Surface modified silica nanoparticles for synchronous magnetic resonance imaging and drug delivery applications

Article abstract of DOI:10.1039/c4ra06367h

This study reports a simple and versatile method of tailoring surface modified silica nanoparticles (SMS NPs) via co-condensation technique. The particles were loaded with gadolinium oxide and an anticancer drug, colchicine, utilizing the aqueous core of the reverse micelle as "nano" host reactors. The surface of the silica NPs was modified with 3-aminopropyltriethoxysilane. Surface modification entails higher content of the drug and allows it to get released in a sustained manner. The particles exhibit spherical morphology with an average diameter of 60 nm as measured by TEM. Gadolinium oxide is paramagnetic in nature as observed from the NMR line broadening effect on proton spectrum of the surrounding water. Preliminary in vitro experiments on MCF-7 reveal good potential of these SMS NPs for cancer therapy. It is expected that these highly versatile multifunctional silica NPs could potentially be employed for simultaneous non-invasive imaging and therapeutic purposes.

Full text of DOI:10.1039/c4ra06367h

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PAPER
Surface modified silica nanoparticles for
synchronous magnetic resonance imaging and
drug delivery applications
Cite this: RSC Adv., 2014, 4, 61028
a
b
a
Henam Premananda Singh, Susmita Mitra* and Rakesh Kumar Sharma*
This study reports a simple and versatile method of tailoring surface modified silica nanoparticles (SMS NPs)
via co-condensation technique. The particles were loaded with gadolinium oxide and an anticancer drug,
colchicine, utilizing the aqueous core of the reverse micelle as “nano” host reactors. The surface of the silica
NPs was modified with 3-aminopropyltriethoxysilane. Surface modification entails higher content of the
drug and allows it to get released in a sustained manner. The particles exhibit spherical morphology with
an average diameter of 60 nm as measured by TEM. Gadolinium oxide is paramagnetic in nature as
observed from the NMR line broadening effect on proton spectrum of the surrounding water.
Preliminary in vitro experiments on MCF-7 reveal good potential of these SMS NPs for cancer therapy. It
is expected that these highly versatile multifunctional silica NPs could potentially be employed for
simultaneous non-invasive imaging and therapeutic purposes.
Received 28th June 2014
Accepted 31st October 2014
DOI: 10.1039/c4ra06367h
www.rsc.org/advances
attractive features exhibited by them. The ability to function-
alize the surface of mesoporous silica based nanocarriers with
1
. Introduction
The ongoing research in the area of nanoscience and nano- stimuli responsive groups, other NPs, proteins, and polymer
technology has fuelled a boom both among the academic and that work as caps and gatekeepers for controlled release of
8–10
the scientic communities. One of the emerging areas for the various cargos
has generated huge excitement. In particular,
biomedical applications of nanotechnology is in drug delivery amino-functionalized silica base NPs can be used to target to
systems for therapeutic purposes. Although conventional specic cell types by conjugating a cell-line-specic ligand or
11
treatment methods such as chemotherapy and radiation tech- antibody in a relatively easy way. Recently, gadolinium based
nique have yielded some advantages over the past decades, materials have been widely employed as positive contrast
cancer therapy is still far from optimal. The main challenges in agents. This rare earth element is associated with seven
the search of effective carrier in most drug delivery systems unpaired electrons on its valence orbital, leading to a high
include in vivo stability, rapid clearance from the circulation, magnetic moment (7.94 m ). Moreover, the electron spin relax-
B
ꢁ
9
ꢁ8
sustained and targeted delivery to site of action, plasma uc- ation time of Gd is long (1 ꢀ 10 to 1 ꢀ 10 s), maximizing
tuations of drugs which either fall below the minimum effective dipole–dipole interactions of electrons and hydrogen protons
1
concentration or exceed the safe therapeutic level, solubility, ( H) in the proximity of the contrast agent. Such interactions
biocompatibility, shelf life, therapeutic effectiveness and side increase the proton relaxation time resulting in signal
1–4
12,13
effects.
Nanoscale materials alleviate the major issues enhancement effects in MRI.
On the other hand, colchicine
accompanied with drug delivery system to a maximum extent, has the ability to inhibit polymerization of microtubules by
offering tremendous potential and a promising approach to binding to tubulin which is one of the main constituents of
deliver large payload of therapeutic agents into targeted tissues microtubules. During mitosis availability of tubulin is essential
or cells. These nanomaterials have been actively developed and therefore colchicine effectively functions as a “mitotic
14
primarily for efficient application in cancer therapy by modu- poison” or spindle poison. One of the dening characteristics
5
–7
lating the characteristic behaviours of the loaded entity.
Among the inorganic based materials, silica NPs represent one indicates that cancer cells are more vulnerable to colchicine
of cancer cells is to signicantly increase rate of mitosis which
15
of the excellent and versatile platforms for drug delivery owing poisoning than are normal cells. Cauda V et al. have recently
to their straightforward synthesis as well as due to several shown the effectiveness of colchicine drug by delivering into
HuH7 liver cancer cells in the form of colchicine loaded lipid
bilayer coated with mesoporous silica NPs. Therefore, an
amalgamation of different nanostructural materials will enable
the development of multifunctional nanomedical platforms for
a
Nanotechnology and Drug Delivery Research Lab, Department of Chemistry,
University of Delhi, Delhi 110007, India. E-mail: sharmark101@yahoo.com; Tel: +91
9
310050453
b
Amity University, Noida, India. E-mail: smitra@amity.edu; Tel: +91 9810333880
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multimodal imaging or simultaneous diagnosis and therapy technique for surface modication not only because of its
techniques aiming towards clinical productivity. simplicity but also offers a homogeneous coverage of functional
In the light of the above information, we have addressed the group, large amount of drug loading and enhanced dispersion
16–20
development of a simple route for the fabrication of surface minimizing particles aggregation
which we have also
modied silica (SMS) NPs for synchronous magnetic resonance observed. Since no harsh chemicals are employed during this co-
imaging (MRI) and versatile drug delivery applications as our condensation synthesis technique, the amine groups in the silica
main endeavour in this particular report. Surface modication layer might not be hampered. The method involved preparation of
of particles was done via co-condensation technique utilizing silica coating at low temperature in order to control their
the aqueous core of the reverse micelle as “nano” host reactors morphology. Fig. 1(a) illustrates the UV-vis spectra of free colchi-
co-encapsulating gadolinium oxide NPs and colchicine drug. cine and the silica particles loaded with the anticancer drug.
Subsequently, cytotoxic effect of these ensuing NPs on MCF-7
The absorption spectrum of the aqueous solution of free
breast cancer cells was successfully evaluated. Designing of colchicine shows three characteristic absorption peaks at
such multifunctional delivery system with potential release 201 nm, 246 nm and 353 nm. The two characteristic absorption
properties is still of paramount importance and may offer a new peaks of colchicine at 246 nm and 353 nm is also exhibited by
dimension to biomedical applications.
the spectra of the synthesized SMS NPs co-encapsulating
gadolinium oxide and colchicine which depicts the presence
of colchicine drug in the fabricated SMS NPs. On the other
hand, colchicine in the presence of an aliquot H SO hydrolyses
2. Results and discussion
2
4
21,22
to give colchiceine,
which exhibits prominent absorption
The overall synthetic schemes employed for the fabrication of
multifunctional composite SMS NPs via co-condensation tech-
nique has been illustrated in Scheme 1.
Gadolinium oxide NPs and colchicine drug were co-
encapsulated within the nanosized silica particles. In this explo-
ration, co-condensation method was chosen as preparation
peaks in ultra violet region at 200 nm, 253 nm and 378 nm as
presented in Fig. 1(b). Such, peaks were also noted with the
silica particles when dispersed in an aliquot of 30% H SO . It
2 4
could be seen that the UV-vis spectra coincided very well, but
absorption intensity corresponding to the loaded particles was
Scheme 1 Diagrammatic representation for the synthesis of SMS NPs co-encapsulating gadolinium oxide and colchicine drug using water-in-oil
microemulsion.
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Fig. 1 UV-vis spectra of (a) free colchicine drug and SMS NPs co-encapsulating gadolinium oxide and colchicine in aqueous solution (b) free
colchiceine solution and colchiceine obtained from the drug loaded silica NPs.
more apparently decreased. This observation further substan-
tiates the above argument regarding the inclusion of colchicine
drug in the so-synthesized SMS NPs doped with gadolinium
oxide. The reaction of colchicine drug in the presence of an
aliquot H SO is displayed in Fig. 2.
2
4
Fig. 3(a) highlights the typical TEM micrograph of the SMS
NPs co-encapsulating gadolinium oxide and colchicine drug.
The particles have a narrow size distribution with uniform,
discrete spherical morphology. The average diameter of the
SMS NPs is about 60 nm while the HRTEM image of a particle Fig. 3 (a) TEM picture of SMS NPs co-encapsulating colchicine and
gadolinium oxide with an average diameter of 60 nm; inset shows
HRTEM of the particle (b) SAED pattern of the synthesized particles.
shown in the inset displays a core shell like structure with a
darker contrast at the central portions than at the periphery of
the particle revealing the incorporation of a solid gadolinium
oxide NPs within it.
SAED pattern shown in Fig. 3(b) indicates the particles are
weakly crystalline in nature probably due to the coating of modi-
ed silica layer over the surface of gadolinium oxide NPs. The
modied silica layer might have permitted the interaction of the
electron beam with the encapsulated gadolinium oxide expressing
its weakly crystalline nature. Furthermore, EDAX provides local-
ized elemental information in case of multi-component nano-
materials. Subsequently, from the data obtained by EDAX
analysis, shown in Fig. 4, we can precisely conclude the presence
of gadolinium along with silica in the reported sample.
Fig. 5 demonstrates the XRD pattern of the particles. The
diffraction pattern of the particles exhibits three sharp peaks at
ꢂ ꢂ ꢂ
1
(
8.98 , 29.28 and 33.86 corresponding to (211), (222) and
23,24
400) planes of cubic gadolinium oxide.
Therefore, XRD
analysis further furnishes a strong evidence of the crystalline
Fig. 4 Energy dispersive spectroscopy (EDS/EDAX) of silica NPs
encapsulating gadolinium oxide NPs.
nature due to the inclusion of gadolinium oxide in the fabri-
cated SMS NPs system.
The FT-IR spectrum of the SMS NPs, presented in Fig. 6,
ꢁ1
Fig. 2 Acid hydrolysis reaction of colchicine drug.
exhibit a broad peak at 1108 cm and a relatively weak peak at
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2
out in D O using 400 MHz spectrometer (JNM-ECX-400P, JEOL,
Tokyo, Japan) and are shown in Fig. 7. The unpaired electrons of
gadolinium ion in gadolinium oxide is a good example of slow
electron relaxation which results in line broadening effect of the
surrounding water proton as displayed in Fig. 7(b). But such
broadening effect of the heavy water protons in proximity with
SMS NPs in absence of gadolinium oxide was not observed as
indicated in Fig. 7(a). In this case only sharp normal peak of the
water proton is seen due to the absence of gadolinium which exerts
13
paramagnetic effect on the water proton resonance. Besides, TGA
was used to examine the thermal properties of the prepared silica
particles. TGA studies of the colchicine drug and the SMS NPs co-
encapsulating gadolinium oxide and colchicine were highlighted
in Fig. 8. The thermograph shows a gradual decrease in weight loss
initially in both the curves as the temperature increases which may
be accounted to the release of the adsorbed moisture, slow
decomposition of colchicine drug and dehydroxylation of silanol
Fig. 5 XRD pattern of SMS NPs co-encapsulating gadolinium oxide
and colchicine.
29
in case of silica particles. Unlike the TGA curve of SMS NPs co-
62 cm which corresponds to Si–O–Si asymmetric stretching encapsulating gadolinium oxide and colchicine drug, TGA curve
ꢁ1
4
vibration and Si–O stretching respectively from the SiO
2
matrix. of free colchicine shows a sudden decrease in its weight at around
The presence of amine group in the synthesized particles can 280 C. Such rapid changes in the weight with rise in temperature
easily be recognized from the peaks at 1592 cm correspond- were not observed in case of the nanodimensional silica particles
ꢂ
ꢁ1
ing to the characteristic NH asymmetric bending and 3436 co-encapsulating gadolinium oxide and colchicine. Thus, silica
2
ꢁ
1
cm which has been assigned to –N–H and O–H stretching shell provides a protective environment of the materials within its
2
vibration. The stretching vibration of the methylene (–CH –) core hereby increasing their thermal stability.
group obtained from the hydrolysis and condensation of
From the concentration of the unloaded drug we have
calculated the entrapment efficiency indirectly using the
ꢁ
1
25,26
–
Si–(CH
2
)
2
–NH
2
of APTES is assigned to the peak at 2936 cm
.
This information validates successful graing of the prepared following equation
ꢁ
1
silica particles. Additionally, the peak around 546 cm is attrib-
uted to the stretching vibrations of cubic phase Gd–O bond which
À
Á
Total colchicine added at the time of synthesis ꢁ Total colchicine present outside the particles
Entrapment efficiency E% ¼
ꢀ 100
Total colchicine added at the time of synthesis
further conrms the existence of Gd
2
O
3
in the composite nano-
The entrapment efficiency was found to be about 72% as
27,28
1
dimensional SMS particles.
Furthermore, H-NMR studies of determined spectrophotometrically from the absorption of
SMS NPs with and without gadolinium oxide doping were carried colchicine in different conditions. In view of the afore
mentioned discussion, drug release prole of the SMS NPs co-
encapsulating gadolinium oxide and colchicine was estimated
by dialysis method using UV-vis spectrophotometer in 0.1 M
phosphate buffer solution of pH 7.4 at room temperature. The
amount of the anticancer drug, colchicine, released from the
particles via diffusion at different point of time was calculated
spectrophotometrically at 353 nm, a prominent characteristic
peak of colchicine, and the percentage of the drug release was
plotted against the duration taken as displayed in Fig. 9. From
the release prole it can be noted that aer 24 h and 48 h of
dialysis about 40% and 70% respectively of the loaded drug gets
released from the SMS NPs. Such release kinetics may have been
controlled by extended interaction between the functional
group(s) of the drug and the introduced amine on the silica
18,30
layer via H-bonding and/or Vander Waals interaction.
Generally, functionalized group(s) via co-condensation tech-
nique also anchored covalently to the pore walls as direct
Fig. 6 FT-IR spectrum of the SMS NPs.
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1
Fig. 7 H-NMR of SMS NPs (a) without and (b) with gadolinium oxide doping.
Fig. 8 Thermogravimetric analysis (TGA) of colchicine drug and SMS
NPs co-encapsulating gadolinium oxide and colchicine.
Fig. 9 Release kinetics of colchicine in phosphate buffer solution of
pH 7.4 at room temperature.
31,32
components of the silica matrix.
Therefore, surface modi-
cation of silica particles not only results in entrapping higher almost 70% of the loaded drug got released during 48 hours as
content of drug but also plays a critical role in the release of the we observed. An important observation during this experiment
drug from the particle itself. To verify the feasibility of using was that void SMS NPs (control 1) exhibits no toxicity on the
SMS NPs co-encapsulating gadolinium oxide and colchicine for cancer cells. A comprehensive cytotoxicity assay including a
cancer therapy, MTT assay of the particles were investigated in range of cancerous cell lines at different exposure conditions
MCF-7 breast cancer cells. The SMS NPs co-encapsulating should be monitored to elucidate the complete anticancer
gadolinium oxide and colchicine drug show good efficiency behavior of these NPs. However, from this preliminary in vitro
against the breast cancer cells, as presented in Fig. 10. Colchi- investigation, we can, conclude that SMS NPs are potentially
cine released from the silica particles is cytotoxic on MCF-7 safe vehicle and have the characteristics for their utilization in
cells. The loaded SMS NPs must have been uptaken by the in vivo experiments for further studies.
cancer cells and the drug released intracellularly by diffusion
process. However, a slight decrease in the activity of the
colchicine loaded in SMS NPs is observed as compared to the
free drug. The NPs having a void core do not exhibit any toxicity. 3.1. Materials
3
. Experimental
This may be attributed to the incomplete release of the drug
from the silica particles during the period of MTT assay as
Sodium 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT)
was purchased from Acros Organics; liquid ammonia (25%) and
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loaded gadolinium oxide NPs was maintained at low tempera-
ꢂ
ture of 4 C and 50 ml each of neat TEOS and APTES were added
simultaneously. The solution was stirred further for 72 h at low
ꢂ
temperature of 4 C. The particles were then extracted and
washed with hexane and ethanol four times. Finally, the
ensuing particles were dispersed in 1 ml of DDW.
3.3. Characterization of the tailored nanosized modied
silica particles
3.3.1. Ultraviolet-visible spectrum. All UV-vis spectra were
recorded on Shimadzu-1601 UV-vis spectrophotometer tted
with a constant temperature cell holder. The temperature of the
cell holder was maintained constant by circulating water
around it by a water circulator from Haake instrument. The
absorption spectra were recorded by taking the aqueous
dispersion of the samples and scanned in the range of 190–890
nm.
Fig. 10 MTT assay on MCF-7 cell line.
3.3.2. High resolution transmission electron microscopy
(HRTEM), selected area electron diffraction (SAED) and energy
dispersive spectroscopy (EDAX). TEM, SAED and EDAX patterns
of the tailored particles were taken with TECNAIG -30 U TWIN
sulphuric acid were obtained from Rankem. Gadolinium(III)
nitrate pentahydrate (Gd(NO ) $5H O) was procured from Central
3 3 2
2
instrument operating at 300 kV. Aer preparation, the NPs were
centrifuged at 9000 rpm for 10 min and re-dispersed in DDW via
sonication for 3–4 min. A drop of dilute solution was put on the
copper grid and the grid was dried under ambient conditions.
Aer complete drying of the grid TEM, SAED and EDAX images
of the particles were taken.
drug House (P) Ltd. India and n-hexane from S.D. Fine Chem. Ltd.
Tetraethoxysilane (TEOS), 3-aminopropyltriethoxysilane (APTES)
and dialysis tubing cellulose membranes (12 kD) were purchased
from Sigma Aldrich. While, absolute ethanol and deutererium
oxide (D O) were obtained from Merck and Alfa Aesar respectively.
2
Colchicine, potassium phosphate monobasic dihydrate (KH PO )
2
4
3.3.3. X-ray diffraction (XRD) analysis. XRD patterns of the
and potassium phosphate dibasic dehydrate (K HPO ) were all
2
4
synthesised SMS NPs co-encapsulating gadolinium oxide and
colchicine drug were taken aer drying the particles completely
at room temperature. X-ray diffraction analysis of the particles
was carried out on Rigaku miniex desktop XRD instrument
procured from SRL India Ltd. Thiazolyl blue tetrazolinium blue
MTT), trypsin, ethylenediaminetetraacetic acid (EDTA), fetal
(
bovine serum (FBS) culture materials were all purchased from
Gibco USA. However, human breast cancer cell line MCF-7 was
obtained as a gi from All India Institute of Medical Science
ꢂ
and scanned in the 2q range of 10–80 . Dried lyophilized
powders were employed to carry out the diffraction experiment.
(AIIMS), Delhi, India and maintained as per instructions. All the
3.3.4. Fourier transform infra red (FT-IR) spectroscopy.
reagents employed were of AR grade and used without further
purication. Double distilled water (DDW) was utilized for
preparing all the solutions.
The particles were dialysed, washed thoroughly with DDW and
dried. FT-IR spectra of SMS NPs were recorded on IR-Perkin
Elmer, FT-IR system, Spectrum BX FTIR in the range 400 to
ꢁ
1
4
000 cm . A sufficient amount of the dried sample was mixed
3.2. Synthesis of surface modied silica (SMS) NPs co-
with dried KBr and lled in a cup. A pressure was applied to
form KBr pallet which was then utilized for IR investigation at
encapsulating gadolinium oxide and colchicine drug
The preparation of the particles was accomplished by preparing room temperature.
microemulsion A which was generated by dissolving 150 ml of 3.3.5. Thermo gravimetric analysis (TGA). The sample was
mg ml of colchicine drug solution along with 200 ml of 0.1 M monitored with Perkin Elmer DTA/TGA/DSC instrument by
ꢁ
1
5
gadolinium nitrate solution in 25 ml of 0.1 M AOT in hexane taking an adequate amount of nanoscale SMS particles on the
solution. Similarly, microemulsion B was prepared by dissolv- sample holder of the instrument in nitrogen atmosphere. Dried
ꢁ1
ing 150 ml of 5 mg ml of colchicine drug along with 200 ml of lyophilized powder sample was utilized for the analysis. The
2
M ammonia solution in 25 ml of 0.1 M AOT in hexane solu- change in weight of the subjected materials with respect to
ꢂ
tion. A calculated volume (100 ml) of water was added to both the temperature in the range 0–1000 C was carried out.
microemulsion solutions A and B to maintain the desired W
value of 10. The two microemulsions were stirred till they
1
1
0
3.3.6. H-Nuclear magnetic resonance ( H-NMR). The
1
H-NMR of SMS NPs with and without gadolinium oxide doped
became optically clear and then miroemulsion B was added to were recorded using 400 MHz spectrometer (JNM-ECX-400P,
microemulsion A in a drop-wise manner with constant stirring JEOL, Tokyo, Japan) in D O as solvent. The particles aer
2
at room temperature. Aer complete transfer, the resultant preparation were washed properly with hexane and ethanol;
solution was stirred further for another 4 h at room tempera- dialysed for 24 hours in DDW to remove unwanted materials
ture. The above reverse micellar solution containing colchicine and then nally lypholized to obtain their dried powder form.
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.4. Estimation of entrapment efficiency
Paper
3
exhibited high drug storage capacity as well as sustained drug
release behaviour as a consequence of probable interaction
between the amine functional group and the functional group
present in the drug molecules. The peak broadening pattern
observed in proton NMR associated with the SMS NPs doped
with gadolinium oxide NPs indicates their signicant edge to
the purpose of magnetic resonance imaging. Our preliminary in
vitro experimental study reveals that the ultra-small silica based
NPs have signicant potential to perform as drug delivery
vehicle and imaging probe. Thus, drug delivery systems based
on SMS nanospheres may efficiently contribute to controlled
release strategies in the future. The inculcation of organic and
inorganic moieties at the molecular level will promote these
silica particles to be tuned for extensively diverse biomedical
applications. We perceive that continuous development of such
novel hybrid nanomaterials and their potential applications in
living beings will open a new dimension for diagnosis and
therapy.
The entrapment efficiency of SMS NPs co-encapsulating gado-
linium oxide and colchicines drug was assayed indirectly by
employing UV-vis spectrophotometer. The particles aer the
preparation in reverse micelles were separated and collected
through centrifugation at 9000 rpm for 10 minutes. Amount of
the colchicines drug present in the supernatant liquid aer
separation via centrifugation was determined spectrophoto-
metrically at wavelength, l ¼ 353 nm, a prominent peak of
colchicine drug.
3.5. Drug release kinetics
For in vitro drug release, 2 ml of phosphate buffer solution (PBS)
of pH 7.4 containing 9 mg of the drug loaded SMS NPs doped
with gadolinium oxide was transferred into a dialysis bag with
and then placed into 70 ml of PBS with gentle stirring at room
temperature. At predetermined time intervals, 3 ml aliquot of
solution outside the dialysis bag was withdrawn and the
amount of colchicine was estimated by measuring the absorp-
tion at 353 nm. Aer the measurement, whole of the solution Acknowledgements
was transferred back in the assembly gingerly. The percentage
of the drug release was plotted against the duration taken.
The authors are thankful to Dr Indrajit Roy and Dr Raj K
Sharma, Department of Chemistry, University of Delhi, for their
valuable comments and fruitful discussions. We thank All India
Institute of Medical Science (AIIMS), Delhi, India for providing
breast cancer cell line MCF-7 and USIC, Delhi University for
allowing us to use the necessary instrumentation facilities. We
are also grateful to CSIR and University of Delhi, India, for
3
.6. In vitro cytotoxicity through MTT assay
The cytotoxicity of free colchicine, as an anticancer drug, and
SMS NPs co-encapsulating gadolinium oxide and colchicine
drug were studied via MTT assay on MCF-7 cell line. MCF-7 cells
were incubated in Eagle's MEM, supplemented with 10% FBS,

nancial assistance.
1% penicillin. When the cells were 90% conuent they were
detached using trypsin–EDTA solution. The trypsinised cells
were added to complete media in 15 ml falcon tubes and
centrifuged at 500 rpm for 5 minutes. The supernatant was
discarded and the cells re-suspended in 1 ml of fresh complete
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ꢂ
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