oxide and hybrid nanostructures for therapeutic apps

8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps

httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 115

Oxide and hybrid nanostructures for therapeutic applications

Sudeshna Chandra KC Barick D Bahadur

Department of Metallurgical Engineering and Materials Science Indian Institute of Technology Bombay Mumbai 400076 India

a b s t r a c ta r t i c l e i n f o

Article history

Received 2 February 2011

Accepted 8 June 2011

Available online 15 June 2011

Keywords

Nanostructures

Hybrid

Stabilizers

Cancer therapy

The research on biomedical applications of nanoparticles has seen an upsurge in recent years due to their

unique capabilities in treatment of ailments Though there are ample reviews on the advances of

nanoparticles right from their fabrication to applications comparatively fewer reviews are available for the

nanostructured materials particularly on oxidesand hybrids These materials possess unique physicochemicalproperties with an ability to get functionalized at molecular and cellular level for biochemical interactions

Keeping the enormosity of the nanostructures in mind we intend to cover only the recent and most

noteworthy developments in this area We particularly emphasize on iron oxide and its derivatives zinc

oxides layered double hydroxides silica and binaryternary metal oxides and their applications in the area of

therapeutics This review also focuses on the designing of biodegradable and biocompatible nanocarriers and

critical issues related to their therapeutic applications Several representative examples discuss targeting

strategies and stimuli responsive nanocarriers and their therapeutics

copy 2011 Elsevier BV All rights reserved

Contents

1 Introduction 1267

2 Properties of the nanostructures to be used as carriers 1268

21 Size and shape 1268

22 Surface functionality 1268

3 Stabilization of oxide and hybrid nanostructures 1269

31 Organic stabilizers 1269

311 Small molecules 1269

312 Macromolecules 1269

32 Inorganic stabilizers 1270

33 Other stabilizers 1270

4 Therapeutic applications of oxide and hybrid nanostructures 1271

41 Challenges faced in the drug delivery 1271

411 Drug loading and release 1271

412 Cellular uptake and Imaging 1274

42 Hyperthermia treatment of cancer 1276

43 Other therapeutic applications 1277

44 Towards clinical trials 1277

5 Conclusion and future scope 1278Acknowledgements 1278

References 1278

1 Introduction

Advances in nanotechnology play an important role in designing

nanomaterials with speci1047297c functional properties that can address the

shortcomings in the area of diagnostics and therapeutics The

potential of nanomaterials has sparked enormous interest in the

Advanced Drug Delivery Reviews 63 (2011) 1267ndash1281

This review is part of the Advanced Drug Delivery Reviews theme issue on ldquoHybrid

Nanostructures for Diagnostics and Therapeuticsrdquo

Corresponding author

E-mail address dhirenbiitbacin (D Bahadur)

0169-409X$ ndash see front matter copy 2011 Elsevier BV All rights reserved

doi101016jaddr201106003

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e w w w e l s ev i e r c o m l o c a t e a d d r



drug industry and has envisaged several applications as can be

evidenced by the exponential growth of activities in this 1047297eld The

advantages of the nanoparticles are mainly due to their nanoscale size

and large surface area with the ability to get functionalized with

targeting ligands therapeutic moieties and biomolecules [1] The fact

that the size of the nanoparticles is quite similar or smaller to the size

range of several bio entities makes them a natural companion in the

hybrid system Furthermore the nanoparticles can easily gain access

to various areas of the body without interfering into normal functionsand has the requisite potential for diagnostic and therapeutics The

ability to manipulatebind individual molecules at nanoscale has

provided ample opportunity for new therapeutic and diagnostic

applications [2] In this way either ldquohybridrdquo nanostructures can be

obtained or it may be embedded in biocompatible materials to impart

new functionalities Since multifunctional nanostructures are desir-

able for many applications like chemical and biological sensing and

diagnosis [3ndash8] sustained drug delivery [9] and hyperthermia [1011]

the fabrication of the nanostructures is signi1047297cant for controlling

crystalline morphology and surface architecture

Drug delivery is a key technology for the realization of nanome-

dicine and nanostructured mediated drug delivery systems play an

important role in improving the properties of already existing

therapeutic and diagnostic modalities Such systems with controlled

composition shape size and surface morphology are designed to

enhance solubility biocompatibility stability of the carrier and

cellular uptake The effectiveness of these has also been improved

signi1047297cantly as delivery vehicles with increased therapeutic payload

[3412] Ideally the nanostructured delivery vehicles should be able

to ef 1047297ciently load high weight fraction of drugs and must form a

stable suspension in an aqueous medium These also need to be

biodegradable andor biocompatible Drugs are usually encapsulated

in conjugated to or adsorbed onto surface of the nanocarrier and are

triggered released by heat pH or other modes of electromagnetic

radiation like ultrasound The nanoscale drug delivery system also

helps in stabilizing drug molecules [61314] which would otherwise

degrade rapidly and reduce drug ef 1047297cacy These bene1047297ts have

accounted for extensive research in the development of nanostruc-

tures and their interactions Most of these are hybrid nanomaterialsand are formed using lsquoweakrsquo molecular interactions such as H-

bonding van der Waal forces and other surface forces which require

low energy thereby allowing reversible and subsequent changes that

are essential for a bioprocess to take place Thus understanding the

interactions helps in broadening therapeutic strategies and designing

and improving drug delivery system In this context researchers have

studied the tunable properties of the nanomaterials by altering the

size shape and chemical composition and have developed strategies

to design biocompatible nanostructures of desired functionality with

and without biomolecules [15ndash21] Quantum dots (QDs) are an

archetype of this hybrid material which have gained interest due to

their tunable optical properties and have been considered as potential

optical probes for biological imaging They are resistant to degrada-

tion than other optical imaging probes and hence can track cellprocesses for longer periods and give more information on molecular

interactions drug delivery or locating a tumor and to arm it with toxic

therapies

Thus while this review aims to cover the fabrication and functiona-

lizationstabilization of various oxide and hybrid nanostructures it will

also attempt to discusstheir therapeutic applications We will emphasize

on magnetic nanostructuresfordrugdeliveryand magnetic hyperthermia

treatment of cancer After a brief introductionto thenanoparticulates and

the hybrids effective methods for functionalization and stabilization of

these structures are discussed The application of the oxides and hybrid

nanostructures in biomedicine is presented in the 1047297nal section In this

review noteworthy and most recent scienti1047297c advances dealing with the

therapeutic application of a wide variety of oxides and hybrid

nanostructures such as silica iron oxide and its derivatives zinc oxide

layereddouble hydroxides and binaryternary metal oxides arereported

We also emphasize here on designing of biodegradable biocompatible

thermosensitiveor pH sensitive nanocarriers fortheir usein drugdelivery

and hyperthermia Some recent advances with respect to sustained and

triggered drug release have been delineated Further the critical issues

relatedto thetherapeuticapplicationsof oxide andhybrid nanostructures

have been addressed and several representative examples to highlight

these applications have been covered brie1047298y in this review

2 Properties of the nanostructures to be used as carriers

The therapeutic applications of oxide and hybrid nanostructures

strongly depend on their physicochemical properties such as

permeability stability morphology (size shape and functionality)

and biocompatibility These physicochemical properties are dictated

by the types structures and orientations of the materials that

comprise the oxide and hybrid nanostructures The nanoparticles

and their hybrids used for therapeutic applications include both

porous and non-porous forms of non-toxic oxides having surface

functionality to which targeting ligands and additional imaging

modalities are anchored One of the most extensively investigated

oxide is iron oxide (γ-Fe2O3 Fe3O4) and its derivatives [22ndash26]

Therapeutic agents like drugs and biomolecules can then either be

physically embedded into the porous matrix or chemically bonded to

its surface Obvious advantages of using magnetic oxides in thera-

peutic applications include magnetic drug targeting heating ability

for hyperthemia and separation under external magnetic 1047297eld

21 Size and shape

The size and size distribution shape and surface functionality of

oxide nanocarriers are important parameters related to intracellular

uptake and biodistribution to a wider range of biological targets due

to their smaller size and relatively higher mobility The small sized

nanoparticles (b100 nm) have higher effective surface area facilitat-

ing easy attachment of ligands lower sedimentation rates (high

stability in colloidal suspension) and improved tissular diffusion For

most of therapeutic applications the 1047297rst signi1047297cant challenge is toavoid undesirable uptake of nanoparticles by the reticulo-endothelial

system (RES) The next step is to achieve selective targeting of the

system to the site of interest for the in-vivo studies In order to

overcome these problems nanoparticles should be small enough with

desired functionality to escape from the RES These nanoparticles

should remain in the circulation for prolonged time after injection

into bloodstream and should be capable of passing through the 1047297ne

capillary systems of organs and tissues avoiding vessel embolism

The size (hydrodynamic size) controls the nanoparticles concen-

tration pro1047297le in the blood vessel affects the mechanism of

nanoparticles clearance and mediates the permeability of nanoparti-

cles out of the vasculature [27] Small sized spherical nanoparticles

have higher diffusion rates which increase the concentration of

nanoparticles at the center of a blood vessel thereby limiting theinteractions of nanoparticles with endothelial cells and prolonging the

nanoparticles blood circulation time [28] Parket al [29] reported that

anisotropic iron oxide having high aspect ratio shows enhanced blood

circulation times over their spherical counterparts Other than size

and shape the pore size and its distribution have signi1047297cant effect on

the therapeutic applications due to its enhanced surface area and its

ability to contain and release drug [30] This aspect is discussed in a

later section

22 Surface functionality

The surface charge (zeta potential) of nanoparticles has an

important role to play in their physiological and aqueous colloidal

stability as well as in functionalization and designing promising

1268 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281



nanostructures It can be easily controlled by the nature of the surface

groups in solution at a particular pH A high positive or negative zeta

potential value is an indication of the colloidal stability of nanopar-

ticles dueto theelectrostatic interaction It is reported that thesurface

of the nanoparticles determines their cellular interaction especially

during endocytosis and phagocytosis A strong correlation between

the surface charge and their cellular uptake ef 1047297ciency into different

cell lines has been observed It is further reported that the

hydrophobic groups on the surface of nanoparticles induce agglom-eration upon injection leading to rapid removal by the RES [31] Thus

surface modi1047297cation with hydrophilic molecules is essential to reduce

the opsonization potential through steric repulsion prolonging the

circulation time of nanoparticles The surface modi1047297cation of

nanoparticles for their aqueousphysiological stabilization is impor-

tant for most of the therapeutic applications and hence will be

discussed in more detail in the following section

3 Stabilization of oxide and hybrid nanostructures

Thecolloidal stabilization of the nanoparticles in both aqueous and

physiological medium is crucial for their therapeutic applications and

can be achieved by either charging the surface or conjugating it by

macromolecules for steric hindrance The surface charge can be

monitored and ensured by suitable means such as changing pH of the

medium or modifying with functional groups The steric stabilization

can be achieved by attachinggrafting of macromolecules such as

surfactant [32] or polymer [33] on the surface The steric stabilization

is indeedless sensitiveto the ionic strength of thesuspension medium

and can be easily achieved in both polar and non-polar medium The

oxide nanoparticles may be stabilized either during their synthesis or

in a post-synthesis process The in situ modi1047297cation during synthesis

process has several advantages including reduced agglomeration [34]

These biocompatible layers stabilize the nanoparticles and provides

accessible surface for routine conjugation of biomolecules

31 Organic stabilizers

311 Small moleculesThe small molecule targeting groups are predominantly attractive

forstabilizingoxide nanoparticles dueto their ease of preparation and

simple conjugation chemistry [35] The binding af 1047297nity of large

surfactant molecules or long polymer chains to the nanoparticles may

be lost due to steric hindrances which could otherwise be easily

overcome by using small molecules having multiple functional groups

such as carboxyl (COOH) amine (NH2) thiol (SH) phosphate and

sulfates These stabilizers can be tailored for dispersibility into

aqueous media or other biocompatible 1047298uids The presence of

hydroxyl groups on the surface of oxide nanoparticles provides a

versatile route for multiple functionalities Furthermore the presence

of large number of functional groups on the surface of nanoparticles

maybe used forlinkage of various biomolecules as well as drugsThus

the stability of the bonding between functional molecules andnanoparticles is crucial for therapeutic applications

Among various small molecules citrate moiety having multiple

carboxylate functionalities has been extensively used for the colloidal

stabilization of oxide nanoparticles The functional groups are

chemisorbed on the surface of the oxide nanoparticles by coordinat-

ing via one or two of the carboxylate functionalities depending upon

size and shape of the particles and leaving at least one carboxylic acid

group exposed to the solvent The free carboxylic groups render

suf 1047297cient negative charge on the surface of particles and hence make

them hydrophilic [36]

The short chain amines and aminosilanes are commonly used as

stabilizing agent in fabrication of various oxide nanoparticles

Recently Barick et al [2232] demonstrated a single-step facile

approach for highly water-stable assembly of amine-functionalized

Fe3O4 nanoparticles using thermal decomposition of Fe-chloride

precursors in ethylene glycol medium in the presence of sodium

acetate and ethylenediamine for bio-applications and compared their

magnetic resonance (MR)contrast behaviorIn addition to shortchain

amine and aminosilanes various amino acids [37] and peptides [38]

having multiple amine molecules have been used as stabilizer for

successful design of oxide nanoparticles

Small molecules having thiol functionality achieved great deal of

attention due to their higher binding af 1047297

nity towards metal and metaloxide nanoparticles The organosulfur compound 23-meso dimercap-

tosuccinic acid (DMSA) having two carboxylic and two thiol groups

have been commonly used as a stabilizing agent for inorganic oxides

MNPs have been stabilized with DMSA for tissue- and cell-targeted

delivery of therapeutic drugs in the lung [39] Speci1047297cally the

mechanism of the pro-in1047298ammatory effects of MNPsndashDMSA has been

investigated Maurizi et al [40] developed a convenient method to

stabilize free thiols onto the surface of iron oxide nanoparticles by post

functionalization using methoxy PEG 2000 silane and observed that

thiol functionalized nanoparticles were stable under physiological pH

Furthermore they have demonstrated that the stability of thiols can be

increased signi1047297cantly when DMSA is protected by polyethyleneglycol

(PEG) chains on the surface of nanoparticles DMSA stabilized aqueous

colloidal Fe3O4 nanoparticles were fabricated by introducing DMSA

molecules onto the surface of hydrophobic nanoparticles through

ligand exchange process [22]

312 Macromolecules

A variety of polymer molecules have been used for steric

stabilization of oxide nanoparticles in aqueous and high ionic strength

media [41ndash43] The polymer shell improves the stability of nanopar-

ticles in solution and allows the encapsulation of a therapeutic agent

Further these stabilizers provide a means to tailor the surface

properties of nanoparticles such as surface charge and chemical

functionality or their thermosensitive properties Major facts with

regard to polymeric stabilizer that may affect the performance of

nanocarriers include the chemical nature of the polymer (ie

hydrophilicityhydrophobicity biocompatibility and biodegradation)

the molecular weight of the polymer the manner in which thepolymer is grafted or attached (ie physically or chemically) the

conformation of the polymer and the degree of particle surface

coverage

Among various macromolecules dextran has been widely used for

surface modi1047297cation mostly because of its favorable size (chain

length) and biocompatibility which enables optimum polar in-

teractions (mainly chelation and hydrogen bonding) Dextran coating

not only provides a smooth outline and narrow size distribution but

also retains the essential superparamagnetic behavior of iron oxide

nanoparticles and a signi1047297cantly prolonged the storage stability [44]

Pradhan et al [45] fabricated dextran coated Fe3O4 nanoparticles by

co-precipitation method and compared their in vitro cytocompat-

ibility and cellular interactions with mouse 1047297broblast and human

cervical carcinoma cell lines with lauric acid-coated Fe3O4 nanopar-ticles The surface modi1047297cation was found to play an important role in

modulating biocompatibility and cellular interaction of MNPs

PEG is a hydrophilic water-soluble biocompatible polymer and

extensively used to increase blood circulation times Xie et al [42]

used controlled PEGylation method and dopamine as a cross-linker to

produce monodisperse Fe3O4 nanoparticles PEG was successfully

anchored on the nanoparticles through a covalent bond which

showed negligible aggregation in cell culture condition and reduced

non-speci1047297c uptake by macrophage cells These MNPs based systems

are capable of site-speci1047297c targeting and controlled drug release with

high biocompatibility The temperature-sensitive poly N-isopropyla-

crylamide (PNIPAAm) based MNPs are also of particular interest

because of their stimuli (temperature) responsiveness and enhanced

drug-loading ability[46]Wongetal [4748] fabricated thermoresponsive

1269S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281



PNIPAAm microgel through LBL technique possessing both thermore-

sponsivity and magnetism withhigh speci1047297c absorption ratewhich could

open up new prospects for remotely controlled drug carriers Other

polymers that display some thermosensitivity near physiological or

hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]

pluronic triblock copolymer surfactants and block copolymers [50] The

formulationof thenanoparticulatescanalso be realized by using Foodand

Drug Administration (FDA) approved biodegradable polymers such as

poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-

ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol

polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other

polymers used for aqueous stabilization of iron oxide magnetic

nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid

(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]

32 Inorganic stabilizers

Silica (SiO2) gold (Au) and silver (Ag) are extensively used for

surface modi1047297cation of the oxide nanoparticles which forms corendash

shell structures and provides stability to the nanoparticles in solution

and further help in binding various biological molecules and drugs to

the surface of nanoparticles through suitable functional groups The

stabilization of oxide nanoparticles by silica can easily be achieved

either by Stoumlber process or microemulsion method [5859] SiO2

stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-

phorescent iridium-complex has been used for applications in

photodynamic therapy [60] Surface modi1047297cation with alumina of a

substituted garnet system in an attempt to tune the TC of the

magnetic oxides for in vivo control during hyperthermia is also

noteworthy [61]

There has been considerable interest in stabilizing oxide nano-

particles with noble metal shells such as Au and Ag The magnetic

oxide nanoparticles with metal coating can be effectively stabilized in

corrosive biological conditions and can be readily functionalized

through the well-established metal-sulfur chemistry The magnetic

corendashshell nanoparticles with tunable plasmonic properties have

great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with

controlled plasmonic and magnetic properties were reported to act as

target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive

breast cancer cells with strong therapeutic effects When compared to

conventional single-component iron oxide NPs the AundashFe3O4 NPs

were advantageous in facilitating stepwise attachment of an antibody

to a platin complex and also for serving as magnetic and optical probe

for tracking the drug in the cells [64] The most signi1047297cant advantage

of this composite system is that it provides controlled magneto-

optical properties long term stability to the magnetic core andfunctionality to the nanoparticles

33 Other stabilizers

The amphiphilic molecules such as liposomes and micelles have

been successfully used to stabilize oxide nanoparticles for therapeutic

applications [6566] Liposomes have also the ability to encapsulate a

large number of nanoparticles and deliver them together to the speci1047297c

target site Both hydrophilic and hydrophobic foreign molecules such as

drugs and biomolecules can be easily anchored to the amphiphilic

liposomes and micelles which can enhance the multifunctionality of a

system Martina et al [67] developed magnetic 1047298uid-loaded liposomes

by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of

egg phosphatidylcholine and DSPE-PEG2000 Further it was also found

that phospholipid molecules (egg phosphatidylcholine) which are

essential precursors for liposome formation may also in1047298uence the

nucleation and growth characteristics of MNPs The effects of phospha-

tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and

their properties have been well discussed [68] Fig 1 shows a schematic

representation of TEM micrographs of various stabilizers used for

stabilizing magnetic nanoparticles

Recently dendrimers a novel class of macromolecules with highly

ordered structure hasreceived signi1047297cantattention for functionalization

and stabilization of oxide nanoparticles Dendrimer coating alters the

surface charge functionality and reactivity and enhances the stability

and dispersibility of the nanoparticles Furthermore the presence of

multiple functional groups with symmetric perfection and nanometer

scale internal cavities enables dendritic stabilized nanoparticles for

incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully

Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)

functionalized Fe3O4 nanoparticles [22] (b) dopamine-PEGfunctionalized Fe3O4 nanoparticles [42] (c) iridium-complex functionalized Fe3O4SiO2 coreshell nanoparticles [60] and

(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John

Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)




stabilized with different generation of polyamidoamine (PAMAM)

dendrimers for gene delivery [69] Chandra et al [70] demonstrated a

facile approach for the preparation of dendrimers coated Fe3O4

nanoparticles for drug delivery application In this method dendritic

structures were grown on the silane coated iron oxide nanoparticles

using methylacrylate and a biocompatible arginine as monomers

Taratula et al [71] reported a multifunctional superparamagnetic

nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5)

for siRNA delivery system for cancer therapy PEG coating and LHRHtargeting peptide was incorporated into SPIO-PPI G5ndashsiRNA complexes

to enhance serum stability and selective internalization by cancer cells

Bulte andcoworkers labeled human neuralstem cells andmesenchymal

stem cells with magnetodendrimers through a non-speci1047297c membrane

adsorption process with subsequent intracellular localization in endo-

somes The labeled neural stem-cells derived oligodendroglial pro-

genitors were readily detected in vivo by MR signals The magnetomers

were also used to track the olfactory ensheathing glia grafted into rat

spinal cord in vivo [72] However there were no speci1047297c interaction

between the particles and the target cells since the magnetodendrimers

did not have any speci1047297c surface modi1047297cation Modi1047297cation of the

magnetodendrimers with biological receptors or antibodies opens up

the possibility of their use for speci1047297c application right from targeting to

a site transiting the cell membrane and making intracellular delivery

4 Therapeutic applications of oxide and hybrid nanostructures

Controlled synthesis of individual monodisperse nanoparticles led to

the evolution of nanostructures with improved magnetic conducting

1047298uorescent and targeting properties for potential bio-medical applica-

tions Corendashshell nanoparticles LBL assembly [73] and other nanocompo-

sites encompassing a broad range of materials and variousnanostructural

morphologies (spherical cylindrical star-likeetc) are becoming themain

building blocks for next generation of drug delivery systems

41 Challenges faced in the drug delivery

Most of the delivery systems have limitations of poor pharmaco-

kinetics and targeting ef 1047297ciency It is important that the drugmolecule is carried only to the affected site without affecting other

parts of organsand tissues In addition many of these systems need to

provide stability a sustained or burst release non toxicity solubility

in aqueous media and bio-distribution to suit a particular therapy

These therapeutic agents could be in the form of microcapsules

dispersion adsorbed entities as a conjugate to nanoparticulates or

loaded to porous or hollow structures Let us look at some of the

potential drug delivery systems which include several oxide systems

as well as hybrid structures Although many organic systems such as

liposomes dendrimers or other macromolecules are used as excellent

drug carriers but we are limiting our discussion only to inorganic

oxidehydroxide systems or their hybrids with organic moieties In

this context a number of organicinorganic hybrids have been

investigated as delivery vehicles to develop effective therapeuticmodalities So far only a few therapeutic products have been

approved by FDA for clinical use of these most are based on non-

targeted delivery system The miniaturization of the materials to

nanoscale incorporates new properties within themselves which

should be carefully characterized to avoid any un-intended side

effects The increased activity of the nanostructures can either be

desirable in terms of therapeutic capacity cell barrier penetration for

drug delivery induction of oxidativestress or cellular dysfunction or a

combine effect of both [74]

The toxicity of the nanoparticles remains a major issue towards

fabrication of nanomedicine and it mainly depends on factors like

chemical composition surface chemistry dose quanti1047297cation particle

size biodistribution and biodegradability etc Fe particles with a

uniform epitaxial shell of MgO and the nanoparticles satis1047297ed all the

technical requirementsfor clinical use including high biocompatibility

in living cells injection through blood vessels without any clotting

high absorption rate for magnetic hyperthermia and as contrast agent

in MRI [75] The in-vivo animal experiments showed that a total iron

dose about 06 mgkg showed no apparent acute toxicity or side

effects over a monitoring period of 3 weeks Biocompatibility results

of PVA coated magnetic nanoparticles on L929 and K562 cells

demonstrated acceptable cell viability levels following exposure of

upto 20 mM iron concentration and neither apoptosis nor necrosistook place [76] Kikumori and co-workers [77] developed anti-HER2

magnetoliposomes (HML) for effective targeting of breast cancer cells

and cytocidal abilities of the HML has been achieved using cell culture

models Their studies show that the growth of tumor is almost

suppressed by just two hyperthermia treatments and no iron

accumulation was observed in the organs (eg liver spleen brain

heart etc) of the HML-injected mice Further in a rat model also no

speci1047297c pathologic changes were observed in liver spleen heart and

brain even after repeated subcutaneous injection of HML A signi1047297cant

decrease in glioblastoma cell survival was observed after treatment

withepidermalgrowth factorreceptor(EGFRvIII)antibody-conjugated iron

oxide nanoparticles Furtheran increase in animal survivalwas found after

convection-enhanced delivery (CED) of magnetic nanoparticles in mice

implanted with tumorigenic glioblastoma xenografts [78] There has to be

focus on developing targeted controlled and sustained drug release

systems which can convey drugs more effectively increase patient

compliancereduce cytotoxicityto normal cells andextend circulationtime

411 Drug loading and release

The ef 1047297ciency of drug loading and release strongly depends upon

the ability to design a biocompatible colloidal nanocarrier that allows

high loading of drug moleculeswithout any premature release of drug

before reaching the destination Thus the carrier should have good

biocompatibility properties with higher encapsulation ef 1047297ciency and

should exhibit site speci1047297c control release of drug molecules

Among a variety of drug carriers mesoporous silica and zinc oxide

nanoparticles have several striking features for use in the drug

delivery These nanoparticles have large surface area and porous

interiorsthat can be used as reservoirs for storing drug molecules Thepore size and surrounding environment can be easily tuned to

preferentially store various drug molecules of interest while the size

and shape of the nanoparticles can be tailored to maximize the

cellular uptake [79] Mesoporous silica has been successfully used for

storing of drug molecules (Ibuprofen) into the pores through

hydrogen bond interaction between the ibuprofen and the silanol

groups present in the pore wall [80] It was observed that the release

rate of ibuprofen in a simulated body 1047298uid solution increased

signi1047297cantly under the pulsed pressure drop An interesting photo-

thermal modulated drug delivery system was designed based on

silicandashgold (SiO2ndashAu) nanoshells consisting of a silica core surrounded

by a gold shell [81] The peak extinctions of the nanoshells are easily

tuned over a wide range of wavelengths particularly in the near

infrared (IR) region of the spectrum and the light in this region istransmitted through tissue with relatively little attenuation due to

absorption Also irradiation of SiO2ndashAu nanoshells at their peak

extinction coef 1047297cient results in the conversion of light to heat energy

that produces a local rise in temperature Further SiO2ndashAu nanoshells

were embedded into a temperature-sensitive hydrogels (N-isopro-

pylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of

initiating a temperature changewith light fortriggered release of drug

molecules The composite hydrogels had the extinction spectrum of

the SiO2ndashAu nanoshells in which the hydrogels collapsed reversibly in

response to temperature (50 degC) and laser irradiation

Recently the drug-loading ef 1047297ciency of a highly mesoporous

spherical three dimensional ZnO nanoassemblies was investigated

using doxorubicin hydrochloride (DOX) as a model drug by our

research group [82] The interaction and entrapment of drug molecules




with ZnO were evident from the quenching of the 1047298uorescence as well

as the shift in band positions The drug release showed strong

dependence on the pH of the medium ultrasound energy (continuous

or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded

ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h

About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies

under continuous irradiation of ultrasoundfor 60 minin aqueous media

whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded

drug was released

Another approach which received great attention is of combining

anti-cancer drug therapy with quantum dot technology Yuan et al

[83] synthesized blue-light emitting ZnO quantum dots (QDs) and

then combined them with biodegradable chitosan (N-acetylglucosa-

mine) to use in tumor-targeted drug delivery The hydrophilicity and

cationic surface charge of chitosan enhanced the stability of the QDs

Drug-loading ef 1047297ciency of these carriers was about ~75 with an

initial rapid drug release followed by a controlled release This study

has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-

term 1047298uorescence stability

Recently Li et al [84] studied the cytotoxicity and photodynamic

effect of different-sized ZnO nanoparticles to cancer cells They have

observed that ZnO nanoparticles exerted time and dose dependent

cytotoxicity for cancer cells The suppression ability of ZnO nanopar-

ticles for cancer cells proliferation was found to be enhanced by UV

irradiation These results suggested that ZnO nanoparticles could play

an important role in drug delivery to enhance the accumulation and

the synergistic cytotoxicity of daunorubicin in the target SMMC-7721

cells Thus the 1047298uorescent ZnO nanoparticles could be developed for

simultaneous detection and localization of multiple solid cancer

biomarkers enabling the personalization of therapeutic regimens for

each patient These nanoparticles can be easily conjugated with

tumor-speci1047297c ligands and used for tumor-selective delivery of

chemotherapeutic agents as well as photodynamic cancer therapy

The slight solubilization of the biocompatible ZnO nanocarriers at

lower pH can also facilitates the drug release Such pH-triggered

release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site

In addition these systems also work under the ultrasound or UV

irradiation (continuous or pulsatile) for controlled and targeted

on-demand drug delivery

Targeting is the biggest challenge Generally when the drug is

administered it would not have any site of preference and hence may

distribute all over the organs which in many cases are undesirable due

to its toxic nature Active targeting is a preferred modality through the

modi1047297cation of nanoparticles with ligands which has the attributes to

enhance the therapeutic ef 1047297cacy and reduce the side effects relative to

conventional therapeutics Various factors such as delivery vehicles

drugs and diseases in1047298uence the targeted delivery It is therefore

desired that the delivery system has some moieties attached to the

carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a

valuable pathway for therapeutics Some of the important targeting

ligands are folate antibodies and their fragments and different

peptides For diseases like tumor or in1047298ation passive targeting also

occurs due to leaky vasculature Most tumors exhibit pores within their

vasculature of typical size between 350and 400 nmThis facilitates drug

concentration in tumor or in1047298ated regions by extravasation Any

targeting however demands that nanocarriers circulate in blood for

extended times Nanoparticulates otherwise exhibit short circulation

half lives which can be enhanced by suitable surface modi1047297cation with

long circulating molecules like PEG Due to its several favorable

properties like hydrophilic nature low degree of immunogenicity and

availability of terminal primary hydroxyl groups for functionalization

PEG is most extensively used for this purpose

Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with

permission from [8270] copyright RSC publications and [66] copyright Elsevier License)




The magnetically targeted-drug delivery system is considered one

of the most popular and ef 1047297cient methods In this technique the drug

carrying MNPs with a suitable carrier system taken orally or injected

through vein may be directed to the diseased area by an external

magnetic1047297eld A novel method forentrapping positively charged drug

molecules (DOX) onto the surface of negatively charged citrate-

stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through

electrostatic interactions is recently developed by Nigam et al [85]

The drug loading ef 1047297

ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-

gated CA-MNP exhibited a sustained release pro1047297le It has been

observed that bound drug molecules are released in appreciable

amounts in the mild acidic environments of the tumor Storage and

release of cisplatin using porous hollow nanoparticles (PHNPs) of

Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)

was stable in neutral or basic physiological conditions and cisplatin

releases from the cavity through a diffusion-controlled slow process

A compositemembranebased on thermosensitive poly(NIPAAm)-

based nanogels and magnetite nanoparticles was developed which

enabled rapid and tunable drug delivery upon the application of an

external oscillating magnetic 1047297eld [87] Onndashoff release of sodium

1047298uorescein over multiple magnetic cycles has been successfully

demonstrated using prototype non-cytotoxic biocompatible mem-

brane-based switching devices The total drug dose delivered was

directly proportional to the duration of the ldquoonrdquo pulse Corendashshell

nanoparticles of similar composition showed signi1047297cantly lower

systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The

drug release study indicated that the polymer is sensitive to

temperature which undergoes phase change at LCST resulting into

the collapse of nanoparticles thereby releasing more drugs After 72 h

78 of the encapsulated DOX was released at 41 degC whereas at 4 degC

and 37 degC ~26 and ~43 was released respectively Released drugs

were also active in destroying prostate cancer cells and the

nanoparticle uptake by these cells was dependent on dose and

incubation time Folate-targeted doxorubicin-containing magnetic

liposomes (MagFolDox) shows temperature dependent drug release

(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS

upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro

drug delivery response of polyethylene glycol (PEG)-functionalized

magnetite (Fe3O4) nanoparticles which were activated with a folic

acid andconjugated with doxorubicin Here the drug release involved

Fickian diffusion through pores in thepolymer matrix Thediffusion of

drug from biodegradable polymer is often dictated by the excluded

volume and hydrodynamic interactions Other factors that in1047298uenced

the drug release response are drug solubility polymer degradation

and polymerndashdrug interaction

The composites of biocompatible bovine serum albumin (BSA)ndash

dextranndashchitosan nanoparticles were effectively used to load DOX into

the nanoparticles after changing the pH of their composite to 74 [90]

These nanoparticles exhibited faster release of doxorubicin at pH 50

(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic

repulsion between the nanoparticles and the doxorubicin thereby

releasing at a faster rate The performance of gelatin coated iron oxide

MNPs as drug carrier was evaluated for drug targeting of doxorubicin

(DOX) [91] where thedrug loading wasdone using adsorptionas well as

desolvationcross-linking techniques Compared to adsorption tech-

nique desolvationcross-linking technique improved the ef 1047297ciency of

drug loading regardless the type of gelatin used for the coating The

DOX-loaded particles showed pH responsive drug release leading to

accelerated release of drug at pH 4 compared to pH 74

Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug

delivery application in presence and absence of AC magnetic 1047297eld are

explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX

loaded DMNCs clearly shows a sustained release over a period of 24 h

with a maximum of 54 Interestingly thesteadylinear release steepens

upon application of the AC magnetic 1047297eld About 35 of the drug was

released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas

the release percentage further increased to 80 under the continuous

application of AC magnetic 1047297eld over the next 15 min The enhanced

release of the drug molecules in the AC magnetic 1047297eld is favorable for

combined therapy involving drug delivery and hyperthermia (Fig 2d)

Furthermore the surface of dendritic magnetic nanocarriers can be

easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-

riers can also incorporate both hydrophilic and hydrophobic drugs

Based on the various studies one may conclude that functional

nanoparticles coupled with biological targeting agents and drug

moleculesis promising as drug delivery vehicles withenhanced imaging

and therapeutic ef 1047297cacy However there are many factors which affect

the ef 1047297cacy of a developed system For example the presence of target

and drug molecules on the nanoparticles may interfere with the

targeting capability and cellular uptake of the nanoparticles Further

coupling of different chemical functionalities on a surface of nanopar-

ticles often leads to a low yield synthetic process This can be overcome

by using multicomponent nanohybrid systems wherein target mole-

cules imaging probe and a drug can be anchored on different surface

functionality on the samesystem [8366] Another concern in theuse of

hybrid nanostructures of different sizes and shapes is their movement

through the systemic circulation as they are intended to experience

various 1047298uid environments and might behave differently due to the

effect of viscous force Agglomeration of the nanosystems cannot be

ruled out as they move through the narrow capillaries which might lead

to clogging of blood vessels [92] Further the nanohybrid systems may

have restricted or indiscriminate movement across the biological

barriers which dictates their behavior and fate upon introduction into

the body (biodistribution) Functionalization of the nanoparticles with

various macromolecules biopolymers or dendrimers enables the

nanoparticles to interact with the biological environment and protect

them from degradation [93] As our knowledge of various multi-

functional and hybrid nanostructures grow the enormity of the

Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells

incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated

by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation

[100] (Reproduced with permission from [96] copyright Springer and [100] copyright

American Chemical Society Publications)




challenges become obvious Thus while designing the hybrid nanos-

tructures one must have to take care of certain features that are

essential for effective intracellular targeting These include (i) clearance

from the circulation (ii) withheld release of drug at non-targeted sites

(iii) delivery of drugndashnanocarrier and release of drug at targeted site

(iv) removal of drugfrom the target site and (v) effective elimination of

the nanocarrier from the body

412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on

the internalization of the nanoparticles within the cells Thus the

ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major

determinant for imaging sensitivity at the single cell level Some cells

such as macrophages can be readily labeled with adequate quantities

of nanoparticles due to their inherent ability to phagocytose material

in the extracellular medium however there are many other cell lines

including cancer cells which do not readily phagocytose This

challenge can be overcome by direct conjugation of cell-penetrating

peptides to the surface of nanoparticles [94] In-vivo studies in rats

showed that magnetic nanoparticles predominantly accumulate in

the liver and spleen after intravenous administration Jain et al [95]

studied the biodistribution clearance and biocompatibility of oleic

acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical

applications Changes in levels of alanine aminotransferase (ALT)

aspartate aminotransferase (AST) alkaline phosphatase (AKP) were

analyzed over 3 weeks after intravenous administration of MNPs to

rats They found that the serum iron levels gradually increased for up

to 1 week and then slowed down Greater fraction of the injected iron

is uptaken in liver and spleen which may be due to the increased

hydrodynamic diameter of the nanoparticles However histological

analyses of the organs showed no apparent abnormal changes

The energy-dependent cellular uptake of biocompatible 1047298uores-

cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles

(FMSN) as well as the delivery of hydrophobic anticancer drug

paclitaxel to PANC-1 cancer cells were investigated [96] The cellular

uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and

metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A

impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of

nanoparticles through energy-dependent endocytic process was also

observed with A549 and HeLa cells [9798]

In another study Guo et al [99] showed that the presence of ZnO

nanoparticles enhanced the cellular uptake of daunorubicin for

leukemia cell lines They have observed that the effective anti-drug

resistance and anticancer effect of photoexcited ZnO nanoparticles

accompanied with the anticancer drug shows synergistic cytotoxicity

suppression on leukemia cell lines under UV irradiation On the other

hand biocompatible ZnO nanocrystals having a non-centrosymmetric

structure was synthesized and used as non-resonant and nonlinear

optical probes for in vitro bioimaging applications [100] The

nanocrystals were dispersed in aqueous media using phospholipid

micelles and incorporated with the biotargeting folic acid (FA)

molecule The confocal images of KB cells treated with an aqueous

dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of

treatment shows robust intracellular signal (Fig 3(c) and (d))

In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored

[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-

cles in different types of cancer cells was studied in the absence and

presence of serum [102] It was observed that the serum reduces the

cellular uptake of Fe3O4 nanoparticles and the internalization of

nanoparticles into cells takes place via endocytosis or by diffusion

penetration across the plasma membrane In another study the

cellular uptake and in vitro cytotoxicity of hollow mesoporous

spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was

found relatively faster [103]

In an interesting study Pan et al [69] reported the development of

a nanoscale delivery system composed of MNPs coated with different

generation of PAMAM dendrimers (dMNP) and investigated the

uptake mechanism with different cell lines after complexing them

with antisense survivin oligodeoxynucleotides (asODN) They ob-

served that asODN-dendrimer-MNPs enter into tumor cells within

15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell

growth in dose- and time-dependent means The intracellular uptake

rate of G50 dMNP (1047297fth generation dMNP) was found to be 60

whereas that of naked MNPs was 10 (Fig 4(b))

Superparamagnetic iron oxide nanoparticles (SPIONs) have been

widely used in magnetic resonance imaging as they can be used as

contrast agent and can be incorporated into magnetic 1047297eld-guided

drug delivery carriers for cancer treatment However the hydropho-

bic nature of some SPION leads to fast reticuloendothelial system

(RES) uptake due to which their systemic administration still remains

a challenge Folate targeted NIPAAM-PEGMA composite magnetic

nanoparticles with imaging potential were reported [104] Co-

polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the

Curie temperature (TC) of the co-polymer to 44 degC enabling

hyperthermia coupled drug delivery The increased binding of the

PEGMA and AA with the iron surface caused prolonged circulation

time of the nanocomposites thereby preventing rapid clearance by

RES system The nanocomposites showed high T1 and T2 relaxivities

and R 1 and R 2 increases linearly with increase in iron concentration

proving their application for imaging purposes A dual imaging

(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated

Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP

without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)




thermally crosslinked SPIONs in mice was studied [105] High level of

accumulation of these nanomagnets within the tumor site was

established by T2-weighted magnetic resonance images as well as in

optical 1047298uorescence images within 4 h of intravenous injection A

multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as

theranostic platforms for targeting SK-BR-3 cells (by MRI and

1047298uorescence) and destroying them (by Au-mediated photothermal

ablation) [106] In another work when a MRI contrast agent

containing targeted herceptinndashdextran coated magnetic nanoparticles

were administered to mice bearing breast tumor allograft the tumor

site was detected in T2-weighted MR images as a 45 enhancement

drop indicating a high level of accumulation of the contrast agent

within the tumor (Fig 5) The potential cytotoxicity of the herceptin-

nanoparticles indicated inhibition of cells that overexpress HER2neu

receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron

concentrations [107]

Yang et al [108109] engineered urokinase plasminogen activator

receptor (uPAR) targeted biodegradable polymer coated magnetic

nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo

magnetic resonance and optical imaging in mouse mammary tumors

A strong magnetic resonance imaging contrast detectable by a clinical

MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was

systemically delivered into the mice bearing mammary tumors It was

also found that the mice administered with ATF-IO nanoparticles

Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)

Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on

the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or

30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)




exhibited lower uptake of the nanoparticles in liver and spleen as

compared with those receiving nontargeted iron oxide nanoparticles

(Fig 6)

42 Hyperthermia treatment of cancer

Functionalized MNPs and ferro1047298uids have been extensively used

for generating heat for magnetic hyperthermia treatment (MHT) as a

promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects

compared to chemotherapy and radiotherapy In this application

MNPs are used as effective heating mediator in the presence of an

alternating current (AC) magnetic 1047297eld The type and thickness of

functional layers used for stabilizing nanoparticles can signi1047297cantly

in1047298uence heating ability The heat produced during MHT not only

destroys the tumor cells but also boosts the activity of the majority of

cytostatic drugs and activates the immunological response of the

body

Kim et al [110] reported that self-heating from MNPs under AC

magnetic 1047297eld can be used either for hyperthermia or to trigger the

release of an anti-cancer drug using thermo-responsive polymers

The heat generated by applying an AC magnetic 1047297eld depends on the

properties of MNPs (composition size shape and functionalization)

as well as the frequency and amplitude of the magnetic 1047297eld In their

study CoFe2O4 nanoparticles were investigated as heating agents for

hyperthermia and thermo-drug delivery Towards this approach our

research group has made signi1047297cant contributions in processing

functionalized MNPs of different ferrites and their ferro1047298uids Along

with CoFe2O4 we have investigated comparative heating ability as

well as biocompatibility of different ferrite based magnetic 1047298uids

[112224111ndash114] It has been observed that CoFe2O4 is rather toxic

compared to other Mn-based ferrites In vitro studies of water-based

ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an

average particle size of about 10ndash12 nm prepared by the co-

precipitation on BHK-21 cells showed that the threshold biocompat-

ible concentration is dependent on the nature of ferrite and their

surface modi1047297cation The reports showed that the value of speci1047297c

absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for

hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]

and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully

prepared which showed high degree of biocompatibility and was

found suitable for hyperthermia treatment of cancer The mechanism

of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3

nanoparticles was 1047297rst investigated by our research group [26] The

hyperthermia induced by the application of an AC magnetic 1047297eld in

the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension

caused the death of HeLa cells The cells showed varying degrees of

membrane blebbing with signi1047297cant disruption of the actin and

tubulin cytoskeletons (Fig 7) following MHT which 1047297

nally led to celldeath The cell death was proportional to the quantity of the particles

and the duration of the applied AC magnetic 1047297eld

Thermoresponsive polymer-coated magnetic nanoparticles can be

used for magnetic drug targeting followed by simultaneous hyperther-

mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-

chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)

magnetic nanoparticles encapsulated magnetic nanohydrogels

(MNHGs) in which it has been observed that CS not only served as a

cross linker during polymerization but also plays a critical role in

controlling the growth of NHG and enhancement in lower critical

solution temperature (LCST) of poly(NIPAAm) which increased with

increasing weight ratio of CS to NIPAAm Also the presence of CS in the

composite makes it pH sensitive by virtue of which both temperature

andpH changes have been used to trigger drugrelease Furthermorethe

encapsulation of iron oxide nanoparticles into hydrogels also caused an

incrementin LCST Speci1047297cally temperature optimized NHGand MNHG

werefabricated havingLCST closeto 42 degC (hyperthermia temperature)

The MNHG shows optimal magnetization good speci1047297c absorption rate

(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith

L929 cell lines which may 1047297nd potential applications in combination

therapy involving hyperthermia treatment of cancer and targeted drug

delivery On a similar line of approach Meenach and coworkers [117]

demonstrated a method for remotely heating the tumor tissue using

hydrogel nanocomposites containing magnetic nanoparticles upon

exposure to an external alternating magnetic 1047297eld (AMF) Swelling

analysis of the systems indicated a dependence of ethylene glycol (EG)

content and cross-linking density on swelling behavior where greater

EG amount and lower cross-linking resulted in higher volume swelling

ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts

indicating potential biocompatibility The hydrogels were heated in an

AMF andthe heating response wasshownto be dependenton both iron

Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)




oxide loading in the gels and the strength of the magnetic 1047297eld The

thermal therapeutic ability of the hydrogel nanocomposites to selec-

tively kill M059K glioblastoma cells in vitro on exposure to an AMF has

been demonstrated

A unique drug delivery system based on mesoporous silica

nanoparticles and magnetic nanocrystals was developed [118] The

combined ability of the mesoporous silica nanoparticles to contain

and release cargos and the ability of the magnetic nanocrystals to

exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide

nanocrystals were incorporated within a mesoporous silica frame-

work and the surface was modi1047297ed with pseudorotaxanes Upon

application of an AC magnetic 1047297eld the nanocrystals generate local

internal heating causing the molecular machines to disassemble and

allowing the cargos (drugs) to be released Folic acid (FA) and

cyclodextrin (CD)-functionalized superparamagnetic iron oxide

nanoparticles FA-CD-SPIONs were synthesized by chemically

modifying SPIONs derived from iron (III) allylacetylacetonate and

the drug was incorporated [119] Heat generated by MNPs under

high-frequency magnetic 1047297eld (HFMF) is useful not only for

hyperthermia treatment but also as a driving force for the drug-

release Induction heating triggers drugrelease fromthe CD cavity on

the particlemdasha behavior that is controlled by switching the HFMF on

and off

MNPs coated with materials having unique properties such as

ordered pore structures and large surface areas hold great potential

for multimodal therapies Recently it has been reported [120] that

composites of maghemite nanoparticles embedded in an ordered

mesoporous silica-matrix forming magnetic microspheres (MMS)

have great abilityto induce magnetic hyperthermia uponexposure to

a low-frequency AMF MMS particles were ef 1047297ciently internalized

within human A549 Saos-2 and HepG2 cells and the MMStreatment

did not interfere with morphological features or metabolic activities

of the cells indicating good biocompatibility of the material

The in1047298uence of MNPs combined with short external AMF

exposure on the growth of subcutaneous mouse melanomas was

evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-

cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles

was protected against rapid biocorrosion by organic dopamine-

oligoethylene glycol ligands The magnetic hyperthermia results

obtained after intratumoral injection indicated that micromolar

concentrations of iron given within the modi1047297ed corendashshell FeFe3O4

nanoparticles caused a signi1047297cant anti-tumor effect on melanoma

with three short 10-minuteAMFexposures Villanuevaet al[122] studied

the effect of a high-frequency AMF on HeLa tumor cells incubated with

ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld

cells induced signi1047297cant cellular damage that 1047297nally caused cell death

by an apoptotic mechanism Cell death is triggered even though the

temperature increase in the cell culture during the hyperthermia

treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ

has been explored as an alternative to superparamagnetic iron oxide

based particles for highly controllable hyperthermia cancer therapy

and imaging [123] Adjusting the silver doping level it was possible to

control the TC in the hyperthermia range of interest (41ndash44 degC) The

nanoparticles were found to be stable and their properties were not

affected by the typical ambient conditions in the living tissue When

placed in AMF the temperature of the nanoparticles increased to the

de1047297nite value near TC and then remained constant if the magnetic 1047297eld

is maintained During the hyperthermia procedure the temperature

can be restricted thereby preventing the necrosis of normal tissue

Recently we have demonstrated magnetic hyperthermia with biphasic

gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO

couldbe usefulfor self regulatingthe temperature the latter wasusedfor

better biocompatibility andhigher SAR values It has been observed that

SAR increases (time required to reach hyperthermia temperature

decreases) with increasing the ratio of Al-substituted maghemite

Such biphasic gel could be very useful for magnetic hyperthermia

with in vivo control of temperature La1minus xSrxMnO3 (LSMO)

nanoparticles were also stabilized by various polymers for biomedical

applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned

biocompatible aqueous suspension of LSMO for magnetic hyperthermia

treatment of cancer with a possibility of in vivo temperature control

43 Other therapeutic applications

In recent years among host-guest hybrid materials layered

double hydroxides (LDH) have received much attention due to their

vast applicability and hence are considered to be the new generation

materials in areas such as nanomedicine [126] LDH materials having

bothcation and anion exchange properties provide an opportunity to

design a material with promising applications Pan et al [127]

established the importance of understanding the microstructure and

nature of LDH that could ultimately control the drug release

properties In their study a series of novel doxi1047298uridine intercalated

MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were

fabricated and diffusion controlled in-vitro release was observed An

anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH

[128] and it was further investigated for in vitro cytotoxicity to tumor

cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH

The in vivo tests reveal that delivery of PPT via LDH nanoparticles is

moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids

in comparison with PPT alone These observations imply that LDH

nanoparticles are the potential carrier of anti-tumor drugs in a range

of new therapeutic applications The intercalation of sulfobutyl ether

β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for

controlled release of prazosin a sympatholytic drug used to treat

high blood pressure [129] Anticancer drug podophyllotoxin (PPT)

[130] and campothecin [131] were encapsulated in the galleries of

MgndashAl LDH which showed that the drugndashinorganic composites can

be successfully used as drug delivery vehicle Cefazolin a cephalo-

sporin class antibacterial agent was also intercalated into LDH in

order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and

intercalation and stability of anti-cardiovascular drugs (pravastatin

and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied

[133] Structural characterization techniques revealed that the

1047298uvastatin anions are attached with the brucite as a monolayer

whereas the pravastatin anions form a multilayer In vitro release

study of nanohybrid particles suggested that there is a signi1047297cant

reduction in release rate of 1047298uvastatin anions from 1047298uvastatin

intercalated LDHs which may probably be due to its hydrophobic

nature however it can be controlled by varying the concentration in

physiological medium The advantage of this method is that the

excess divalent metal ions in LDHs can be used as high-temperature

inorganic surfactant to restrict the growth and agglomeration of

MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment

44 Towards clinical trials

Though cancer is a pervasive problem the improvement in

technologies in diagnosis and treatments has signi1047297cantly decreased

themortality rates all over theworld It may be possibleto detect the

cancer at an early stage with the use of nanodevices when the initial

molecular changes start occurring at the nanoscale level inside the

cells Thus thescenario for treatment of cancer is completely changed

in most of the cancers if detected early After diagnosis nanoscale

devices can potentially improve cancer therapy over conventional

chemotherapy and radiotherapy Cancer drugs being mostly cyto-

toxic to both healthy and cancer cells cause severe side effects




thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it

becomes necessary to develop drug formulations which can

transport the toxic drug speci1047297cally to the cancer cells and release

them in a timely and controlled manner Advancement in nanotech-

nology has opened up opportunities to nanodevices especially in

developing new therapeutic formulations for improved cancer drug

delivery The nanodevices cannot only be used in the area of

multifunctional therapeutics (ie to create therapeutic devices

which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection

and imaging diagnostics Several engineered nanoparticulates in-

volving dendrimers liposomes or other macromolecules aretargeted

to cancer cells which increase the selectivity of the drug towards

cancer cells thereby reducing toxicity to the normal cells This is

normally done by attaching monoclonal antibodies or receptor

ligands that speci1047297cally bind to the cancer cells Research on folate

conjugated nanoparticles showed high speci1047297city for human cancer

cells and an improved drug uptake [135] Conjugation of FITC

(imaging agent) folic acid (targeting molecule) and paclitaxel

(drug) to a dendrimer and their in vitro targeted delivery to cancer

cells has been discussed [136] It was found that the cells containing

thefolic acid receptor took up the dendrimer whichhad a toxic effect

while the dendrimers had no effect on the cells without folic acid

receptor Liposomal nanodevices are extensively investigated as

harmless drug delivery carriers which not only carry 1047297xed dose of

anti cancer drug combinations but also circulate in the blood stream

for a longer time [137138] Substantial improvements in using the

magnetic nanoparticles for clinical applications such as drug

delivery MRI magnetic drug targeting and hyperthermia has been

made in the recent past However the clinical breakthrough was

achieved by Maier-Hauff et al [139] in 2007 when deep cranial

thermotherapy using magnetic nanoparticles was safely applied to

14 glioblastoma multiforme patients The patients were intratumo-

rally injected with theiron oxide nanoparticles and exposed to an AC

magnetic 1047297eld to induce particle heating MRI was followed to

evaluate the amount of 1047298uid and spatial distribution of the depots

and the actually achieved magnetic 1047298uid distribution was measured

by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial

[140] insterstitial heating of tumors following direct injection of

magnetic nanoparticles has been carried out for the treatment of

prostate cancer However patient discomfort at high magnetic 1047297eld

and irregular intratumoral heat distribution remained the limiting

factor of thetrialsJohannsenet al [141] reported theresultsof phase

I clinical trial using magnetic nanoparticles involving 10 patients

with locally recurrent prostate cancer No systemic toxicity was

observed at a median follow-up of 175 months and prostate speci1047297c

antigen (PSA) were found to reduce however acute urinary

retention occurred in four patients with previous history of urethral

retention Although there are a number of successful phase I clinical

trials based on therapeutic magnetic targeting very little successful

clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-

therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic

1047298uid hyperthermia (MFH) in murine model of malignant glioma

which is under evaluation for phase II study From brain autopsies it

was found that the instillation of magnetic nanoparticles for MFH in

patients result in uptake of nanoparticles in glioblastoma cells to a

minor extent andin macrophages to a major extent as a consequence

of tumor inherent and therapy induced formation of necrosis with

subsequent in1047297ltration and activation of phagocytes Intracranial

thermotherapy using aminosilane magnetic nanoparticles were

performed on 14 patients who were then exposed to an AC magnetic

1047297eld All the patients tolerated instillation of the nanoparticles

without any complications and the ef 1047297cacy of the treatment is under

evaluation in phase II study [145]

5 Conclusion and future scope

The developing market in this decade has already seen the use of

nanotechnology to develop ef 1047297cient drug delivery system The next

evolution will be using nanotechnology for in vivo uses such as

implanting multifunctional particles in biological tissue to deliver

medicine destroy tumors and stimulate immune responses Some of

these multifunctional nano-sized assemblies can act as biological

systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the

desired goals of early detection tumour regression with limited

collateral damages and ef 1047297cient monitoring of response to chemo-

therapy In the foreseeable future the most important clinical

application of nanotechnology will probably be in pharmaceutical

development These applications take advantage of the unique

properties of nanoparticles as drugs or constituents of drugs or are

designed for new strategies to stabilize drugs and their control

release drug targeting and salvage of drugs with low bioavailability

Although the nanosized materials can be useful in medicine but

they can be potentially dangerous to human body as far as the toxicity

of the nanocarriersnanocomposites is concerned The nanomaterials

have unrestricted access to the human body and have the ability to

pass through the blood brain barrier thereby evading their detection

by the bodys immune system Usually foreign substances are

absorbed by phagocytes once they enter the blood stream however

any substance in the nanoscale range is no longer absorbed by the

phagocytes and thus they travel though the blood and move

randomly throughout the body Within this physiological compart-

mentthe nanomaterials may interact with cell populationresulting in

internalization through receptor-mediated endocytosis phagocytosis

and pinocytosis The materials remain in the endosomes and

accumulate within the organs and its eventual localization dictates

their toxicity

Despite immense impact of nanomedicines in cancer societal

implications cannot be overlooked The danger of derailing nanome-

dicines alwaysexists if thescience leaps ahead of the ethical legal and

social implications It is of utmost importance that the area of

nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of

any development

Futuristic nanotechnology will also see medical implants as

another sector for better biomedical implants such as a small active

pacemaker Besides all the developments the exciting milestones

made in these areas need to be paralleled with safety evaluations of

the platforms before they are translated to the clinics Nevertheless

we believe that the next few years are likely to see an increasing

number of nanotechnology-based therapeutics and diagnostics reach-

ing the clinic

Acknowledgements

The 1047297nancial support by Nanomission of Department of Science

and Technology and Department of Information Technology Govt of

India is gratefully acknowledged

References

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[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100

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induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3

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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717

[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641

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[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330

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[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641

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[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287

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[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227

[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452

[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739

[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071

[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4

nanoparticles Conjugation and release of doxorubicin for therapeutic

applications J Magn Magn Mater 323 (2011) 237ndash

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delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644

[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657

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[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327

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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of

magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326

[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693

[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126

[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724

[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612

[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331

[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478

[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167

[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115

[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763

[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260

[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732

[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449

[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396

[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004

[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61

[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730

[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of

potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3

[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101

[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194

[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046

[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625

[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911




[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531

[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127

[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C

114 (2010) 1976ndash

1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055

[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492

[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416

[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100

[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771

[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and

in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230

[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555

[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202

[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816

[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688

[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567

[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651

[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464

[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and

functionality Biomacromology 7 (2006) 572ndash

579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351

[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190

[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60

[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795

[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323

[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474

[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323

[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57





drug industry and has envisaged several applications as can be

evidenced by the exponential growth of activities in this 1047297eld The

advantages of the nanoparticles are mainly due to their nanoscale size

and large surface area with the ability to get functionalized with

targeting ligands therapeutic moieties and biomolecules [1] The fact

that the size of the nanoparticles is quite similar or smaller to the size

range of several bio entities makes them a natural companion in the

hybrid system Furthermore the nanoparticles can easily gain access

to various areas of the body without interfering into normal functionsand has the requisite potential for diagnostic and therapeutics The

ability to manipulatebind individual molecules at nanoscale has

provided ample opportunity for new therapeutic and diagnostic

applications [2] In this way either ldquohybridrdquo nanostructures can be

obtained or it may be embedded in biocompatible materials to impart

new functionalities Since multifunctional nanostructures are desir-

able for many applications like chemical and biological sensing and

diagnosis [3ndash8] sustained drug delivery [9] and hyperthermia [1011]

the fabrication of the nanostructures is signi1047297cant for controlling

crystalline morphology and surface architecture

Drug delivery is a key technology for the realization of nanome-

dicine and nanostructured mediated drug delivery systems play an

important role in improving the properties of already existing

therapeutic and diagnostic modalities Such systems with controlled

composition shape size and surface morphology are designed to

enhance solubility biocompatibility stability of the carrier and

cellular uptake The effectiveness of these has also been improved

signi1047297cantly as delivery vehicles with increased therapeutic payload

[3412] Ideally the nanostructured delivery vehicles should be able

to ef 1047297ciently load high weight fraction of drugs and must form a

stable suspension in an aqueous medium These also need to be

biodegradable andor biocompatible Drugs are usually encapsulated

in conjugated to or adsorbed onto surface of the nanocarrier and are

triggered released by heat pH or other modes of electromagnetic

radiation like ultrasound The nanoscale drug delivery system also

helps in stabilizing drug molecules [61314] which would otherwise

degrade rapidly and reduce drug ef 1047297cacy These bene1047297ts have

accounted for extensive research in the development of nanostruc-

tures and their interactions Most of these are hybrid nanomaterialsand are formed using lsquoweakrsquo molecular interactions such as H-

bonding van der Waal forces and other surface forces which require

low energy thereby allowing reversible and subsequent changes that

are essential for a bioprocess to take place Thus understanding the

interactions helps in broadening therapeutic strategies and designing

and improving drug delivery system In this context researchers have

studied the tunable properties of the nanomaterials by altering the

size shape and chemical composition and have developed strategies

to design biocompatible nanostructures of desired functionality with

and without biomolecules [15ndash21] Quantum dots (QDs) are an

archetype of this hybrid material which have gained interest due to

their tunable optical properties and have been considered as potential

optical probes for biological imaging They are resistant to degrada-

tion than other optical imaging probes and hence can track cellprocesses for longer periods and give more information on molecular

interactions drug delivery or locating a tumor and to arm it with toxic

therapies

Thus while this review aims to cover the fabrication and functiona-

lizationstabilization of various oxide and hybrid nanostructures it will

also attempt to discusstheir therapeutic applications We will emphasize

on magnetic nanostructuresfordrugdeliveryand magnetic hyperthermia

treatment of cancer After a brief introductionto thenanoparticulates and

the hybrids effective methods for functionalization and stabilization of

these structures are discussed The application of the oxides and hybrid

nanostructures in biomedicine is presented in the 1047297nal section In this

review noteworthy and most recent scienti1047297c advances dealing with the

therapeutic application of a wide variety of oxides and hybrid

nanostructures such as silica iron oxide and its derivatives zinc oxide

layereddouble hydroxides and binaryternary metal oxides arereported

We also emphasize here on designing of biodegradable biocompatible

thermosensitiveor pH sensitive nanocarriers fortheir usein drugdelivery

and hyperthermia Some recent advances with respect to sustained and

triggered drug release have been delineated Further the critical issues

relatedto thetherapeuticapplicationsof oxide andhybrid nanostructures

have been addressed and several representative examples to highlight

these applications have been covered brie1047298y in this review

2 Properties of the nanostructures to be used as carriers

The therapeutic applications of oxide and hybrid nanostructures

strongly depend on their physicochemical properties such as

permeability stability morphology (size shape and functionality)

and biocompatibility These physicochemical properties are dictated

by the types structures and orientations of the materials that

comprise the oxide and hybrid nanostructures The nanoparticles

and their hybrids used for therapeutic applications include both

porous and non-porous forms of non-toxic oxides having surface

functionality to which targeting ligands and additional imaging

modalities are anchored One of the most extensively investigated

oxide is iron oxide (γ-Fe2O3 Fe3O4) and its derivatives [22ndash26]

Therapeutic agents like drugs and biomolecules can then either be

physically embedded into the porous matrix or chemically bonded to

its surface Obvious advantages of using magnetic oxides in thera-

peutic applications include magnetic drug targeting heating ability

for hyperthemia and separation under external magnetic 1047297eld

21 Size and shape

The size and size distribution shape and surface functionality of

oxide nanocarriers are important parameters related to intracellular

uptake and biodistribution to a wider range of biological targets due

to their smaller size and relatively higher mobility The small sized

nanoparticles (b100 nm) have higher effective surface area facilitat-

ing easy attachment of ligands lower sedimentation rates (high

stability in colloidal suspension) and improved tissular diffusion For

most of therapeutic applications the 1047297rst signi1047297cant challenge is toavoid undesirable uptake of nanoparticles by the reticulo-endothelial

system (RES) The next step is to achieve selective targeting of the

system to the site of interest for the in-vivo studies In order to

overcome these problems nanoparticles should be small enough with

desired functionality to escape from the RES These nanoparticles

should remain in the circulation for prolonged time after injection

into bloodstream and should be capable of passing through the 1047297ne

capillary systems of organs and tissues avoiding vessel embolism

The size (hydrodynamic size) controls the nanoparticles concen-

tration pro1047297le in the blood vessel affects the mechanism of

nanoparticles clearance and mediates the permeability of nanoparti-

cles out of the vasculature [27] Small sized spherical nanoparticles

have higher diffusion rates which increase the concentration of

nanoparticles at the center of a blood vessel thereby limiting theinteractions of nanoparticles with endothelial cells and prolonging the

nanoparticles blood circulation time [28] Parket al [29] reported that

anisotropic iron oxide having high aspect ratio shows enhanced blood

circulation times over their spherical counterparts Other than size

and shape the pore size and its distribution have signi1047297cant effect on

the therapeutic applications due to its enhanced surface area and its

ability to contain and release drug [30] This aspect is discussed in a

later section

22 Surface functionality

The surface charge (zeta potential) of nanoparticles has an

important role to play in their physiological and aqueous colloidal

stability as well as in functionalization and designing promising
























































































312 Macromolecules













coverage























































noteworthy [61]






















































































































































































drug was released





































































































































































































































































































(Fig 6)












body






































































been demonstrated



















and off





































































































































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash

















































































































312 Macromolecules













coverage























































noteworthy [61]






















































































































































































drug was released





































































































































































































































































































(Fig 6)












body






































































been demonstrated



















and off





































































































































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash
























































noteworthy [61]






















































































































































































drug was released





































































































































































































































































































(Fig 6)












body






































































been demonstrated



















and off





































































































































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash

































































































































































drug was released





































































































































































































































































































(Fig 6)












body






































































been demonstrated



















and off





































































































































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash







































































































































































































































































(Fig 6)












body






































































been demonstrated



















and off





































































































































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash
































been demonstrated



















and off





































































































































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash


























































































































their toxicity






any development








ing the clinic

Acknowledgements




References






150









































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash


































































































































J Pharma 365 (2009) 180ndash189





































114 (2010) 1976ndash
































114 (2010) 1976ndash



























oxide and hybrid nanostructures for therapeutic apps

Documents