Construction of Magnetocarried Nanocomposites for Medico-Biological Applications
The research work deals with studies on interactions of nanomaterials with components of biosystems, development of new medicines based on magnetite, their application efficiency, chemical engineering of multilevel magnetosensitive nanocomposites with a hierarchical architecture and functions of bio...
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Інститут хімії поверхні ім. О.О. Чуйка НАН України
2010
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| Cite this: | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications / P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk, N.V. Abramov, V.F. Chekhun, N.Yu. Lukyanov // Хімія, фізика та технологія поверхні. — 2010. — Т. 1, № 3. — С. 360-370. — Бібліогр.: 26 назв. — англ. |
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| author | Gorbyk, P.P. Petranovska, A.L. Turelyk, M.P. Abramov, N.V. Chekhun, V.F. Lukyanov, N.Yu. |
| author_facet | Gorbyk, P.P. Petranovska, A.L. Turelyk, M.P. Abramov, N.V. Chekhun, V.F. Lukyanov, N.Yu. |
| citation_txt | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications / P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk, N.V. Abramov, V.F. Chekhun, N.Yu. Lukyanov // Хімія, фізика та технологія поверхні. — 2010. — Т. 1, № 3. — С. 360-370. — Бібліогр.: 26 назв. — англ. |
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| description | The research work deals with studies on interactions of nanomaterials with components of biosystems, development of new medicines based on magnetite, their application efficiency, chemical engineering of multilevel magnetosensitive nanocomposites with a hierarchical architecture and functions of biomedical nanorobots.
Дослідження спрямовані на вивчення взаємодій наноматеріалів з компонентами біосистем, розробку новітніх терапевтичних засобів на основі магнетиту, аналіз ефективності їх використання, хімічне конструювання багаторівневих магніточутливих нанокомпозитів з ієрархічною архітектурою та функціями медико-біологічних нанороботів.
Исследования направлены на изучение взаимодействий наноматериалов с компонентами биосистем, разработку новых терапевтических средств на основе магнетита, анализ эффективности их применения, химическое конструирование многоуровневых магниточувствительных нанокомпозитов с иерархической архитектурой и функциями медико-биологических нанороботов.
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Хімія, фізика та технологія поверхні. 2010. Т. 1. № 3. С. 360–370
_____________________________________________________________________________________________
360 ХФТП 2010. Т. 1. № 3
UDC 539.211:544.723.23
CONSTRUCTION OF MAGNETOCARRIED NANOCOMPOSITES
FOR MEDICO-BIOLOGICAL APPLICATIONS
P.P. Gorbyk1, A.L. Petranovska1, M.P. Turelyk1, N.V. Abramov1, V.F. Chekhun2, N.Yu. Lukyanova2
1Chuiko Institute of Surface Chemistry of National Academy of Sciences of Ukraine
17 General Naumov Street, Kyiv 03164, Ukraine
2Kavetsky Institute of Experimental Pathology, Oncology, and Radiobiology of NAS of Ukraine
45 Vasilkovskaya Street, Kyiv 03022, Ukraine
The research work deals with studies on interactions of nanomaterials with components of biosystems, deve-
lopment of new medicines based on magnetite, their application efficiency, chemical engineering of multilevel
magnetosensitive nanocomposites with a hierarchical architecture and functions of biomedical nanorobots.
INTRODUCTION
Technology in the twenty first century requires
the miniaturization of devices into nanometer sizes
while their ultimate performance is dramatically
enhanced. This raises many issues regarding to
new materials for achieving specific functionality
and selectivity [1]. Nanophase and nanostructured
materials, a new branch of materials research are
attracting a great deal of attention because of their
potential applications in such areas as electronics,
optics, catalysis, ceramics, magnetic data storage,
and nanocomposites. The unique properties and
the improved performances of nanomaterials are
determined by their sizes, surface structures, and
interparticle interactions. The role played by
particle size is comparable, in some cases, to the
particle chemical composition adding another
flexible parameter for designing and controlling
their behavior. Modern nanotechnologies provide
tools for creation of unique agents for medicine
and biology. Their practical usage is mostly based
on the knowledge about interaction of
nanomaterials with the components of biological
environment.
Among the large amount of known materials,
oxides are of a great interest for scientists. This
class of compounds possesses a wide variety of
properties while accumulated knowledge is used
for their further optimization with respect to cer-
tain applications. This work highlights synthesis
of highly-dispersive magnetic nanosized oxides
for various functional purposes and, in particular,
for cancer therapy.
Magnetic oxides, magnetite in particular,
which possess high biocompatibility are of a great
interest for medico-biological usage [2]. The
purpose of our work concerns creation of the
polyfunctional nanocomposite via usage of
magnetite in a nanosized state as a reactive
component for targeted design of multilevel
nanocomposites with hierarchical architecture and
functions of nanorobots which include recognition
of specific microbiological objects in biological
environment, targeted delivery and deposition of
medicinal products into organs or cells, diagnostics
and therapy of diseases at the cell level, adsorption
of cell decomposition products after application of
chemotherapeutic agents or hyperthermia, their
removal from the organism using magnetic field.
The application of polyfunctional nanocomposites
of combined action, which contain monoclonal
antibodies and highly efficient cytostatic compo-
unds, in oncology may be accompanied by a syner-
getic effect of chemo- and immunotherapeutic
drugs and result in decreased toxico-allergic
response of the organism.
For any practical application, the
fabrication of nanoparticles needs to be
controlled in such a way that resulting
nanoparticles have the following characteristics:
(i) identical size of all particles, (ii) identical
shape or morphology, (iii) identical chemical
composition and crystal structure desired among
different particles and within individual particles,
such as core and surface composition must be the
same, and (iv) individually dispersed or
monodispersed, i.e. no agglomeration. If
agglomeration does occur, nanoparticles should
be readily redispersible [3–5].
In view of the increasing interest in magnetic
nanoparticles in the field of medical care as
described above, a facile synthetic process which
allows to control the size, magnetic properties,
Construction of Magnetocarried Nanocomposites for Medico-Biological Applications
_____________________________________________________________________________________________
ХФТП 2010. Т. 1. № 3 361
and surface properties of Fe3O4 nanoparticles,
needs to be developed because those properties
required for the Fe3O4 nanoparticles depend on
the specific application. For example, the size of
Fe3O4 nanoparticles needs to be controlled for
target materials such as proteins, genes, and cells
whose sizes are 5–50 nm, 2 nm wide and 10–
100 nm long, and 10–100 µm, respectively.
Furthermore, it is possible that particle size plays
an important role in determining the state of
aggregation of the nanoparticles and even the
uptake property to living organisms. Additionally,
magnetic nanoparticles synthesized by the facile
method are expected to have surface properties
which are easy to be characterized or modified
with biomolecules for biomedical applications [6].
Magnetic nanoparticles are attractive for their
unique properties, such as single domain structure
and superparamagnetism, which are not observed
for bulk materials, and are expected to be
applicable in various fields including ultrahigh-
density magnetic recording media, drug delivery
systems, and medical imaging. Important for
these applications are the techniques for
stabilizing the nanoparticles in the solvent and
those for functionalizing the nanoparticles surface
by surface modifications. Especially for the
bioapplications of magnetic nanoparticles, the
surface modification with organic molecules or
surfactants is essential for inhibiting the
aggregation of nanoparticles and for controlling
interparticle interactions and solubility in an
aqueous solution. In addition, surface
modification by biologically relevant substances
improves the biocompatibility which enables the
bioapplications of magnetic nanoparticles. Thus,
surface modification of magnetic nanoparticles has
become one of the most challenging issues recently.
The cell-based therapy is one of advanced
treatments applied to various fields of scientific
study, and it includes immunotherapy, gene
therapy, and regenerative medical treatment.
Recently, immunotherapy has been vigorously
investigated in the field of oncology because of
specific anti-tumor activity and less side-effect.
Cancer treatment by immunotherapy takes
advantage of having efficient effector cells which
exhibit specific killing activity against cancer
cells. However, local accumulation inside the
tumor of these effector cells remains one of
critical issues to be overcome from a point of the
clinical view. Therefore, drug delivery system is a
good candidate to achieve the efficient
localization of drugs in the tumor. Actually,
successful local delivery of drugs is reported
using magnetic nanoparticles such as magnetite
(Fe3O4) or maghemite (γ-Fe2O3) as a nanocarrier
[7]. Thus, the application of magnetic drug
delivery system to immunotherapy could make
the development of magnetically mediated
immunotherapy possible in the clinical field.
SYNTHESIS AND PROPERTIES OF
MAGNETITE
Highly disperse magnetite was prepared via
co-precipitation of salts [7, 8] in accord to the
reaction
Fe+2+2Fe+3+8NH4OH →
→ Fe3O4+4H2O+8NH4
+. (1)
Fractionation of the prepared magnetite was
carried out with magnetic field.
The method [7, 8] permits obtaining
magnetite with broad size distribution of the
particles (from microns to nanometres) which
requires additional fractionation.
In order to achieve a better control over size
distribution, we developed a cryochemical
method of heterogeneous synthesis of magnetite
at interface of solid (frozen iron II and III salts
solution) and liquid (ammonia solution of a
certain concentration) phases [3]. The ammonia
solution is taken in excess while the second phase
melts and releases the solution which has
predetermined concentrations of the reactive
components. A permanent concentration gradient
is maintained at the thin interface upon melting
the iron-containing solid. On the contrary to the
homogeneous synthesis, growth of the
nanoparticles is terminated at a certain distance
from the solid phase due to absence of the iron
salts. This prevents the further growth of the
formed nanoparticles and preserves their initial
size. The nanoparticles are collected with non-
uniform magnetic field and the supernatant
solution is removed. The precipitate is washed
many times with water in order to dispose off the
anions present in the solution.
Samples of the nanocrystalline magnetite
with specific surface area of ~ 90–180 m2/g
(measured by thermal desorption of Ar) were
prepared using the cryochemical method.
Depending on the synthetic conditions, the
P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk et al.
_____________________________________________________________________________________________
362 ХФТП 2010. Т. 1. № 3
particles size comprised 6–50 nm revealing a
quite narrow distribution interval. The fraction of
the mostly monodomain magnetite particles of
20–50 nm in diameter was used for preparation of
the magnetic carriers.
The advantages of the proposed method
comprise the increased yield of the monodomain
magnetite particles directly from the synthesis
and their narrower size distribution.
COATING OF MAGNETITE SURFACE WITH
POLYACRYLAMIDE
Stabilization and biocompatibilization of the
nanosized magnetite particles were achieved via
coating their surface with cross-linked poly-
acrylamide (PAA). The PAA layer was prepared
via co-polymerization of acryl amide and N,N’-
methylene-bis-acryl amide in high-frequency
(HF) discharge plasma at the radiator power
20 W [9–11]. The monomer and the cross-linker
were coated onto the magnetite surface in a rotor
evaporator at 303 K. Plasma polymerization was
carried out in glowing discharge at 1⋅10-3 Pa.
Conversion degree of carbon-carbon double bonds
was measured by the method of Kaufmann based on
titration in a non-aqueous solution and the ability of
the С=С bonds to combine with Br2 [12]. The
obtained samples were studied in the wavelength
range 400–4000 см-1 with a FTIR "Perkin Elmer"
spectrometer (the model 1720Х) [13–15]. The
spectra revealed absorption bands related to the
initial magnetite and the PAA coating [16].
We studied magnetic properties of the
magnetite particles modified with PAA and the
impact of the coating thickness. The coating
weight was varied from 5 to 50% of the total
weight of the composite. The specific
magnetization σі and its function σі = f(Н) were
calculated from the experimental data. From
them, the ultimate magnetization at saturation
condition σs, the remnant magnetization σr, and
the coercive force Нс were determined [17].
The experimental functions of the specific
magnetization on magnetic field strength for the
bare magnetite and the magnetite with various
PAA coating contents showed that the coating
fraction up to 15 wt. % does not cause notable
deviations from the initial magnetite magnetic
properties. The values σs, Нс are located in the
ranges from 61.5 10-7 to 62.0·10-7 Т·m3/kg and
from 7.20 to 3.44 kА/m, respectively, while σr is
equal to 15.12·10-7 Т·m3/kg. Increase in the coating
weight up to 50% leads to the lower σs, Нс, σr
values: down to 51.1·10-7 Т·m3/kg, 6.31 kА/m, and
10.74·10-7 Т·m3/kg, respectively. These results
show that the increase in the weight fraction of the
PAA layer up to 50% makes a negligible
contribution to the specific magnetic properties.
MODIFICATION OF MAGNETITE WITH
γ -AMINOPROPYLSILOXANE
Surface of magnetite nanoparticles was
coated with γ-aminopropylsiloxane (γ-APS) in
toluene [18]. The reaction of polycondensation
was carried out in accord to the scheme
–OH+(C2H5O)3Si(CH2)3NH2 →
→ –O–Si(CH2)3NH2+3C2H5OH . (2)
γ-Aminopropyltriethoxysilane (γ-APTES)
was dried over molecular sieves and purified with
distillation in vacuum. Magnetite was exposed to
a solution of γ-APTES (10% vol.) in toluene for
8 h, precipitated in a centrifuge, washed with
toluene, acetone, and dried at 293 K.
The content of functional groups on the
surface of magnetite was found with X-ray
Photoelectron Spectroscopy (XPS) and Differen-
tial Scanning Calorimetry (DSC) combined with
Differential Thermo-gravimetric Analysis (DTA).
The thermal graphs were recorded in the tempe-
rature range 293–1273 К at the heating rate
0.16 deg/s on a Q-1500D thermal analyzer
purchased from the company MOM (Hungary).
Concentration of the –OH groups at the surface of
the magnetite nanoparticles calculated from the
DTA data was equal to 2.2 mmol/g or
2.4 µmol/m2 at Sspecific = 90 m2/g [19].
Presence of the amino-groups at the surface
of the obtained nanocomposite was confirmed
with XPS [20]. The XPS spectra were recorded
on a spectrometer EC-2402 with an analyzer
"PHOIBOS-100" SPECS using the Кα radiation
of a Mg anode (EMgKα = 1253.6 eV). The
spectrometer was calibrated using the line Au
4f7/2 which has the binding energy Eb = 84 eV.
Fourier Transfrom Infrared spectra were
recorded on a spectrometer "Perkin Elmer" (the
model 1720X) in the range 400–4000 cm-1.
Pronounced absorption bands at 1037 and 1130
cm-1 of approximately equal intensities indicates
formation of a polymer layer Si–О–Si at the
magnetite surface resulted from hydrolytic
polycondensation of the modifier molecules [19].
Construction of Magnetocarried Nanocomposites for Medico-Biological Applications
_____________________________________________________________________________________________
ХФТП 2010. Т. 1. № 3 363
SURFACE-IMMOBILIZATION OF HUMAN
IMMUNOGLOBULIN
We developed procedures for
immobilization of antibodies at surfaces of the
magnetite-based nanocomposites coated with
polyacrylamide (PАА) [16] and polysiloxane
(γ-АPS) [19] using a model preparation of
human normal immunoglobulin (Ig) produced by
Biofarma, Kyiv. The Ig was purified via dialysis
in order to remove low molecular weight
preserving compounds.
We measured isotherms of physical adsorption
of Ig to the surfaces of the nanocomposites.
Samples of the nanocomposites (100 mg) were
introduced into Ig solutions (5 ml) of varying
concentration. Adsorption of Ig was carried out in
physiological conditions during 2 h upon shaking
at ambient temperature. The amount adsorbed at
the surfaces of the nanocomposites was
determined from the difference between the Ig
concentrations before and after adsorption. The
concentrations were measured on a Lambda
35 uv/vis Spectrometer supplied by Perkin Elmer
Instruments at the wavelength λ = 280 nm using a
calibration curve. The results are presented in
Tables 1, 2 and Fig. 1 a, b.
Table 1. Isotherm of non-specific adsorption of human
normal immunoglobulin to the nanocompo-
site Fe3O4/ PАА
С0, mg/ml D(280 nm) Сeq., mg/ml Аphys., mg/g
0.35 0.485 0.33 0.84
0.45 0.629 0.43 0.90
0.55 0.776 0.53 0.85
0.71 0.966 0.66 2.32
0.86 1.153 0.79 3.40
1.40 1.762 1.21 9.48
Table 2. Isotherm of non-specific adsorption of human
normal immunoglobulin to the nanocomposite
Fe3O4/ γ-АPS
С0, mg/ml D(280 nm) Сeq., mg/ml Аphys, mg/g
0.15 0.249 0.18 0.00
0.25 0.305 0.22 0.00
0.45 0.607 0.44 0.64
0.55 0.745 0.54 0.66
0.71 0.964 0.69 0.80
0.86 1.178 0.85 0.57
1.00 1.361 0.98 0.97
1.40 1.911 1.38 1.18
We recorded isotherms of covalent binding of
Ig to the surfaces of the nanocomposites. The
chosen mechanism of the covalent binding
comprises reaction of aldehyde groups created
upon periodate oxidation of Ig side carbohydrate
chains with amino-groups located at the grafting
surfaces leading to formation of Schiff-bases
(imines). An advantage of this mechanism is
oriented immobilization of the antibody molecules
with the Fc fragment (fragment crystallisable)
facing the surface and the Fab fragment (fragment
antigen binding) sticking out [21, 22].
a
b
Fig. 1. Comparison of isotherms of physical adsorption of
human normal Ig (1) and the covalent binding of
the oxidized human Ig (2) to the nanocomposites:
а – Fe3O4/PАА; b – Fe3O4/γ-АPS
The nanocomposites consisting of magnetite
nanoparticles coated with PAA were activated by
ethylenediamine (ED) in order to form amino-
groups at the surface in accord to the reaction
scheme [23]
–PAA–CO–NH2+H2N–(CH2)2–NH2 →
│–PAA–CO–NH–(CH2)2–NH2. (3)
Since the surface of the nanocomposite
Fe3O4 / γ-АPS contains native amino-groups, no
additional treatment was carried out.
P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk et al.
_____________________________________________________________________________________________
364 ХФТП 2010. Т. 1. № 3
Oxidation of human normal immunoglobulin
was carried out in 0.1 M NaIO4 solution prepared
on the basis of aqueous 0.02 M acetate buffer
(pH 5.0) in accord to the reaction scheme
Ig–gly + NaIO4 →Ig–COH + NaIO3. (4)
The oxidized Ig was purified with dialysis
against 2 l of 0.02 M acetate buffer (pH 5.0). The
solution obtained after the dialysis was set to
pH 8–9 with 0.06 M carbonate-hydrocarbonate
buffer based on 0.15 M NaCl (pH 9.5).
Covalent binding of Ig to the nanocomposites
Fe3O4/PАА activated by ED and Fe3O4/γ-APS
(30 mg) was carried out from 7 ml solution of
0.06 M carbonate-hydrocarbonate buffer (pH 9.0)
and 0.15 M NaCl during 2 h at the ambient
temperature upon shaking in accord to the
reaction scheme
carrier–R–NH2–Ig →
→ carrier–R–N=CH–Ig+H2OSchiffbase. (5)
The bound Ig amount was determined from
the difference between the initial and the final
concentrations of the contact solution. The
concentrations were measured by UV absorption
at λ = 280 nm using a calibration curve. The data
on isotherms of the covalent binding are shown in
Tables 3, 4 and Fig. 1 a, b.
Table 3. Isotherm of the covalent binding of oxidized
human normal immunoglobulin to the
nanocomposite Fe3O4/PАА
С0, mg/ml D(280 nm) Сeq., mg/ml А(Ig/PАА), mg/g
0.15 0.201 0.128 5.07
0.25 0.288 0.184 15.52
0.35 0.420 0.268 19.14
0.45 0.528 0.337 26.48
0.55 0.630 0.402 34.59
0.71 0.841 0.536 40.57
0.86 0.974 0.621 55.79
1.00 1.144 0.730 63.04
1.40 1.416 0.903 116.00
The obtained isotherms of non-specific
adsorption (Tables 1, 2) and the covalent binding
(Tables 3, 4) of Ig to the nanocomposites are
linear functions with no saturation in the studied
concentration range (Fig. 1 a, b). The experi-
mental data were converted to the analytical form
using the equation y = E·x, and the respective
distribution coefficients E (ml/g) were calculated.
The coefficients reflect the Ig distribution
between the nanocomposites surfaces and the
contacting solutions. The coefficients (E) and the
Ig amounts immobilized at the nanocomposites’
surfaces at the concentration of the Ig initial
solution 1.4 mg/ml (the maximal in the
experiment) are summarized in Table 5. The
coefficients for the covalent binding exceed the
respective coefficients for non-specific adsorption
by more than an order and reflect equilibrium
shift towards surface immobilization of Ig.
Table 4. Isotherm of covalent binding of oxidized
human normal immunoglobulin to the
nanocomposite Fe3O4/ γ-АPS
С0, mg/ml D(280 nm) Сeq., mg/ml А(Ig/PАА), mg/g
0.15 0.282 0.140 2.42
0.25 0.352 0.224 6.14
0.35 0.468 0.298 12.07
0.45 0.594 0.379 16.67
0.55 0.723 0.461 20.70
0.71 0.924 0.590 28.08
0.86 1.025 0.653 48.19
1.00 1.207 0.770 53.71
1.40 1.742 1.111 67.41
Table 5. Values of human Ig adsorption to the nano-
composites surfaces of different nature at the
concentration of the initial Ig solution
С = 1.4 mg/ml
Nanocomposite Аphys.,
mg/g
Еphys.,
ml/g
Аcov.,
ml/g
Еcov.,
ml/g
Fe3O4/PАА 9.48 6.1 116.00 83.53
Fe3O4/γ-АPS 1.18 0.92 67.41 59.51
It should be noted that a significant part of Ig
(64–80%) remains in the solution upon covalent
binding since the reaction of Schiff base
formation is reversible (Tables 3, 4).
The nature of nanocomposite surface
influences the values of both the physical and the
covalent immobilization of Ig. The amounts of
immobilized Ig and the distribution coefficients
are higher for the nanocomposite Fe3O4/PAA.
We studied kinetics of release of Ig to model
environment (0.15 M NaCl) for the
nanocomposites Fe3O4/PАА and Fe3O4/γ-АPS
which carried physically and covalently bound Ig
and had been prepared upon measurements of the
respective isotherms. The samples of the
nanocomposites (0.030 g) carrying physically or
covalently bound Ig were placed into 5 or 7 ml of
0.15 M NaCl, respectively, and the UV
absorption at 280 nm of the solution was
Construction of Magnetocarried Nanocomposites for Medico-Biological Applications
_____________________________________________________________________________________________
ХФТП 2010. Т. 1. № 3 365
measured after gentle shaking for certain time
intervals. The concentration of the desorbed Ig
was calculated using the calibration curves.
Physically immobilized Ig desorbed during
1–2 min, the desorption curves are not shown.
The data on desorption of covalently bound Ig are
summarized in Tables 6, 7 and Fig. 2 a, b.
Parameters of the release kinetic curves were
calculated by the method of least squares using
the equation y(х)=y0+Ae-x/t, where y0 is the
amount of bound Ig which is not released at the
given conditions, A is the amount of bound Ig
which is being released, 1/t characterizes release
dynamics and curvature of the kinetic function.
a
b
Fig. 2. Kinetics of release of covalently bound human
immunoglobulin from the surface of the
nanocomposites а – Fe3O4/PАА, b – Fe3O4/γ-
APS. The initial bound amounts of
immunoglobulin are shown in the right panels.
The curves y=y(0)+Ae-x/t were calculated from the
experimental data by the method of least squares
Table 6. Parameters of the equation y=y(0)+ Ae-x/t
describing release kinetics of covalently
bound human immunoglobulin from the
nanocomposite Fe3O4/PАА
у(0)=55.8
mg/g
у(0)=40.6
mg/g
у(0)=34.6
mg/g
у(0)=19.1
mg/g
у(0)=15.6
mg/g
у0 49.77±3.25 30.40±41.22 25.94±0 11.09±0 0±0
А 2.76±5.62 11.35±0 8.65±0 8.05±0 15.52±0
t 0.27±1.45 1.80±19.54 2.64±1.24 4.37±1.35 6.51±2.45
Table 7. Parameters of the equation y=y(0)+Ae-x/t
describing release kinetic of covalently
bound human immunoglobulin from the
nanocomposite Fe3O4/γ-APS
у(0)=48.2 mg/g у(0)=28.1 mg/g у(0)=12.1 mg/g
у0 28.69±3.89 9.13±0 0±0
А 17.60±4.89 18.93±3.11 12.06±3.97
t 60.15±55.12 14.93±8.03 12.18±17.68
The obtained kinetic data show that the
released Ig amount decreases upon increase of the
amount initially immobilized at the surfaces of
both nanocomposites. For small amounts of
immobilized Ig 15.5 mg/g (Fe3O4/PAA) and
12.0 mg/g (Fe3O4/γ-APS), up to 30% of the Ig is
released during the first 5–10 min. For higher
immobilized Ig amounts 55.8 mg/g (Fe3O4/PAA)
and 48.2 mg/g (Fe3O4/γ-APS), 16–18% of the Ig
is released during the first 10–15 min. Release of
surface-immobilized Ig bound via Schiff bases
occurs slower and at lower extent than of
physically bound Ig.
IMMOBILIZATION OF THE CD 95
ANTIBODY
We prepared nanocomposites carrying anti-
tumour drug cisplatin and monoclonal mouse
antibody CD 95 against the human Fas-antigen of
the isotype IgG1, kappa, the clone DX2 produced
by DakoCytomation (Denmark). The
concentration of the initial solution of the
antibody was 20 µg/ml.
We studied both non-specific (physical)
adsorption and the covalent binding of the
monoclonal antibody CD 95 to the
nanocomposites Fe3O4/PAA and Fe3O4/γ-APS.
We prepared 4 samples (0.03 g). Each sample
was introduced into 1.0 ml solution of the
antibody or 1.7 ml solution of the oxidized
antibody, respectively:
P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk et al.
_____________________________________________________________________________________________
366 ХФТП 2010. Т. 1. № 3
1. Fe3O4 / PАА + СD 95;
2. Fe3O4 / γ-APS + СD 95;
3. Fe3O4 / PАА + СD 95oxidized;
4. Fe3O4 / γ-APS + СD 95oxidized.
Physical adsorption of the monoclonal
antibody CD 95 (20 µg/ml) to the
nanocomposites (the samples 1 and 2) was carried
out in 0.15 M NaCl (1.0 ml) during 2 h upon
shaking at the ambient temperature.
Oxidation of the monoclonal antibody CD 95
was carried out in acetate buffer-based solution of
0.1 M NaIO4 (pH 5.0). The oxidized CD 95 was
purified by dialysis against 2 l of 0.02 M acetate
buffer (pH 5.0). The solution of the oxidized
antibody was set to pH 8–9 after dialysis against a
solution of 0.06 M carbonate-hydrocarbonate
buffer (pH 9.5) and 0.15 M NaCl. The
concentration of the antibody CD 95 after the
dialysis was equal to 13 µg/ml.
Covalent bonding of the oxidized and
purified monoclonal antibody to the
nanocomposites Fe3O4/PАА (activated with ED)
and Fe3O4/γ-APS (the samples 3 and 4) was
carried out in a solution of 0.06 M carbonate-
hydrocarbonate buffer (pH 9.0) and 0.15 M
NaCl during 2 h upon shaking at the ambient
temperature. Then the nanocomposites were
separated using magnetic field and the antibody
concentrations in the contact solution were
measured using a combined reader for a
microplate Synergy HT, Model SIAFRTD,
Serial Number 202993 (Bio Tek).
Quantitative measurements of protein
contents in the solutions were carried out by the
method of Bradford [24]. The method is based on
recording light absorption of a complex between
Coomassie Blue G-250 dye and protein which has
a maximum at 595 nm. The antibody
concentration was determined from a calibration
curve. The adsorbed amount of the antibody was
calculated from the difference between its
concentrations in the contact solution prior and
after adsorption (Table 8).
The obtained results show that the covalent
binding via Schiff bases has the following
advantages with respect to non-specific
adsorption: higher thermodynamic stability of the
immobilized layer originating from the covalent
bonding and better kinetic stability due to
hampered release arising from slow hydrolysis of
the Schiff bases.
Table 8. Immobilization of the monoclonal antibody
CD 95 at the surfaces of magnetosensitive
nanocomposites Fe3O4/PАА and Fe3O4/γ-APS
Nanocomposite С0,
µg/ml
D Сeq.,
µg/ml
А(СD 95),
µg/g
Fe3O4/PАА
+ СD 95
20.00 0.44 19.93 2.3
Fe3O4/γ-APS
+ СD 95
20.00 0.42 19.96 1.2
Fe3O4/PАА
+ СD 95oxidized
3.88 0.73 1.00 163.2
Fe3O4/γ-APS
+ СD 95oxidized
3.88 0.72 1.45 137.7
where С0 is the initial antibody concentration;
D is the optical density;
Сeq,is the equilibrium concentration of the
antibody upon adsorption;
А is adsorbed amount of СD 95 at the sur-
faces of the nanocomposites
IMMOBILIZATION OF CISPLATIN AT THE
SURFACES OF THE NANOCOMPOSITES
Cisplatin (CP) is an anti-tumour platinum-
containing drug supplied as aqueous solution.
Mechanism of the anti-tumour activity of platinum
derivatives comprises DNA chains bifunctional
alkylating which suppresses biosynthesis of
nucleic acids and induces cells’ apoptosis.
CP passes poorly through the hematoencephalic
barrier and is quickly transformed into inactive
metabolites. Binding to proteins in the state of the
metabolites reaches 90%.
The period τ1/2 of half-excretion of the drug
from blood is equal to 20–49 min at the initial
stage, 58–73 h at the final stage assuming normal
excretion kidney function, and 240 h upon anuria.
The drug is excreted by kidneys in the amount of
27–43% in 5 days while platinum can still be
found in tissues during 4 months after introduction.
We studied stability of CP via measuring its
cytotoxic activity after 10, 20, and 30 days and
found that it remains constant within a month.
Adsorption kinetics of CP at surfaces of the
nanocomposites [25] was measured upon shaking
an aqueous solution of CP (50 ml) with magnetic
particles of the nanocomposites (200 mg) during
18 h at the ambient temperature. Probes (5 ml)
were taken from the solutions every 2 h. The
adsorbed amounts were determined as the
difference between the initial and current
concentrations of Pt2+ ions in the contact
solutions. The measurements were carried out
with a single beam two-channel atomic-
Construction of Magnetocarried Nanocomposites for Medico-Biological Applications
_____________________________________________________________________________________________
ХФТП 2010. Т. 1. № 3 367
absorbance spectrophotometer C-115 M1 with
flame atomizer, deuterium background corrector,
and digital registration. A hollow cathode lamp
for platinum (the analytical line 265.9 nm) and
the fuel-oxidizer system acetylene-air were used.
The adsorption kinetic curves are shown in
Fig. 3 a, b.
a
b
Fig. 3. Kinetic curves of adsorption of cisplatin at the
surfaces of the magnetosensitive nanocomposites
Fe3O4/PАА (a) and Fe3O4/γ-АPS (b)
The adsorbed amounts of cisplatin (calculated
for Pt2+) at the surfaces of the nanocomposites
Fe3O4/PАА and Fe3O4/γ-АPS comprise 128 mg/g
and 98.3 mg/g, respectively. The major part of the
drug is adsorbed during the first 2–3 hours.
PREPARATION AND CYTOTOXIC
PROPERTIES OF MAGNETICALLY DRIVEN
POLYFUNCTIONAL NANOCOMPOSITES
(MODELS OF NANOROBOTS)
We prepared the following samples for
studies of impact of the magnetically driven
nanocomposites carrying the cytostatic drug and
the monoclonal antibody on vital activity of
cancer cells:
1. Fe3O4 / PАА + CD 95;
2. Fe3O4 / PАА + CP;
3. Fe3O4 / PАА + CD 95 + CP;
4. Fe3O4 / γ-АPS + CD 95;
5. Fe3O4 / γ-АPS + CP;
6. Fe3O4 / γ-АPS + CD 95 + CP.
The antibody CD 95 was bound to the
nanocomposites via formation of Schiff bases
(the samples 1, 3, 4, 6). The samples 3 and 6 were
prepared in two steps: firstly, the oxidized
monoclonal antibody CD 95 was conjugated with
the nanocomposites Fe3O4/PАА (activated with
ED) and Fe3O4/γ-АPS, then the cytostatic drug
was adsorbed.
Oxidation of the monoclonal antibody CD 95
was carried out in accord to the reaction scheme (4).
Covalent binding of the monoclonal antibody
CD 95 (V = 1.7 ml, C = 3.88 µg/ml) to the
surfaces of the nanocomposites Fe3O4/PАА
(activated with ED) and Fe3O4/γ-АPS was carried
out during 1.5 hours upon shaking at the ambient
temperature in accord to the reaction scheme (5).
The obtained magnetic samples were collected in
magnetic field of a permanent magnet.
The nanocomposites containing the
covalently bound monoclonal antibody (the
immobilized amounts of CD 95 were 163.2 mg/g
for Fe3O4/PАА and 137.7 mg/g for Fe3O4/γ-АPS)
were introduced into 10 ml of CP aqueous
solution (1 mg/ml). Adsorption was carried out
for 4 hours upon shaking. The precipitate was
collected in magnetic field of a permanent
magnet. The adsorbed amounts of CP were
128 mg/g for Fe3O4/PАА and 98.3 mg/g for
Fe3O4/γ-АPS.
Cytotoxic impact of the nanocomposites
carrying immobilized the monoclonal antibody
and the cytostatic drug on cancer cells was
studied in vitro. The nanocomposites were taken
in the amounts which contained the quantity of
CP equal to the biological equivalent of
efficiency IC25, i.e. 25% of the IC concentration
which 100% suppresses the cells. Our earlier
experiments showed that IC50 = 5 µg/ml,
therefore IC25 = 2.5 µg/ml. At that concentration
of the nanocomposites, the concentration of the
monoclonal antibody CD 95 was equal to
0.2 µg/ml (the doze used for clinical treatment is
equal to 10–30 µg/ml). The studies of
cytotoxicity were carried out at P.E. Kavetsky
Institute of Experimental Pathology, Oncology,
and Radiobiology of the National Academy of
P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk et al.
_____________________________________________________________________________________________
368 ХФТП 2010. Т. 1. № 3
Sciences of Ukraine [26]. The cytotoxic impact of
the nanocomposites Fe3O4/PАА and Fe3O4/γ-АPS
carrying immobilized the monoclonal antibody
CD 95 and CP was measured for the human
mammary gland cancer cell line MCF-7. The
cytotoxic activity of the respective
nanocomposites carrying only CP or only the
monoclonal antibody was also measured for
comparison. The following solutions were used as
the control samples: pure nutrient medium, CP
(2.5 µg/ml), and the monoclonal antibody CD 95
solution (0.2 µg/ml). We studied also the
cytotoxic effect of the bare magnetite
nanoparticles and the bare nanocomposites
Fe3O4/PАА and Fe3O4/γ-АPS.
The volumes 100 µl of the MCF-7 line cells
(1·105 cells/ml) were deposited into 96-cavity
microplates. The cells were cultivated in a
modified medium Dulbecco – ISCOV (Sigma,
Germany) with addition of 10% embryonic calve
serum and antibiotic gentamycin at 40 µg/ml in
standard conditions at 37оС and air saturation
with 5% CO2. The samples being studied were
added to the cells after a 24 hour period of the
cells adapting to the cultivating conditions. Each
sample was added in 3 parallels and incubated in
the same conditions. Cytotoxicity was measured
after 24 hours.
The impact was evaluated with the MTT-
colorimetric test, The method is based on the
ability of mitochondrion ferments of living cells
to convert 3-[4,5-dimethylthiazol-2-yl]-2,5-
diphenyltetrazolium bromide (MTT) (yellow salt)
into crystalline MTT-formazan (lilac) [26]. The
MTT solution (Sigma, 20 µl, 5 mg/ml in
phosphate-saline buffer) was added to the cavities
of the plastic plate and incubated for 3 hours.
Then the plate was centrifuged at 1500 rev/min
for 5 min and the supernatant was removed with
an automated suction. Dimethylsulfoxide (Serva,
100 µl) was added to each cavity to dissolve the
formazan crystals. The optical absorbance was
measured with a multi-cavity spectrophotometer
at the wavelength 540 nm. The results of the
study are summarized in the Table 9.
In accord to the obtained data, the
magnetosensitive nanocomposites carrying
adsorbed CP in quantity twice below the
therapeutic range and the amount of the
monoclonal antibody CD 95 almost by one order
lower cause death of 46–57% of the tumour cells
which exceeds the impact of the control solution
(CP+CD 95) by up to 50%. This synergy effect
can be explained as follows. Firstly, the targeted
delivery of the complex cytostatic drug–
antibody to the tumour cells was accomplished.
The cytotoxic effect of CP is achieved through
formation of covalent bonds between the drug
and DNA. Traumatic effect of the
nanocomposite on the cell membrane facilitates
the process and improves transport of the
therapeutic preparation through the membrane
barrier. Bifuctional products of the interaction,
the so-called DNA-adducts, block replication,
transcription, and, as a consequence, cell
proliferation. Secondly, the system
ligand/receptor plays an important role in
apoptosis of malignant cells. The antibody
binding its receptor launches a system of signal
transmission which leads to apoptosis. There are
also reports [6] that this system may cause death
of tumour cells upon influence of cytotoxic drugs.
Table 9. Impact of the magnetosensitive
nanocomposites Fe3O4/PAA and Fe3O4/γ-
APS carrying adsorbed cisplatin (CP) and the
conjugated monoclonal antibody CD 95 on
the vital activity of the MCF-7 line cells
Fe3О4/
γ-APS
+ CP
Fe3О4/
γ-APS
+ CD 95
Fe3О4/
γ-АPS
+ CP
+ CD 95
Fe3О4/
PАA
+ CP
Fe3О4/
PАА +
CD 95
Fe3О4/
PАА
+ CP
+ CD 95
Suppres-
sed cells,
%
31 20 46 38 21 57
CP,
2,5 µg/ml
CD 95,
0,2 µg/ml
CP, 2,5 µg/ml +
CD 95, 0,2 µg/ml
Suppres-
sed cells,
%
25 10 38
Consequently, the impact of the
magnetically driven nanocomposites (models of
nanorobots) carrying the anti-tumour drug and
the monoclonal antibody CD 95 on the cancer
cells MCF-7 exerts a synergic effect and
provides the desired cytotoxicity at lower
concentrations. Thus the toxic effect of the
medical chemotherapeutic preparation on a
whole organism can be decreased. Magnetic
properties of the nanorobot models,
peculiarities of their transport in the vascular
system, their use for creation of hyperthermia
zones, desorption kinetics of the cytostatic drug
and efficiency of its influence on cell lines are
discussed elsewhere [3].
Construction of Magnetocarried Nanocomposites for Medico-Biological Applications
_____________________________________________________________________________________________
ХФТП 2010. Т. 1. № 3 369
CONCLUSIONS
A method for preparation of magnetosensitive
nanocomposites on basis of surface-modified
magnetite carrying immobilized cisplatin and
monoclonal antibody CD 95 (a medico-biological
nanorobot model) was developed.
Adsorption and covalent immobilization of
monoclonal antibody CD 95 and human normal
immunoglobulin on nanocomposites comprising
magnetite coated with polyacrylamide and γ-
aminopropylsiloxane. Isotherms of covalent
attachment of oxidized immunoglobulin via
formation of Schiff bases and non-specific
(physical) adsorption of the normal
immunoglobulin were compared. Kinetics of
release of the immunoglobulin to a model
environment was studied.
Interaction of the prepared models of
nanorobots with the cell line MCF-7 was studied.
It was shown that use of magnetically driven
nanocomposites carrying the anti-tumour drug
and the monoclonal antibody CD 95 causes a
synergic cytotoxic effect which exceeds the
influence of the control dozes up to 50%.
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Received 14.07.2010, accepted 17.08.2010
Конструювання магнітокерованих нанокомпозитів
медико-біологічного призначення
П.П. Горбик, А.Л. Петрановська, М.П. Турелик, М.В. Абрамов,
В.Ф. Чехун, Н.Ю. Лук’янова
Інститут хімії поверхні ім. О.О. Чуйка Національної академії наук України
вул. Генерала Наумова 17, Київ 03164, Україна
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
вул. Васильківська, 45, Київ 03022, Україна
Дослідження спрямовані на вивчення взаємодій наноматеріалів з компонентами біосистем, розробку
новітніх терапевтичних засобів на основі магнетиту, аналіз ефективності їх використання, хімічне
конструювання багаторівневих магніточутливих нанокомпозитів з ієрархічною архітектурою та
функціями медико-біологічних нанороботів.
Конструирование магнитоуправляемых нанокомпозитов
медико-биологического назначения
П.П. Горбик, А.Л. Петрановская, М.П. Турелик, Н.В. Абрамов,
В.Ф. Чехун, Н.Ю. Лукьянова
Институт химии поверхности им. А.А. Чуйко Национальной академии наук Украины
ул. Генерала Наумова 17, Киев 03164,Украина
Институт экспериментальной патологии, онкологии и радиобиологии им. Р.Е. Кавецкого НАН Украины
ул. Васильковская 45, Киев 03022, Украина
Исследования направлены на изучение взаимодействий наноматериалов с компонентами биосистем,
разработку новых терапевтических средств на основе магнетита, анализ эффективности их применения,
химическое конструирование многоуровневых магниточувствительных нанокомпозитов с иерархической
архитектурой и функциями медико-биологических нанороботов.
|
| id | nasplib_isofts_kiev_ua-123456789-29008 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 2079-1704 |
| language | English |
| last_indexed | 2025-12-07T18:26:36Z |
| publishDate | 2010 |
| publisher | Інститут хімії поверхні ім. О.О. Чуйка НАН України |
| record_format | dspace |
| spelling | Gorbyk, P.P. Petranovska, A.L. Turelyk, M.P. Abramov, N.V. Chekhun, V.F. Lukyanov, N.Yu. 2011-11-27T18:18:34Z 2011-11-27T18:18:34Z 2010 Construction of Magnetocarried Nanocomposites for Medico-Biological Applications / P.P. Gorbyk, A.L. Petranovska, M.P. Turelyk, N.V. Abramov, V.F. Chekhun, N.Yu. Lukyanov // Хімія, фізика та технологія поверхні. — 2010. — Т. 1, № 3. — С. 360-370. — Бібліогр.: 26 назв. — англ. 2079-1704 https://nasplib.isofts.kiev.ua/handle/123456789/29008 539.211:544.723.23 The research work deals with studies on interactions of nanomaterials with components of biosystems, development of new medicines based on magnetite, their application efficiency, chemical engineering of multilevel magnetosensitive nanocomposites with a hierarchical architecture and functions of biomedical nanorobots. Дослідження спрямовані на вивчення взаємодій наноматеріалів з компонентами біосистем, розробку новітніх терапевтичних засобів на основі магнетиту, аналіз ефективності їх використання, хімічне конструювання багаторівневих магніточутливих нанокомпозитів з ієрархічною архітектурою та функціями медико-біологічних нанороботів. Исследования направлены на изучение взаимодействий наноматериалов с компонентами биосистем, разработку новых терапевтических средств на основе магнетита, анализ эффективности их применения, химическое конструирование многоуровневых магниточувствительных нанокомпозитов с иерархической архитектурой и функциями медико-биологических нанороботов. en Інститут хімії поверхні ім. О.О. Чуйка НАН України Хімія, фізика та технологія поверхні Біомедичні аспекти поверхневих явищ Construction of Magnetocarried Nanocomposites for Medico-Biological Applications Конструювання магнітокерованих нанокомпозитів медико-біологічного призначення Конструирование магнитоуправляемых нанокомпозитов медико-биологического назначения Article published earlier |
| spellingShingle | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications Gorbyk, P.P. Petranovska, A.L. Turelyk, M.P. Abramov, N.V. Chekhun, V.F. Lukyanov, N.Yu. Біомедичні аспекти поверхневих явищ |
| title | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications |
| title_alt | Конструювання магнітокерованих нанокомпозитів медико-біологічного призначення Конструирование магнитоуправляемых нанокомпозитов медико-биологического назначения |
| title_full | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications |
| title_fullStr | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications |
| title_full_unstemmed | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications |
| title_short | Construction of Magnetocarried Nanocomposites for Medico-Biological Applications |
| title_sort | construction of magnetocarried nanocomposites for medico-biological applications |
| topic | Біомедичні аспекти поверхневих явищ |
| topic_facet | Біомедичні аспекти поверхневих явищ |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/29008 |
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