Surface Engineering of Iron Oxide Nanoparticles for...

Surface Engineering of Iron Oxide Nanoparticles for

Cancer Therapy

Iron oxide nanoparticles (IONPs) have attracted extensive applications in biomedical fields such as drug

delivery, magnetic resonance imaging (MRI) for medical diagnosis and cancer therapeutics. Designing

efficient IONPs for cancer treatment requires their surface modification with suitable biocompatible organic

and inorganic molecules having multifunctional groups. This review focuses on recent developments in the

area of surface engineering of IONPs and their potential applications in cancer therapy. The imaging and

targeting potential of IONPs in conjugation with luminescent markers and receptor molecules are briefly

discussed.

1,2 1 1, 1, 2,Santosh L. Gawali , Bijaideep Dutta , K. C. Barick *, and P. A. Hassan *

1Chemistry Division, Bhabha Atomic Research Centre, Mumbai – 400085, India2Homi Bhabha National Institute, Anushaktinagar, Mumbai – 400094, India

Review

INTRODUCTION

Nanotechnology involves the study of

materials at a nanometer length scale

(1–100 nm at least in one dimension), for

searching new properties and

applications. When particle size is

reduced to the nanometer length scale,

materials exhibit remarkably unique size-

dependent physical, chemical and

biological properties. Among the others,

magnetic nanoparticles (MNPs) have

received a great deal of attention due to

their unique physico-chemical properties

and potential applications in biomedical

fields including magnetic resonance

imaging (MRI), targeted drug delivery

and hyperthermia treatment of cancer

(Mornet et al., 2004; Chandra et al.,

2011; Barick et al., 2012; Barick et al.,

2015). These biomedical applications

require narrow particle size distribution

and their long term colloidal and

chemical stability in biological fluid

(Cheng et al., 2009; Gao et al., 2008).

Further, significant challenges lie in

avoiding undesirable uptake of these

particles by reticulo-endothelial system

(RES) as well as their site-specific

targeting in in vivo studies. The human

Key words: Iron oxide, nanoparticles, functionalization, cancer therapy, drug delivery, hyperthermia, MRI.*Corresponding Authors: K. C. Barick and P. A. Hassan, Chemistry Division, Bhabha Atomic Research Centre, Mumbai – 400 085, IndiaEmail: [email protected] (K. C. Barick), [email protected] (P. A. Hassan)

Biomed Res J 2017;4(1):49–66

body is a highly complex system that

enforces significant biological barriers to

external objects. Thus, MNPs introduced

into the blood undergo a complex

pathway before reaching the site of

interest. Therefore, the diagnostic and

therapeutic efficacy of MNPs primarily

depends on the design of nanoparticles

(Revia and Zhang, 2016). Finally,

clearance of nanoparticles from spleen

and kidney needs to be considered. Thus,

the surface of MNPs should be

engineered with suitable surface

functionality to provide colloidal

stability, optimal blood circulation time

and efficacy to pass through the capillary

systems.

Among various MNPs, surface

functionalized iron oxide (Fe O and γ-3 4

Fe O ) nanoparticles have been widely 2 3

used for various biomedical applications

because of its unique magnetic properties

and biocompatibility (Peng et al., 2008;

Barar and Omidi, 2014). Combining the

optimal magnetization of iron oxide

nanoparticles (IONPs) with appropriately

designed/ engineered surface, IONPs can

be conjugated with various therapeutic

agents, biomolecules and luminescent

markers (Figure 1). The coating materials

used for surface engineering provide

colloidal and chemical stability to

IONPs, and create suitable sites for

further conjugation. The universal

strategy involved in surface engineering

is coating of nanoparticles with

biocompatible materials (Wu et al., 2008;

Laurent et al., 2008; Chandra et al.,

2011; Barick et al., 2015). The current

review summarizes recent developments

in the area of surface functionalization of

IONPs with various organic/inorganic

molecules as well as biomolecules, with

a discussion on their therapeutic, imaging

and diagnostic applications.

Surface Functionalization

The surface properties such as surface

charge and surface chemistry primarily

plays a crucial role in improvement of

chemical and colloidal stabilization of

nanoparticles as well as their

biocompatibility (Laurent et al., 2008;

Barick et al., 2015; Ding et al., 2010; Lei

et al., 2013). Further, the protein-

particles interaction is a significant issue

for biomedical applications of

Figure 1: Schematic representation of surface

engineered IONPs conjugated with various therapeutic

agents, biomolecules and luminescent markers.

50 Iron oxide nanoparticles for cancer therapy

Biomed Res J 2017;4(1):49–66

nanoparticles (Nel et al., 2009; Moyano

and Rotello, 2014). Recently, it has

attracted considerable attention due to its

importance in nanotoxicity and

prevention of opsonization in biological

medium. The dynamic layer of proteins

(protein corona) on the nanoparticle

surface determines its ability to interact

with the living system and thereby

modifies the cellular uptake of

nanoparticles. Hence, there is a need to

provide stealth coatings on nanoparticles

surface with suitable biocompatible

materials for the enhancement of long

term blood circulation time by reducing

of its non-specific binding with serum

proteins after the intravenous

administration. Various coating agents

such as polymers/organic molecules,

inorganic materials and biomolecules

were extensively used for surface

engineering/functionalization of IONPs,

which provides a protective shell to

stabilize IONPs, avoid agglomeration

and prevent the dissolution and release of

toxic ions. These coating agents can be

introduced (either adsorbed or end

grafted) onto the surface of nanoparticles

during their synthesis (in situ) or post-

synthesis (ex situ) process (Wu et al.,

2008; Chandra et al., 2011; Nigam et al.,

2011; An et al., 2012; Barick and Hassan,

2012; Barick et al., 2015).

Biocompatible and biodegradable

polymer, polyethylene glycol (PEG) is

widely used in stabilizing IONPs. Rana

et al. (2015) prepared water dispersible

carboxyl PEGylated Fe O nanoparticles 3 4

2+(CPMN) by co-precipitation of Fe and 3+Fe ions in basic medium followed by in

situ coating of bifunctional PEG-diacid

molecule. The negatively charged CPMN

used as a core material for preparation of

polyaniline shell cross-linked Fe O 3 4

magnetic nanoparticles (PSMN) and

reported that the use of PSMN,

composed of PEG and polyaniline, may

be advantageous for effective transport of

heat from Fe O core to surrounding 3 4

medium during magnetic hyperthermia

(Rana et al., 2014). Rezayan et al. (2016)

prepared Fe O IONPs modified with 3 4

water soluble polymer (carboxyl

functionalized PEG via dopamine linker)

for diagnosis of breast cancer by MRI.

These PEG-grafted Fe O nanoparticles 3 4

were less toxic and more biocompatible

(long survival rate of breast cancer cells,

MDA-MB-231) than unmodified nano-

particles. The cellular uptake of modified

MNPs was 80%, whereas it was reduced

to 9% for unmodified MNPs. Kumar et

al. (2013) prepared mesoporous Mg

doped IONPs (MgFe O ) nanoassemblies 2 4

Gawali et al. 51

Biomed Res J 2017;4(1):49–66

through a PEG-diacid mediated polyol

method for chemo-thermal therapy. Sahu

et al. (2015) developed highly aqueous

stable, carboxyl enriched, PEGylated

mesoporous FePt-Fe O composite 3 4

nanoassemblies by a simple hydro-

thermal approach. The use of

multidentate polymeric molecule such as

PEG–polymeric phosphine oxide also

improves the water stability of γ-Fe O2 3

nanoparticles (Jun et al., 2007). The

polymeric shell provides colloidal

stability and allows the encapsulation of

drugs. In addition, the natural polymers

including dextran, polylactic acid,

chitosan, starch, gelatin, albumin and

ethyl cellulose have also been

extensively used for enhancement of

biocompatibility and aqueous stabili-

zation of IONPs (Yu and Yang, 2010).

Further, organic molecules with

functional groups such as carboxyl,

amine, thiol and phosphate have been

used as coating agents for preparation of

water-dispersible and biocompatible

IONPs (Barick and Hassan, 2012; Barick

et al., 2012; Nigam et al. 2011; Majeed et

al., 2015; Sharma et al., 2014). These

organic molecules usually conjugated to

the surface of particles via chemisorption

of functional groups; while, the free

groups provided stability to particles in

the water medium by forming hydrogen

bonding with water. In addition, the free

functional groups create sufficient

surface charge on particles making them

hydrophilic through electrostatic

repulsion. Barick and Hassan (2012)

reported that glycine is a striking

molecule for in situ surface passivation

of IONPs due to the strong binding

affinity of the carboxylate groups

towards Fe O nanoparticles. The free 3 4

amine molecules may be exploited for

conjugation of biomolecules, fluorescent

markers and receptor molecules. The

amine coated particles have been used as

core material for growing multifunctional

peptide mimic shell consisting of glycine

and arginine by Michael addition and

amidation reactions. Further, these

particles showed negligible cytotoxicity

effect to HeLa cells (Barick et al., 2012).

Nigam et al. (2011) reported citrate

stabilized Fe O nanoparticles via 3 4

chemical conjugation of some of its

carboxylate group. From SRB assay, they

have found that these citrate stabilized

nanoparticles are reasonably bio-

compatible and do not have toxic effect

for further in vivo use. Majeed et al.

(2015) and Sharma et al. (2014) prepared

phosphate coated nanocarriers by in situ

modification of Fe O nanoparticles with 3 4


Biomed Res J 2017;4(1):49–66

sodium tripoly-phosphate (STTP) and

sodium hexametaphosphate (SHMP),

respecti-vely. This phosphate

modification not only enhanced the

colloidal stability of nanoparticles but

also rendered minimal inherent toxicity

to them.

The hydrophobic Fe O nanoparticles 3 4

(HMNPs) are converted to hydrophilic

by post-synthesis processes of ligand

exchange and ligand addition. In ligand

exchange process, the initial hydrophobic

ligand presents on the surface of particles

are replaced by strongly bonded water-

dispersible hydrophilic ligand. The

organic ligands like dopamine (DA), 2,3-

meso dimercaptosuccinic acid (DMSA)

and dendron molecules were used for

stabilizing HMNPs by ligand exchange

method (Singh et al., 2011; An et al.,

2012; Hofmann et al., 2010). An et al.

(2012) prepared hydrophilic magnetic

suspension by ligand exchange of oleic

acid coated Fe O nanoparticle with 3 4

dopamine hydrochloride. Hofmann et al.

(2010) reported the preparation of water-

dispersible hydroxamic acid stabilized

IONPs by modifying oleic coated

particles with dendron ligands. They

have evaluated the cytotoxicity effect of

these IONPs by WST-8 assay and

observed no significant decrease in cell

viability up to 100 μg/ml of Fe. Calero et

al. (2015) developed DMSA coated

IONPs and investigated their interaction

with MCF-7 breast cancer cell line.

These nanoparticles showed efficient

internalization without inducing either

cytotoxicity, alteration of the major

cytoskeletal components, vinculin

protein dynamics, cell cycle or reactive

oxygen species (ROS) formation.

In ligand addition process, an

additional layer of ligand molecules is

introduced thorough covalent and non-

covalent interaction. In covalent

interaction, the second layer formed by

strong covalent bonding between the free

function groups present on the surface of

particles and available ligands, whereas

in non-covalent process the second layer

formed through weak hydrophobic-

hydrophobic interaction. For instance,

bifunctional Fe O MNPs (carboxyl for 3 4

drug binding and amine for receptor

tagging) were prepared by covalently

binding the bioactive cysteine molecules

on the surface of hydrophobic

undecenoic acid coated Fe O magnetic 3 4

nanoparticles via thiol-ene click reaction

between the double bond of undecenoic

acid and thiol group of cysteine (Rana et

al., 2016). Similarly, non-covalent ligand

addition method is used in developing

53Gawali et al.

Biomed Res J 2017;4(1):49–66

pluronic stabilized Fe O magnetic 3 4

nanoparticles (PSMNPs) by introducing

amphiphilic PEG based block co-

polymer, Pluronic P123 on the surface of

HMNPs (Barick et al., 2016). These

PSMNPs are highly biocompatible (more

than 90% of MCF-7 cells were viable

even at a concentration of 1 mg/ml) and

easily dispersible in aqueous medium.

The hydrophobic groups of the Pluronic

polymer form robust coating around

HMNPs through hydrophobic-

hydrophobic interaction; while the

hydrophilic groups of Pluronic extends

into the water medium conferring high

degree of aqueous stability to MNPs.

Further, hydrophilic external shell of

inorganic materials can be provided on

the surface of hydrophobic nanoparticles

by formation of core-shell structure

without removal of the initial ligands. Lai

et al. (2008) developed iridium-complex-

functionalized Fe O /SiO core/shell 3 4 2

nanoparticles for multifunctional

applications by introducing inorganic

SiO shell containing iridium complex 2

ligand. The second layer provides

colloidal stability and allows

encapsulation of foreign molecules. Zhu

et al. (2012) developed various surface

coated superparamagnetic iron oxide

(SPIO) nanoparticles (bare SPIO,

SPIO@SiO , SPIO@SiO -NH , and 2 2 2

SPIO@dextran) and compared their

cellular uptake in mammalian cell lines

and mouse mesenchymal stem cells. The

authors claimed that the cellular uptake

efficiency of SPIO depends on both the

cell type and surface characteristics. For

instance, aminosilane functionalized

SPIO significantly enhanced the cellular

uptake efficacy without inducing cyto-

toxicity in most of these cell lines.

Applications of IONPs in Cancer

Therapy

Surface functionalized IONPs are

extensively used in hyperthermia therapy,

MRI diagnosis and drug delivery

applications (Chandra et al., 2011;

Barick et al., 2012; Barick et al., 2014).

In hyperthermia therapy, IONPs acted as

heating source for killing of cancer cells oat 5–7 C above human body temperature

under AC magnetic field (ACMF)

(Barick et al., 2012; Chandra et al.,

2011). Tumor cells are more sensitive

than normal cells to heating in the range

of 42–45°C (Hervault et al., 2014;

Behrouzkia et al., 2016). Due to

disorganized and compact vascular

structure, tumor cells have difficulty in

dissipating heat. Therefore at 42–45°C,

hyperthermia may cause cancerous cells


Biomed Res J 2017;4(1):49–66

to undergo apoptotic cell death. Above

45°C, tumour cell die due to necrosis but

it may also affect healthy cells.

Coagulation or carbonization occurs as a

result of thermal ablation. In thermal

activation of IONPs under ACMF, an

increase in temperature is the collective

effect of different types of loss processes

such as hysteresis loss, Néel and

Brownian relaxation (Tomitaka et al.,

2011). In nanoparticulate systems,

hysteresis losses can be neglected due to

superparamagnetic nature of particles.

The use of IONPs in magnetic

hyperthermia depends on their heating

ability, which is expressed in terms of the

specific absorption rate (SAR). Recently,

Barick et al. (2014) developed carboxyl

decorated iron oxide nanoparticles

(CIONs) and investigated the heating

efficacy and MR contrast properties. The

authors observed superparamagnetic

behavior of CIONs with magnetic

moment of 58 emu/g at 20 kOe and

blocking temperature (T ) of ~200 K. B

The inductive heating experiments

showed that a magnetic field of 0.251

kOe at fixed frequency of 265 kHz

produces sufficient energy for localized

heating of these magnetic suspension (1 omg/ml) to 42–43 C within 20 min (Figure

2a). The aqueous suspensions of CIONs

showed excellent contrast properties in

MRI with transverse relaxivity (r ) value 2

-1 -1of 215 mM s (Figure 2b–c). Stability of

the particles in water and the high r value 2

indicate IONPs as promising candidate

for high-efficiency T contrast agent in 2

MRI diagnosis even at lower dose.

Nigam et al. (2011) prepared citrate-

stabilized superparamagnetic IONPs

having magnetization of 57 emu/g at 20

Figure 2: (a) Temperature vs. time plot of aqueous

suspension of CIONs under different ACMF, (b) T -2

weighted MR images of CIONs for different concentrations

of Fe, and © 1/T vs. Fe concentration plot at 1.5 T. 2

Reproduced from Barick et al. (2014) with permission from

Elsevier.

55Gawali et al.

Biomed Res J 2017;4(1):49–66

kOe and Curie temperature of about o580 C by co-precipitation method (Figure

3a), and demonstrated their heating

efficacy under different ACMF. The SAR

values of these IONPs were reported to

be 32.26, 38.63 and 49.24 W/g of Fe with

ACMF of 7.64, 8.82 and 10.0 kA/m,

respectively (at a frequency of 425 kHz).

Giri et al. (2005) explored the heating

efficacy of Mn substituted ferrites,

Fe Mn Fe O (0x1) at variable field 1−x x 2 4

from 10 to 45 kA/m with a fixed

frequency of 300 kHz and observed that

SAR value increases with increasing the

field strength and magnetic moment of

ferrites. In vitro studies on these

substituted ferrites showed that the

threshold biocompatible concentration is

dependent on the nature of ferrite and

their surface modification.

Rana et al. (2014, 2015) performed in

vitro hyperthermia on WEHI-164 cell

lines in presence of carboxyl PEGylated

Fe O magnetic nanoparticles (CPMN) 3 4

and polyaniline shell cross-linked Fe O3 4

nanoparticles (PSMN) at ACMF of 0.335

kOe for 10 min (frequency of 265 kHz).

They have not observed any significant

change in viability of WEHI-164 cells in

presence of these particles. However,

PSMN (1 mg) under ACMF showed

about 22.5% decreases in cell viability as

compared to the marginal (~8%)

decrease with CPMN under similar

condition.

It is noteworthy to mention that both

the particles exhibited good aqueous

dispersion with maximum magnetiza-

tions of 67.5 and 63.5 emu/g for CPMN

and PSMN, respectively at 20 kOe

(Figure 3b). Further, Prasad et al. (2007)

Figure 3: Figure 3. Room temperature M vs. H plots of (a)

citrate-stabilized IONPs (inset shows its M vs. T plot) and

(b) CPMN and PSMN (inset shows the photographs of

PSMN in presence and absence of permanent magnet of

field strength ~2.5 kOe). Reproduced from Nigam et al.

(2011) and Rana et al. (2016) with permission from

Elsevier and The Royal Society of Chemistry, respectively.

56

a

b

Iron oxide nanoparticles for cancer therapy

Biomed Res J 2017;4(1):49–66

Maier-Hauff et al. (2007). The side

effects of intra-tumoral thermotherapy

approach using IONPs were moderate

and no serious complications were

observed (Maier-Hauff et al. 2011). ,

Johannsen et al. (2010) performed

insterstitial heating of tumors following

direct injection of MNPs in treatment of

human prostate cancer. In an interesting

review article, Luo et al. (2014)

summarized various clinical trials of

magnetic hyperthermia for treatment of

tumors.

Surface engineered IONPs are

engulfed more easily by cells than larger

molecules. Thus, they can be used as

smart drug delivery vehicle. Various

surface engineered IONPs were

developed for delivery of anticancer drug

molecules (Barick et al., 2012; Rana et

al. 2015; Nigam et al., 2011;Majeed et

al., 2015; Sharma et al., 2014). In these

systems, the drug molecules are usually

adsorbed onto the nanoparticles or bound

on their surface through covalent or

electrostatic interaction or encapsulated

in the core-shell structure. In many

studies, the positively charged anticancer

drug, doxorubicin hydrochloride (DOX)

was loaded onto the surface of negatively

charged citrate, phosphate and cysteine

functionalized IONPs through

investigated the mechanism of cell death

induced by magnetic hyperthermia with

Mn substituted IONPs (γ-Mn Fe O ). x 2–x 3

In general, the thermal activated

killing of cancer cells depends on the

heat efficacy of IONPs, which in turn

dependent on the magnitude of applied

ACMF and frequency in addition to

physical properties of IONPs such as

magnetization, particles size and size

distribution (Samanta et al., 2008; Barick

and Hassan, 2012). Theoretical and

experimental investigations performed by

Brezovich (1988) have shown that for

whole-body exposure, the product of

ACMF (H) and frequency (f) should not 8 −1 exceed the limit H.f = 4.85×10 A m

−1s , at least in the case of exposure times

in the order of one hour or more.

However, this factor will be accordingly

weaker for smaller body regions being

under ACMF. Hilger et al., (2005)

demonstrated that a combination of field

amplitude of about 10 kA/m and 9frequency of about 400 kHz (H.f = 4×10

−1 −1A m s ) is suitable for breast cancer

treatment.

Clinical studies for application of

magnetic hyperthermia therapy in

humans were initiated in 2007 by intra-

tumoral injection of IONPs on

glioblastoma multiforme patients by

57Gawali et al.

Biomed Res J 2017;4(1):49–66

passive or magnetic targeting

mechanisms (Barick et al., 2015; Lübbe

et al., 2001). In a recent study, Rana et al.

(2016) used folic acid conjugated

bifunctional MNPs (FBMNPs) as a drug

delivery vehicle that significantly

enhanced the accumulation of DOX in

KB cells with over-expressed folate

receptors as compared to bifunctional

MNPs (BMNPs) without folate labeling

(Figure 4). Drug targeting by external

magnetic field is a platform technology

for site-specific drug delivery (Alexiou et

al., 2003). In an in vivo study, Gang et al.

(2007) investigated the anti-tumor effects

caused by magnetic (Fe O ) poly ε-3 4

caprolactone (PCL) nanoparticles

containing anticancer drug (gemcitabine)

in nude mice bearing subcutaneous

human pancreatic adenocarcinoma cells

(HPAC). Authors claimed that the

magnetic PCL nanoparticles may provide

a therapeutic benefit by delivering drugs

efficiently to magnetically targeted tumor

tissues, thereby achieving anti-tumor

effects with low toxicity.

In order to deliver hydrophobic

anticancer drugs, various Pluronic

stabilized Fe O MNPs have been 3 4

developed. In these systems, hydrophobic

drugs are loaded in the interface between

hydrophobic MNPs and Pluronic layer.

electrostatic interactions (Rana et

al.,2015; Nigam et al., 2011; Majeed et

al., 2015; Sharma et al., 2014; Rana et

al., 2016). The covalent binding of DOX

with IONPs through formation of amide

and azo bonds was reported by

Purushotham et al. (2009) and Chen et

al. (2016). The bound drug molecules are

release under the influence of external

stimuli such as pH, temperature, light,

ultrasound and magnetic field etc.

(Chandra et al., 2011).

These drug loaded particles can be

targeted to cancer cells by either active or

Figure 4: Fluorescence microscopy images of KB cells

after incubation with DOX-FBMNPs and DAPI at culture

conditions. For comparative purpose, fluorescence

microscopy images of control KB cells, and KB cells after

incubation with DOX-BMNPs and DAPI were also shown

(scale bar: 25 μm, red filter for DOX and blue filter for

DAPI). Reproduced from Rana (2016) with et al.

permission from The Royal Society of Chemistry.


Biomed Res J 2017;4(1):49–66

Barick et al. (2016) prepared Pluronic

P123 stabilized Fe O MNPs (PSMNPs) 3 4

for delivery of hydrophobic drug

curcumin, and observed that curcumin

loaded PSMNPs formulation were

superior to pure curcumin in causing

tumor cytotoxicity, possibly due to the

increase in bioavailability of drug to the

targeted site. Curcumin-loaded

nanoparticles composed of Fe O MNPs 3 4

coated with β-cyclodextrin (β-CD) and

Pluronic F68 polymer have been used in

breast cancer therapeutics and imaging

(Yallapu et al., 2012). Besides in vitro

evaluation of drug loaded IONPs, there

are also numerous investigations on in

vivo targeted delivery of anticancer drugs

to tumor site in animal models (Foy et

al., 2010; Pisciotti et al., 2014).

Magnetic hyperthermia in association

with chemotherapeutic agents enhances

the effectiveness in cancer treatment.

Magnetic hyperthermia increases the

amount of drug carrier at tumor site by

increasing flow and vessel permeability,

and enhances drug toxicity in certain

drug resistant cancer cells (Chen et al.,

2008). Thus, combination therapy

involving hyperthermia and chemo-

therapy is evolving as an attractive

strategy to optimize cancer therapy. The

induction heat is also acts as a driving

force for drug-release. Kim et al. (2008)

reported that self-heating from Co

substituted IONPs (CoFe O ) under 2 4

ACMF can be used either for

hyperthermia or to trigger the release of

anticancer drug using thermo-responsive

polymers. Oliveira et al. (2013) observed

intracellular drug release and increased

cytotoxic effect from hybrid

polymersomes (loaded with DOX and

IONPs) when exposed to high frequency

ACMF. Our group developed peptide

mimic shell cross-linked magnetic

nanocarriers (PMNCs) with higher

cytotoxicity in conjugation with DOX

under ACMF as compared to individual

treatment (Figure 5) (Barick et al., 2012).

The enhanced toxicity of DOX-PMNCs

under an ACMF suggested a strong

potential of PMNCs in conjugation with

drug for combination cancer therapy. Jia

et al. (2012) developed MNPs (Fe O ) 3 4

and drug (doxorubicin) co-encapsulated

PLGA nanocarriers and compared the

antitumor effect of drug-MNPs with or

without an external magnetic field and

free drug in the subcutaneous tumor

model of Lewis lung carcinoma (LLC).

The authors claimed that tumor growth

rates in mice were significantly

decreased upon treated with drug-MNPs

and an external magnetic field, whereas

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Biomed Res J 2017;4(1):49–66

free drug treatment only slightly reduced

the tumor growth. Yang et al. (2013)

reported that the tumor growth in mice

treated with paclitaxel loaded Fe O 3 4

nanoparticles was significantly inhibited

compared with the controls and the

groups that received nanoparticles alone

or paclitaxel alone.

Combination of cellular imaging with

hyperthermia permits verification and

quantification of treatment, and can serve

as an efficient modality for targeted

cancer therapy. In addition, IONPs

coated with a specific fluorescent probe

may provide better understanding of

cellular processes. Hence, magnetic

luminescent hybrid nanostructures have

received a great deal of attention in

biomedical applications. Various

fluorescent organic dye and quantum dot

(QD) tagged multifunctional IONPs have

been developed and investigated to

overcome limitations of conventional

therapy (Mahmoudi et al., 2011; Sharrna

et al., 2006; Ma et al., 2009). The less

toxic rare-earth based luminescent

nanomaterials are useful for biological

labeling as they offer various advantages

over organic fluorescent molecules and

QDs (Wang et al., 2010; Di et al., 2011;

Barick et al., 2015). Wang et al. (2010)

reported increased imaging capability of

Fe O @YPO :Ln (Ln = Tb, Eu) 3 4 4

magnetic-fluorescent hybrid spheres. Di

et al. (2011) demonstrated the in vitro

imaging capability of Eu doped TbPO 4

nanoparticles. Recently, we have

developed a bifunctional Fe O decorated 3 4

YPO : Eu hybrid nanostructure by 4

covalent bridging of carboxyl PEGylated

Fe O and amine coated YPO : Eu 3 4 4

particles (Barick et al., 2015). These

nanostructures showed colloidal stability,

tunable magnetic and optical properties,

and self-heating capacity under an

external ACMF. Sahu et al. (2014)

developed biphasic system (BPS) 3+consisting of PEGylated Tb -doped

Figure 5: Viability of HeLa cells during combination

therapy using DOX-PMNCs with a DOX concentration of 8

μM along with various control groups. Reproduced from

Barick et al. (2012) with permission from WILEY-VCH

Verlag GmbH& Co.


Biomed Res J 2017;4(1):49–66

3+GdPO nanorice sensitized with Ce 4

(PEG-NRs) and glutamic acid coated

IONPs with multifunctional capabilities.

These PEG-NRs exhibit green light

luminescence properties and a high

degree of aqueous stability.

Recently, the development of

upconversion-magnetic hybrid materials

has received a great deal of attention due

to the potential benefits of multimodal

functionality in biomedical applications

(Li et al., 2013). Hu et al. (2011)

prepared core-shell-structured NaYF : 4

Yb,Er/Tm@SiO @Fe O nanoparticle 2 3 4

having very good superparamagnetic and

luminescent properties for bio-

applications. Liu et al. (2008)

developed monodisperse silica nano-

particles encapsulating upconversion

fluorescent (NaGdF : Yb, Er) and 4

superparamagnetic (Fe O ) nanocrystals 3 4

(SiO /UC-SPM) capable of both imaging 2

and drug targeting. Mi et al. (2010)

demonstrated the biolabeling and

fluorescent imaging of cancer cells by

using multifunctional nanocomposites of

superparamagnetic (Fe O ) and NIR-3 4

responsive rare earth-doped

upconversion fluorescent (NaYF : Yb, 4

Er) nanoparticles. Specifically, the hybrid

nanostructure provides an excellent

platform to integrate luminescent and

magnetic materials into a single entity for

use as a potential tool for simultaneous

cellular imaging and therapy.

SUMMARY AND FUTURE SCOPE

The review highlighted various strategies

for surface engineering of IONPs and

applications in cancer therapy. Emphasis

is laid on tagging the surface of IONPs

with suitable organic/inorganic moieties

to obtain colloidal stability,

biocompatibility and chemical

functionality for further conjugation with

drugs, luminescent markers and targeting

molecules.

Although several materials and

methods are available, the challenges lie

in development of suitable strategies in

surface engineering of IONPs to achieve

long-term colloidal stability in body

fluid. The real time monitoring/imaging

and issues related to for safe application

of IONPs will facilitate clinical

applications. Further, the matter of safety

and toxicity of nanoparticles has become

an issue of interest to the public.

Therefore, understanding the interactions

of nanoparticles with biological systems

should be emphasized in future.

61Gawali et al.

Biomed Res J 2017;4(1):49–66

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