable carriers for anionic siRNA. In fact,polyallylamine hydrocholoride as a cationic polymer iscapable of interacting with anionic siRNA, forming areproducible complex which is stable aqueous suspen-sion and has low cell toxicity. For instance, nanodia-monds coated with polyallylamine hydrocholoride utilizedby Alhaddad et al.78 to delivery siRNA to Ewings sar-coma cells. In another investigation Medarova et al.122

combined siRNA (9L-GFP) silencing therapeutic methodwith MRI and and near-infrared optical imaging togethervia functionalized IONPs and tracked gliosarcoma tumorcell uptake of these probes. As other nucleotides appliedwith nanomaterials in order to perform gene therapy ofdiverse sarcoma cancers are shRNA as a recent patentfor Ewings sarcoma,92 and antisense oligonucleotide(AS-ON).77!93!227

Sarcoma Treatment with HyperthermiaHyperthermia which leads to cancer cells death by increas-ing temperature is another way to abolish sarcoma cells.Tumor tissues have less vasculature endurance rather thannormal tissues. There are some difficulties in hyperthrmaltherapy including uniform heating of only the tumor regionwithout damaging normal tissue, variation in heating abil-ity because of tumor size,228 the position of the electrodes,adhesion of the electrodes at uneven sites in radiofre-quency thermal therapy, and considerably injury to thepatient in treating large tumors by microwave thermal ther-apy. These problems could be substantially diminished byapplying nanomaterials to generate local heat in tumorregion or carrying thermal agents towards tumor cells. Asan instance, Tang et al.98 conveyed indocyanine green asthermal-Optical agents by polymeric nanocarrier to uterinesarcoma cells to generate heat for hyperthermia.Magnetic NPs which are able to produce local hyper-

thermia in tumor regions via an alternative magnetic fieldseem promising therapeutic method. Figure 4 shows thehyperthermia effect of IONPs under fluctuating externalelectromagnetic field. For example Babincova et al.22 uti-lized magnetic NPs hyperthermia (4244 "C was achievedafter 710 minutes of exposure) in vivo and in vitro toabolish BP-6 rat sarcoma cells. In a recent study mag-netic heating effect of Fe3O4 ferrofluids (48.6 "C57 "C)were applied in ex vivo condition on sarcoma 180 cells byLuong et al.112 which caused elimination of 50% of can-cer cells after 45 minutes. There are many similar other

Figure 4. Hyperthermia effect of IONPs under fluctuating externalelectromagnetic field.


Xuchuanhyperthermal

Xuchuan

Xuchuan

Xuchuan

Xuchuan

Xuchuan

Xuchuan

Xuchuan

Xuchuanradio fre-

Xuchuanoptical


researches113115 which have used hyperthermia againstsarcoma 180 cells.Moreover hyperthermia could be applied along with

drug delivery to increase permeability of nanocrriers ofdrugs into sarcoma cells. Issels et al.91 ran a clinical inves-tigation including 341 STS patients and studied the apply-ing chemotherapy (consisting of etoposide, ifosfamide,and doxorubicin) together with regional hyperthermia oralone. They found chemotherapy with local hyperther-mia enhances local control compared with chemotherapyalone. In fact, drug delivery based on nanocarriers per-meability into tumor vasculature could be limited due tonanocarries size, compact nature of the interstitial matrixin tumors and being permeable in only a fraction of thetumor vessel. In order to overcome these challenges Liet al.105 in a recent investigation utilized local mild hyper-thermia in fibrosarcoma to increase permeability of drugcarried by liposome NPs. In other words, hyperthermiaincreased the pore size in tumor vasculature (about 30%),whilst decreased steric and hydrodynamic hindrances. Liet al. also applied optimized thermo sensitive liposomeas nanocarrier to enable a triggered drug release uponmild hyperthermia. Also, Hyperthermia healing effect ofIONPs has been used along with other therapeutic meth-ods in order to treat sarcoma. For example, Brusentsovet al.229 applied heat generated from different kinds of fer-romagnetic fluids and radiotherapy singly or together toeliminate MX11 sarcoma cells. They observed the elimi-nation of MX11 cells using both ferrofluids hyperthermiaand radiofrequency was much more effective than withradiofrequency alone.

CONCLUSIONS AND OUTLOOKIn summary, IONPs (alone and engineered) have shownpromising features in application of sarcoma diagnosisand treatment, such as being an effective magnetic res-onance imaging contrast agent, and a versatile vehiclefor genetic materials, small drug molecules, targeting lig-ands or all of them together, as well as hyperthermiaeffect. The IONPs are able to produce local hyperther-mia in sarcoma regions via an alternative magnetic field.Also, using IONPs could be more affordable diagnosis.Therefore, establishing new modified and functionalizedIONPs to diagnosis and treatment of sarcoma could be stillattractive future investigations. However, to our knowledgejust a few preclinical and clinical investigations regard-ing applying IONPs against sarcoma have been reportedwhich presents some major issues that need to be care-fully considered. These include, development of novelsurface modified IONPs that are able to carry target agentsagainst the targets overexpressed by sarcoma cells, as wellas special drugs and genes, and bring about improve-ment of diagnosis and treatment efficiency. Therefore, itis highly demanded to crate magnetic nanoparticels with

optimum physiochemical properties, including size, mor-phology, surface characteristics, amount of administration,reversibility and strength of binding between therapeu-tic agent and magnetic NPs as well as most favorablemagnetic field characteristics consist of geometry, strengthand duration. Moreover, understanding mechanism beyondphysical experiments or tests for finding the principlesgoverning diagnosis, treatment and safety assessment arealso demanding research areas.

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