RESEARCH PAPER

Design and surface modication of potential

luminomagnetic nanocarriers for biomedical applications
Ranu K. Dutta

Prashant K. Sharma

Avinash C. Pandey
Received: 7 July 2009 / Accepted: 2 November 2009 / Published online: 19 November 2009
Springer Science+Business Media B.V. 2009
Abstract Targeted delivery of therapeutics possesses
the potential to localize therapeutic agents to a specic
tissue as a mechanismto enhance treatment efcacy and
mitigate side effects. Moeities that combine imaging
and therapeutic modalities in a single macromolecular
construct may confer advantages in the development
and applications of nanomedicine. Here is an insight
into the synthesis of luminomagnetic (luminescent and
magnetic, simultaneously) nanocarriers of ZnO:Fe,
synthesized by a simple co-precipitation method and
surface modied by the ligand folate. This functional-
ized luminomagnetic nanocarrier system is a bioconju-
gationapproachwhichcombines the specicityof folate
receptors on cancer cells with the excellent optical and
magnetic properties of the nanoparticles soas todevelop
biocompatible molecular imaging agents, drug delivery
systems, and hyperthermia agents. The vibrating sample
magnetometer (VSM) studies showed clear hysteresis
loops having coercivity 5.1 mT with corresponding
magnetization of remanence 7.6 9 10
-3
emu/g, indi-
cating strong magnetic character of the samples. X-ray
diffraction (XRD) and transmission electron micros-
copy (TEM) measurements show that these nanoparti-
cles are spherical with 69 nm size and hence are quite
appropriate for in vivo applications as well. The
immobilization of folic acid was conrmed by fourier
transform infrared (FTIR) analysis. All these properties
make these luminomagnetic nanocarriers one of the
most feasible candidates for folate receptor-mediated
biomedical applications.
Keywords Magnetic nanoparticles
Folic acid Surface modication
Bioimaging Hyperthermia Targeted drug delivery
Nanomedicine
Introduction
Since the emergence of nanotechnology, great atten-
tion has been paid to the synthesis and modications
of nanoparticles for their size-dependent physical and
chemical properties. The major applications of the
luminomagnetic (luminescent and magnetic, simulta-
neously) nanocarriers lie in the eld of nano-
biotechnology because surface modications dene
the properties of nanoparticles. For biomedical
applications and bioanalysis, the ability to solubilize
the nanoparticles in water and modify their surfaces
with molecules, proteins, oligonucleotides, or other
targeting agents is a crucial step toward their
widespread use. A variety of magnetic nanoparticle
and microparticle carriers have been developed to
deliver drugs to specic target sites in vivo, e.g.,
(Knauth et al. 2001; Alexiou et al. 2000; Bulte et al.
1992). An optimal targeted drug delivery system
requires a platform that is able to carry multiple
R. K. Dutta (&) P. K. Sharma A. C. Pandey
Nanophosphor Application Centre, University
of Allahabad, Allahabad 211002, India
e-mail: ranu.dutta16@gmail.com
1 3
J Nanopart Res (2010) 12:12111219
DOI 10.1007/s11051-009-9801-0
components, such as a drug, a cancer-detecting agent,
and a uorescent sensing agent (Kojima et al. 2000).
Current approaches available are based on nanomag-
nets conjugated to several groups like drugs, uores-
cent dyes, etc. making them very bulky and rendering
them inappropriate for many biomedical applications.
Here is an insight into the design of luminomagnetic
nanocarriers functionalized with the ligand folic acid.
This approach combines the luminescent and mag-
netic properties of the luminomagnets with the
specicity of folic acid making them feasible for
folate receptor-mediated molecular imaging and
targeted drug delivery. Besides these, the small size
of these luminomagnetic particles can be exploited
for their easy elimination from the body after delivery
of the drugs.
Current drawbacks associated with anticancer
drugs are accumulation, non specicity, limited
stability in vivo, and rapid clearance from the body
due to short half lives. Targeted delivery of therapeu-
tics possesses the potential to localize therapeutic
agents to specic tissue as a mechanism to enhance
treatment efcacy and mitigate side effects. Therefore,
ligand specic targeting using molecules like folate
(Kim et al. 2007; Kim et al. 2005; Nayak et al. 2004),
thiamine (Oyewumi and Mumpe 2002), transferrin
(Yang et al. 2005), antibodies (Zhang et al. 2008a, b),
peptides (Stefova et al. 2007), and oligonucleotides
(Nitin et al. 2007) are being investigated. Nanoparti-
cles have also been capped with various biocompatible
polymers such as PVA, dextran, silica (Santra et al.
2001) and inorganic capping agents like biotin (Kes-
hari et al. 2007), citric acid (Sharma et al. 2009a, b, c),
avidin, carbodiimide, SiO
2
(Sharma et al. 2009a, b, c),
and chitosan-PEG (Aktas et al. 2005). These mole-
cules then act as attachment points for the coupling of
cytotoxic drugs or target antibodies.
By tagging folic acid with these luminomagnets,
tumors, and other lesions can be detected at the cellular
and molecular level (Jaffer and Weissleder 2004;
Schellenberger et al. 2004). Folate receptors are up-
regulated on a variety of human cancers, including
cancers of the breast, ovaries, endometrium, renal cell
carcinoma, lungs, kidneys, colon, brain metastases,
colorectal, and neuroendocrine carcinoma (Sudimack
and Lee 2000; Gabizon et al. 1999; Sirotnak and
Tolner 1999; Stella et al. 2000) due to their enhanced
mitosis rates. This over-expression of folate receptors
(FR) on cancer tissues has been identied as tumor
markers and can be exploited to target folate-linked
imaging and therapeutic agents specically to FR-
expressing tumors, thereby avoiding uptake by most
healthy tissues that express few, if any, FR. The
expression of FR increases with the advancement in
the stage of cancer (Nikki et al. 2005). Folic acid is a
short chain, non immunogenic, and high afnity
ligand. The FR is a glycosyl phosphotidylinositol-
linked membrane glycoprotein with an apparent
molecular weight of 3840 KDa. Folate is an essential
precursor for the synthesis of nucleic acid and some
amino acids. It is not produced endogenously by
mammalian cells and requires internalization by cells
via receptor-mediated endocytosis or carrier-based
uptake mechanism. Conjugation of folate to anticancer
drugs, liposomes and micelles facilitated their cellular
uptake (Kohler et al. 2005). Besides this, FR is
expressed on the basolateral surface (blood side) of
transformed cells as compared to the apical surface
expression in normal cells (Leamon et al. 1993). This
property complements the cancer cell specicity of
folic acid as a targeting agent when delivered through
the blood. These along with their capability of being
manipulated by an external magnetic eld leads to
highly sensitive agents for biolabelling and magnetic
resonance imaging with enhanced contrast. Besides,
these can be designed to be used as delivery vector of
external genetic material and enhance efciency of
transfection and transformation. They can also be used
for immunodetection, bioimaging, folic acid-based
biosensors, hyperthermia, and study of the cell
signaling mechanism.
In the conventional nanomagnets used, several
modications have to be done to make themfunctional
for a single use. Several groups like uorescent
molecules, tumor targeting agents, etc. have to be
attached which make the particles very bulky and
exceed the nano range. Therefore, to overcome these
drawbacks we have synthesized the luminomagnet
which seems to possess all the relevant properties like
small size, luminescence, good magnetism, and sur-
face modied by tumor marker targeting agent folate.
These will make the single luminomagnetic nanocar-
riers multifunctional. These expedition motivated us to
design luminomagnets of ZnO:Fe. The luminomagnets
were surface immobilised with the ligand folic acid.
For this the luminomagnets were rst surface-modied
with (3-aminopropyl)-trimethoxysilane to form a self-
assembled monolayer and subsequently conjugated
1212 J Nanopart Res (2010) 12:12111219
1 3
with folic acid through amidation between the
carboxylic acid end groups on folic acid and the
amine groups on the particle surface. Particle size as
estimated by X-ray diffraction (XRD), transmission
electron microscope (TEM) investigations seem to be
relevant for use in living system, without any risks of
aggregation or clogging effect in smaller capillaries.
Experimental procedures
Sample preparation
For synthesis of ZnO:Fe nanoparticles, the zinc
nitrate hexahydrate (99.2%) Zn(NO
3
)
2
6H
2
O, iron
nitrate (99.4%) Fe(NO
3
)
3
9H
2
O potassium hydroxide
KOH, methanol and ethanol were, procured from E.
Merck Limited, India. Three amino ethyl trimethoxy
silane (AEAPS), folic acid, toluene, N-hydroxy-
succinimide (NHS), and 1-ethyl-3-[3-(dimethyl-
amino)-propyl] carbodiimide (EDC) were procured
from Alfa Aesar, Germany for surface modication.
All chemicals were of analytical reagent grade and
were directly used without special treatment.
Synthesis of ZnO:Fe (10% Fe doped) nanophos-
phors was carried out using the same technique which
we have already used in our earlier work (Sharma et al.
2009a, b, c). For synthesizing ZnO:Fe, appropriate
amount of metal nitrates were dissolved in 100 mL of
methanol while stirring for 2 h continuously at room
temperature (Solution A). Simultaneously, 140 mmol
KOH solution was prepared in 100 mL of methanol
with reuxing through water condenser for 2 h at
50 C (Solution B). Now, the solutions A and B were
mixed and reuxed at 50 C using a water condenser
for 2 h. The nal solution was allowed to cool at room
temperature, aged overnight, centrifuged and washed
several times with absolute ethanol and double
distilled water in order to remove the impurities. The
obtained product was placed in a vacuumoven for 24 h
at 50 C to get white ZnO:Fe powders.
Characterization techniques used
The prepared ZnO:Fe nanoparticles were character-
ized by X-ray diffraction (XRD) and transmission
electron microscopy (TEM) in order to elaborate
structural properties in a precise manner. XRD was
performed on Rigaku D/max-2200 PC diffractometer
operated at 40 kV/20 mA, using CuK
a1
radiation with
wavelength of 1.54 A

in the wide angle region from

25 to 70 on 2h scale. The size and morphology of
prepared nanoparticles were found using a transmis-
sion electron microscope (model Technai 30 G
2
S-
Twin electron microscope) operated at 300 KV accel-
erating voltage by dissolving the as-synthesized
powder sample in ethanol and then placing a drop of
this dilute ethanolic solution on the surface of copper
grid. Room temperature magnetization measurement
was carried out using a vibrating sample magnetom-
eter (VSM, ADE Magnetics, USA) up to an applied
eld of 1.75 T with pressed pellets of prepared
powdered samples. Photoluminescence (PL) studies
were performed for k
ex
= 320 nm on a Perkin Elmer
LS 55 luminescence spectrophotometer using a Xenon
discharge lamp as the excitation source at room
temperature, equivalent to 20 kW for 8 ms duration.
FTIR spectra of both as prepared, AEAPS modied
and folic acid-conjugated particles were performed
with the FTIR spectroscope model Nicolet 20 SXB.
Results and discussion
Characterizations of synthesized ZnO:Fe
nanoparticles
Figure 1 shows the XRD pattern of the ZnO:Fe
nanoparticles synthesized by co-precipitation
method. XRD Spectra showed broad peaks at the
positions of 31.63, 34.50, 36.25, 47.50, 56.60,
62.80, and 67.92, which were in excellent agree-
ment with the JCPDS le for ZnO (JCPDS 36-1451,
a = b = 3.249 A

, c = 5.206 A

) and indexed as the

hexagonal wurtzite structure of ZnO having space
group P6
3mc
. All available reections of the present
phases were tted with the Gaussian distribution.
The broadening of XRD peaks (i.e., Scherrers
broadening) gave clear indication of nanosized for-
mation of ZnO. Particle sized of ZnO was estimated
by DebyeScherrers Equation.
d
0:9k
B Cosh
where, d is the particle size, k is the wavelength of
radiation used, h is the Bragg angle and B is the full
width at half maxima (FWHM) on 2h scale. For ZnO
J Nanopart Res (2010) 12:12111219 1213
1 3
samples, average particle size using DebyeScher-
rers equation was of the order of *6 nm. The XRD
results were well supported by TEM measurements.
Figure 2a, shows the TEM results of the synthe-
sized samples. The morphology of the sample was
found to be spherical in nature having diameters
ranging from 5 to 9 nm with very narrow distribution
(Fig. 2b). Figure 2 clearly shows that the diameters
of these spherical nanoparticles were in good agree-
ment with those obtained using XRD results. In order
to conrm the presence of Fe in the synthesized ZnO
nanoparticles, EDX measurements were performed.
Figure 2c shows the EDX spectra of ZnO:Fe nano-
particle. From the similarity of the Zn and Fe peak
intensity line traces, it is clear that after the synthesis
process, zinc and iron were homogenously distributed
inside the nanoparticle. From the EDX line traces it
can also be concluded that Fe was successfully
substituted into the crystal structure of ZnO nano-
particles. The estimated amount of Fe ions were
*9.8%. EDX measurements on single nanoparticle
found that zinc and iron are homogeneously distrib-
uted throughout the ZnO:Fe nanoparticle. Figure 3
shows the dependence of magnetization with applied
Fig. 1 X-ray diffraction spectra of ZnO:Fe. The XRD spectra
showed crystalline nature having hexagonal Wurtzite structure
of ZnO having space group P6
3mc
Fig. 2 a TEM image of
ZnO:Fe nanoparticles; inset
shows high resolution
image (HRTEM), b particle
size distribution, c EDX
spectra of ZnO:Fe
nanoparticles. EDX
measurements on single
nanoparticle found that zinc
and iron are homogeneously
distributed throughout the
ZnO:Fe nanoparticle
1214 J Nanopart Res (2010) 12:12111219
1 3
magnetic eld (MH loop) for the ZnO:Fe sample at
room temperature. Clear hysteresis loops showing
strong paramagnetic nature with coercivity 5.1 mil-
litesla (mT) was observed and the corresponding
magnetization of remanence was found to be
7.6 9 10
-3
emu/g.
The noticeable coercivity of MH loop could be
attributed to strong paramagnetism at room temper-
ature. The narrow hysteresis implies a small amount
of dissipation of energy in repeatedly reversing the
magnetization which is imperative for quick magne-
tization and demagnetization of the synthesized
samples. The paramagnetic behavior can be attributed
to the presence of small magnetic dipoles located at
the surface of nanocrystals, which antiferromagneti-
cally interacts between neighboring FeFe ions
suppressing the ferromagnetism, and enhancing the
paramagnetism in the synthesized samples. The
details of XRD and VSM characterization results
were well explained in our earlier paper (Sharma
et al. 2009a, b, c).
As is evident from Fig. 4, the increased lumines-
cence intensity of emission band peaked at 528 nm in
doped ZnO strongly suggests involvement of Fe ions
in the samples. Inset of Fig. 4 shows the as synthe-
sized liquid samples in white light (1) and in UV
lamp (2). Several workers (Eugene et al. 2008;
Seonghoon et al. 2007; Zhang et al. 2008a, b) have
already suggested that Fe doped ZnO can produce
green emission. Doping of Fe in ZnO causes two
main impacts. First one is introduction of iron ion and
the other is to create some defects in the host ZnO
lattice. In order to understand the mechanism, one
can suggest that Zn ions are replaced by Fe ions, and
then the Fe ions donate two electrons in the process
of band formation and will be in a neutral state with
respect to that of the Fe state. In our case, iron ion
diffusion takes place in the host ZnO lattice causing
rapid increase in the luminescence intensity.
Surface modication of synthesized ZnO:Fe
nanoparticles
ZnO:Fe magnetite nanoparticles were conjugated with
folic acid by a chemical method as designated in
Fig. 5 diagrammatically. First, the nanoparticles were
surface modied with AEAPS (3 amino ethyl tri-
methoxy silane) to form particles with NH
2
groups,
which were subsequently conjugated with folic acid
through amidation between NH
2
groups on nanopar-
ticle surface and c-carboxylic acid group (COOH) of
c-{N-{2-[2-(2-aminoethoxy) ethoxy] ethyl} folic
acid. 0.2 g of ZnO:Fe was taken and dissolved in
50 mL toluene and sonicated for 30 min. To this
solution, 10 mL of AEAPS was added. The suspen-
sion was stirred for 2 h and the particles were
recovered and washed with millipore water. 0.1 g of
folic acid was taken and dissolved in 10 mL aqueous
solution of N-hydroxysuccinimide (NHS) (358 mmol,
41 mg) and 18 mg of 1-ethyl-3-[3-(dimethylamino)-
propyl] carbodiimide (EDC) and kept in the dark for
Fig. 3 Room temperature MH loop of synthesized ZnO:Fe
nanoparticles
Fig. 4 Photoluminescence spectra of ZnO:Fe nanoparticles.
Inset shows the liquid samples in white light (1) and UVlamp (2)
J Nanopart Res (2010) 12:12111219 1215
1 3
2 h. The particles were then immersed in this mixture
and left overnight for proper reaction to occur.
Determination of surface modications by FTIR
FTIR spectroscopy was used for the conrmation of
the folic acid immobilization on the magnetic nano-
particle surface. The spectra were recorded by
making pressed pellet of the prepared samples in
potassium bromide (KBr). The corresponding FTIR
spectrum is shown in Fig. 6. All the samples showed
clear ZnOZn stretching modes at 620 and
816 cm
-1
corresponding to ZnO nanoparticles and
were well supported by available literature (Xiong
et al. 2004). Due to adsorption of CO, few peaks at
1,406 and 1,572 cm
-1
were observed, while stretch-
ing modes at 1,470 and 3,310 cm
-1
were due to OH
groups present on the surface of ZnO nanoparticles.
The broadening of these modes could be attributed to
the overlapping of different peaks.
FTIR spectra of the unmodied and surface
modied samples are shown in Fig. 6a, c, respec-
tively. The unmodied nanoparticles show prominent
peak at 1,030 cm
-1
. Other peaks observed are at 823
and 1,770 cm
-1
. Sample modied with AEAPS
(Fig. 6b) shows broad band at 9001,100 cm
-1
corresponding to SiO stretching depicting the con-
jugation of nanoparticles with AEAPS. The peak at
1,551 cm
-1
is due to the primary amine group of
AEAPS, indicating that the nanoparticles have been
surface modied by amine group. In Fig. 6c, peak at
1,606 cm
-1
corresponding to benzene group of folic
acid is observed, indicating the immobilization of
folic acid on nanoparticles surfaces. Furthermore,
the peak at 1,640 cm
-1
corresponding to carbonyl
(C=O) group indicates attachment of c- carboxyl
group of folic acid and NH
2
group of AEAPS,
forming peptide bond. Peak at 1,648 cm
-1
is due to
bending vibration of NH bond, indicating the
formation of peptide bond between NH
2
group on
nanoparticle surface and carboxyl group of folic acid.
Presence of peak at 1,023 cm
-1
is due to SiO group
of AEAPS. In Fig. 6d, the prominent peaks of folic
Fig. 5 Reaction
mechanism for surface
modication of
luminomagnet with folic
acid
Fig. 6 FTIR Spectra of ZnO:Fe samples after different steps
of surface modications. FTIR spectra of a only ZnO
nanoparticle, b ZnO treated with AEAPS, c ZnO ? AE-
APS ? Folic Acid, and d only Folic Acid
1216 J Nanopart Res (2010) 12:12111219
1 3
acid are clearly visible. Peak due to benzene group at
1,606 cm
-1
is evident due to folic acid. In Fig. 6d,
peaks at 3,540 and 3,315 cm
-1
is due to OH and
secondary NH groups, respectively, and can be
attributed to the folic acid. From these discussions it
is evident that the immobilization of Folic acid on the
luminomagnets has been accomplished.
Bio-medical implication of the synthesized
magnetic nanoparticles of ZnO:Fe
Targeted drug delivery
Magnetic nanoparticles functionalized with the drug
can serve as potential drug carriers in a new drug
delivery strategy, based on the application of external
magnetic elds. The principle of drug delivery by
nanomagnets is based on the use of both constant and
high-frequency oscillating magnetic elds. Since
these particles are magnetic in nature, they can be
targeted to specic areas (for e.g., cancer tissues) by a
constant external magnetic eld. Releasing mecha-
nism is accomplished by thermal excitations of these
conjugated magnetic nanoparticles induced by an
external high-oscillating magnetic eld. Magnetic-
eld-induced excitations produce heat that increases
the temperature of nanomagnets. Such specic heat-
ing represents an eliciting mechanism for the con-
trolled release of conjugated drug from the
nanomagnets when they are heated to adequately
high temperatures (around 40 C). This specic
heating can be achieved by calculating hysteresis
loss (heat loss) from the magnetic loop.
The functionalized magnetic nanoparticle experi-
ences a force which is produced by the magnetic eld
gradient and can be expressed as:
F
m
Vvr
B
2
2l
0
Vvr
1
2

B:

H

For this reason, high-gradient, magnetic elds are
commonly used for both magnetic nanoparticle-based
drug delivery as well as for magnetofection applica-
tions. This equation also indicates that the variable
parameters that can be used to increase the force
(and, in vivo, the likelihood of capture) on the
magnetic particle carrying the therapeutic drug or a
gene of interest, are the particle volume, magnetic
eld strength, magnetic eld gradient and the
magnetic susceptibility of the particles. Earlier the-
oretical work done by researchers like Voltairas et al.
(2002) indicated that for the most of the magnetic
carriers, the magnetic ux density (eld strength) at
the target site must be of the order of 200700 mT in
order to efciently attract particles owing in the
blood vessels. In addition to this, for targeted drug
delivery the nanoparticles must have dimensions
around 310 nm. In the same pursuit, the folic acid-
conjugated magnetic ZnO:Fe nanoparticles can be
used for targeted drug delivery.
The ligand molecules along with the magnetic
eld help to drag the drug-conjugated nanomagnet to
the target site when a high gradient magnetic eld is
applied outside the body near the tumor. A magnet is
focused outside the body so that its magnetic eld
gradient attracts the magnetic nanoparticles to the
target site. Once the complex reaches the desired
location, the drug can be released by the way of self
specic heating of magnetic nanoparticles as dis-
cussed earlier. The enlarged schematic diagram of the
mechanism of the receptor-mediated endocytosis of
folic acid and drug-conjugated luminomagnetic
nanocarriers in cancer cells is depicted in Fig. 7.
Localized hyperthermia
The therapeutic power of heat has been used to
alleviate a variety of diseases. This heat treatment is
recognized as new and promising form of cancer
rehabilitation out-of-the-way from surgery, chemo-
therapy, and irradiation. It is well established that
cancer growth stops at temperatures higher than about
42 C (Wilfried and Nowak 1998). Hyperthermia is
heating of certain organs or tissues to temperatures
between 41 and 48 C as a treatment of cancer.
The major consequences of current study are:
1. Successful synthesis of luminomagnetic ZnO:Fe
nanoparticles.
2. Surface modication with folic acid makes them
feasible nanocarriers for specic folate receptor-
mediated drug delivery, bioimaging and hyper-
thermia applications.
3. Localized heating can be achieved by subjecting
these ZnO:Fe magnetic nanoparticles to alternat-
ing magnetic eld.
4. The 3.63.9 C temperature rise can be obtained
by applying 2 GHz frequency of the external
J Nanopart Res (2010) 12:12111219 1217
1 3
alternating magnetic eld in a single second or
few minutes for hundred KHz or MHz frequency
of external alternating magnetic eld. This rise in
temperature is estimated by taking specic heat
values of Liver, Lung, Prostate tissues in the
range of 3.63.9 kJ Kg
-1
K
-1
.
Thus, in a very short time period the temperature
of cancerous tissue can be raised to 42 C or above.
Conclusions
We have successfully synthesized luminomagnetic
nanoparticles of ZnO:Fe by a simple co-precipitation
method, followed by surface modication with folic
acid which make them feasible nanocarriers for
biomedical applications. The synthesized particles
are small (*8 nm) with the enhanced magnetic
moment and magnetic anisotropy, rendering them
utilizable for several biological applications. These,
along with their capability of being manipulated under
an external magnetic eld, provide controllable means
for magnetically tagging of all biomolecules, leading
to highly efcient bio-separation/bio-delivery, highly
sensitive bio-labeling and magnetic resonance imag-
ing (MRI) with enhanced contrast. They can be used
as a delivery vector of external genetic material and
enhance efciency of transfection or transformation
making them the most feasible candidates for targeted
drug delivery systems and seizes great potential in
bio-medical applications, underlying the importance
of the current study.
Acknowledgments Authors are thankful to DST and CSIR,
India for supporting Nanophosphor Application Centre
under IRHPA, Nano-Mission, and NMITLI schemes.
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