Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles
The aim of this paper is to study the ultrastructure and some functional indexes of tumor cells treated with stabilized iron nanoparticles in vitro.
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2010
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| Цитувати: | Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles / O.V. Yurchenko, I.N. Todor, I.K. Khayetsky, N.A. Tregubova, N.Yu. Lukianova, V.F. Chekhun // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 237–242. — Біліогр.: 28 назв. — англ. |
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irk-123456789-323022012-04-17T12:23:10Z Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles Yurchenko, O.V. Todor, I.N. Khayetsky, I.K. Tregubova, N.A. Lukianova, N.Yu. Chekhun, V.F. Original contributions The aim of this paper is to study the ultrastructure and some functional indexes of tumor cells treated with stabilized iron nanoparticles in vitro. 2010 Article Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles / O.V. Yurchenko, I.N. Todor, I.K. Khayetsky, N.A. Tregubova, N.Yu. Lukianova, V.F. Chekhun // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 237–242. — Біліогр.: 28 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/32302 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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English |
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Original contributions Original contributions |
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Original contributions Original contributions Yurchenko, O.V. Todor, I.N. Khayetsky, I.K. Tregubova, N.A. Lukianova, N.Yu. Chekhun, V.F. Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles Experimental Oncology |
| description |
The aim of this paper is to study the ultrastructure and some functional indexes of tumor cells treated with stabilized iron nanoparticles in vitro. |
| format |
Article |
| author |
Yurchenko, O.V. Todor, I.N. Khayetsky, I.K. Tregubova, N.A. Lukianova, N.Yu. Chekhun, V.F. |
| author_facet |
Yurchenko, O.V. Todor, I.N. Khayetsky, I.K. Tregubova, N.A. Lukianova, N.Yu. Chekhun, V.F. |
| author_sort |
Yurchenko, O.V. |
| title |
Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles |
| title_short |
Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles |
| title_full |
Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles |
| title_fullStr |
Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles |
| title_full_unstemmed |
Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles |
| title_sort |
ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2010 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/32302 |
| citation_txt |
Ultrastructural and some functional changes in tumor cells treated with stabilized iron oxide nanoparticles / O.V. Yurchenko, I.N. Todor, I.K. Khayetsky, N.A. Tregubova, N.Yu. Lukianova, V.F. Chekhun // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 237–242. — Біліогр.: 28 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-03T12:49:03Z |
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2025-07-03T12:49:03Z |
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| fulltext |
Experimental Oncology 32, 237–242, 2010 (December) 237
Nanotechnologies are one of the main directions
of modern technological processes in medicine. It is
predicted, that these technologies would be applied
in oncology via synthesis of new nanodrugs with their
target delivery to tumor cells. Methodology of antitu-
mor drug delivery with application of nanotechnologies
is the one that would allow overcoming some physical
and pharmacological barriers to elevate the treatment
efficacy of patients with cancer [1–3].
At present time the search for new technologies
that on one hand will allow decreasing toxicity of
drugs via generation and use of special constructions,
particularly, liposomes, and on the other hand, will
promote targeted delivery of drugs directly to tumor
with the use of nanotechnologies, is being actively
performed. Among constructive approaches to solve
this task is the development of magnet-operated
forms of anticancer preparations. This approach con-
sists in general of a complex of cytostatic drugs with
nano-sized particles of ferri-ferrous oxide that allows
concentrating anticancer preparation in target area
under influence of magnetic field.
Presently there are going trials of many nano-sized
substances that possess ability for targeted delivery
of anticancer preparations to malignant cells with
simultaneous decrease of general toxicity [4]. It was
shown that physico-chemical properties and bio-
logic activity of substances in form of nanoparticles
often significantly differ from substances in their
standard physico-chemical state [5]. Particularly,
metal nanoparticles reveal potent catalytic properties
exerted in temperature differences up to hundreds
of degrees, huge magnetic resistance, abnormally
great magneto-calorimetric effect etc [6]. That’s why
oncologists pay special attention to possible use of
nanoferromagnetics.
The first task for determining possible clinical ap-
plication of nanoscale complexes in different branches
of medicine, particularly in oncology, is study of bio-
logical effects which are able to cause toxic damage in
cells after their contact with nanoparticles of different
compositions.
Despite the clinical use of ferromagnetic nanopar-
ticles as magnetic resonance imaging contrast agents
[7, 8], yet there is insufficiency of experimental
studies in vitro [9–11] about toxic effects and biologi-
cal action of ferromagnetics on cells and influence
of nanosized complexes containing ferromagnetic
in liposomal form.
In several studies it was shown that toxic effect
of nano-sized complexes on cells depends on ma-
terial from which they were composed, their size,
the presence of reactive groups on the surface of
these complexes, their concentration, and cell his-
togenesis [3, 4]. Along with this it was demonstrated
that the majority of nanosized complexes revealed
their toxic effect on cells only at high concentrations
(100–250 g/ml) [12, 13].
The mechanism of penetration of coated and un-
coated nanocomplexes is related to soluble phase of
endocytosis that has been documented by elevated
content of protein clarin in cell periphery [14–17] and
by the data of study that showed that dextran-coated
nanocomplexes are not receptor-dependent [17].
So, presently there are no final decisions con-
cerning toxic effect and mechanism of biological
action of stabilized ferromagnetics on malignant
cells. Also, there is no data about ultrastructural and
functional changes in tumor cells after the influence
of ferromagnetics. That’s why we have performed
a study of ultrastructure and some functional in-
ULTRASTRUCTURAL AND SOME FUNCTIONAL CHANGES IN TUMOR
CELLS TREATED WITH STABILIZED IRON OXIDE NANOPARTICLES
O.V. Yurchenko, I.N. Todor, I.K. Khayetsky, N.A. Tregubova, N.Yu. Lukianova*, V.F. Chekhun
Department of Mechanisms of Anticancer Therapy, R.E. Kavetsky Institute of Experimental Pathology,
Oncology and Radiobiology of NAS of Ukraine, Vasylkivska str. 45, Kiev 03022, Ukraine
Aim: To study the ultrastructure and some functional indexes of tumor cells treated with stabilized iron nanoparticles in vitro.
Methods: 3-[4,5dimethylthiazol-2-1]-2,5-diphenyltetrazolium bromide (MTT)-test, electron microscopy, polarography with
applying of closed Clark’s electrode. Results: It was shown that cultivation of cells with stabilized Fe3O4 leads to intracellular ac-
cumulation of ferromagnetic nanoparticles. The most active ferromagnetic uptake by cells has been observed after 24 and 48 h
of incubation. The presence of ferromagnetic in cells led to altered mitochondrial structure that caused the decrease of oxygen
uptake rate in the cells of all studied lines. Ferromagnetic released from the majority of cells via exocytosis or clasmacytosis after
a certain period of time. The number of dead cells or cells with severe damage was moderate, so cytotoxic action of stabilized iron
oxide nanoparticles was minimal toward the studied cell lines. Conclusion: the presence of ferromagnetic nanoparticles in culture
medium led to alterations in mitochondria ultrastructural organization and decrease of oxygen uptake by mitochondria in sensitive
and anticancer-drugs resistant cells.
Key Words: MCF-7 cells, A2780 cells, stabilized iron oxide nanoparticles, ultrastructure, mitochondria oxygen uptake.
Received: October 8, 2010.
*Correspondence: Fax: +380442581656;
E-mail: oncom@onconet.kiev.ua
Abbreviations used: МТТ — 3-[4,5dimethylthiazol-2-1]-2,5-diphe-
nyltetrazolium bromide.
Exp Oncol 2010
32, 4, 237–242
238 Experimental Oncology 32, 237–242, 2010 (December)
dexes of tumor cells treated in vitro by stabilized
iron nanoparticles.
MATERIALS AND METHODS
The objects of our study were wild type, cisplatin-
resistant and doxorubicin-resistant human breast
cancer cells (MCF-7 cell line) and human ovarian
cancer cells (А2780 cell line). Original MCF-7 and
А2780 cells were cultured in modified Dulbecco IS-
COVE medium (Sigma, Germany) supplemented with
10% fetal calf serum (“Sangva”, Ukraine) at 37 оС in 5%
СО2 atmosphere. The cells were passaged twice per
week at the density of 2–4 x 104 cell/cm2. The resistant
variants (cisplatin-resistant MCF-7/DDP and А2780/
DDP) and doxorubicin-resistant (MCF-7/Dох, А2780/
Dох) cells were generated by culturing original cells in
the presence of increasing concentrations of cispla-
tin or doxorubicin. Each two months, cell resistance
was analyzed by proliferative method with the use of
3-[4,5dimethylthiazol-2-1]-2,5-diphenyltetrazolium
bromide (МТТ) method. At the time of experiment,
the resistance degrees of MCF- 7 cells yielded 4 for
cisplatin and 8 for doxorubicin, and 5 and 8, respec-
tively , for А2780 cells .
We used magnetite (Fe3O4) synthesized by the
method of electron-beam evaporation and Fe3O4 and
NaCl deposition in vacuum. The stabilization of
ferromagnetic was carried out by adding polydex-
trane-90 and phosphatidylcholine/cholesterol during
dispersion. Size of stabilized particles was determined
using laser correlation spectrometry. Iron concentra-
tions (mg/ml) were measured by atomic-absorption
spectroscopy [18].
The cells of studied lines were cultured with sta-
bilized ferromagnetic at concentration of 100 g/ml
for 1, 2 and 3 days. For electron microscopy study,
the cells were fixed for 1 h in 1.6% glutaraldehyde
solution prepared in 0.1 М cacodylate buffer (рН
7.3). To remove glutaraldehyde, the cells were
washed in 0.1 М cacodylate buffer for 16–18 h. To
achieve optimal isotonic quality of fixing and wash-
ing buffers, cacodylate buffer was supplemented
with saccharose (50 mg per ml). Post-fixation of the
cells was done in 4% osmium tetroxide, with further
dehydration in alcohols and placement in araldite by
standard method [19]. Ultrathin slides prepared with
the use of LKB-8800 ultratome, were contrasted with
uranyl acetate and plumbous citrate and examined
using electron microscope JEM-100B at accelerated
voltage of 80 kV.
The rate of oxygen uptake by the cells was de-
termined by polarographic method with the use of
closed Clark’s electrode. In polarographic well, the
abovementioned medium for cell incubation satu-
rated with oxygen, was placed. The temperature of
incubation medium was 24 оС. Oxygen uptake rate
was expressed in nanoatoms of О2/min/1 х 106 cells.
Statistical analysis of obtained data was performed
using Student’s t-test.
RESULTS
In our previous studies it was shown that acquire-
ment of resistance to cisplatin and doxorubicin in
human ovarian cancer cells of А2780 line and human
breast cancer cells of MCF-7 line is accompanied
by ultrastructural changes of the cells [20, 21]. For
drug resistant cells the presence of well developed
granular endoplasmic reticulum with long channels,
and 2–3 Golgi apparatus loci was typical. Close to
Golgi apparatus, a significant quantity of multivesicu-
lar bodies was always present. Resistant cells have a
nucleus of irregular shape with invaginations and active
nucleoli located near nuclear membrane that could
be considered as a pattern of activated metabolism
in the cells that acquired drug resistance. A lot of
microtubules, and microfilaments in form of bundles
of various thickness appeared in resistant cells of
А2780 and MCF-7 lines.
So, А2780 and MCF-7 cells resistant to doxorubicin
and cisplatin possess more developed cellular com-
plex connected with elements of cytoskeleton, and
complicated ultrastructural organization compared
with wild type cells that evidences a higher degree of
their differentiation.
After 1 day of incubation with stabilized dispersed
Fe3O4 in culture medium one could observe the
changes of ultrastructural organization in all studied
cell lines. In cytoplasm phagosomes with ferromag-
netic granules appeared (Fig. 1, а). Some part of
phagosomes acquired more complex structure being
united with lysosomes and transformed into phagoly-
sosomes. Only in insignificant part of the cells no fer-
romagnetic was present in cell cytoplasm. The number
of cells with necrotic patterns was insignificant, and
was characterized by the presence of a large quantity
of accumulated granules of ferromagnetic nanopar-
ticles in the content of multiple phagolysosomes. We
have detected that ferromagnetic nanoparticles were
localized only in the cytoplasm of studied cells but not
in cellular organelles. Meanwhile, according to the data
of literature, TiO2 nanoparticles were accumulated in
cell mitochondria and nucleus [22].
Ultrastructural organization of wild-type cells in
contrary to resistant ones was also practically not
altered. In А2780/S and MCF-7/S cells one could
observe just an elevation of endoplasmic reticulum
channels number with a large quantity of ribosomes on
the outer membrane and elements of Golgi apparatus
(Fig. 1, b), while in the cells of resistant lines the in-
creased quantity of cell organelles could be detected.
Altered ultrastructure of all studied lines evidences
functional loading of this cell organelle in response on
the presence of Fe3O4 dispersion.
In all studied sublines the changes of cell shape
detected by light microscopy examination, as well
as altered ultrastructural organization have been ob-
served. The cells acquired a more round shape with
the formation of cytoplasm protrusions that promoted
cell contact perturbation.
Experimental Oncology 32, 237–242, 2010 (December) 239
The most damaged organelles seemed to be
mitochondria that possessed small dimensions with
electron-dense matrix. These alterations of mito-
chondrial structure indicate a significant functional
failure of these organelles and have been supported
by the data of experiments on the rate of oxygen
uptake by mitochondria. Altered structure of mito-
chondria may be caused by release of free radicals
by iron present in nanoparticles that leads to inhibition
of functional activity of mitochondria and some other
cell organelles [23].
One of the characteristic features of resistant
sublines was the presence of significantly larger
numbers of phagosomes that were composed from
conglomerates of electron-dense ferromagnetic
granules of various forms and in different quantity
(Fig. 1, с). It could be related to quicker accumula-
tion of ferromagnetic in resistant cells compared with
sensitive ones or with the functional state of resistant
cells that possess more complex structural organiza-
tion with the presence of significantly higher quantity
of cell organelles that leads to rapid formation of
complex phagolysosomes.
Intact resistant cells of А2780 and MCF-7 sublines
are characterized by the presence of large numbers of
microtubules, microfilaments, that form the bundles
of different thickness localized near nucleus invagi-
nations in A2780/Dox cells, or plasma membrane in
А2780/DDP cells. So, drug resistant cells possess well
developed cell complex associated with elements of
cytoskeleton. However, after action of ferromagnetic
cytoskeleton structural regularity became disturbed
or the components of cytoskeleton underwent de-
orientation which is illustrated by the presence of
only few small bundles of microfilaments localized in
cytoplasm of studied cells (Fig. 1, d). It could be re-
lated to an appearance of phagolysosomes which, as
it is known, move in cells along microtubules with the
help of microfilaments and fibrilla. Phagosomes are
bound to cytoskeleton filaments with the use of motor
proteins (like myosin, kinesin, or di nein), which leads
to ATP release and promotes transfer of phagolyso-
somes containing ferromagnetic, inside the cells [24].
Possibly, exactly the presence of large quantity of pha-
golysosomes leads to re-distribution of cytoskeleton
elements that is required for cell functioning in altered
conditions. Apart from this, ferromagnetic may cause
alterations in cytoskeleton structure and function via
direct influence on the structure of proteins that form
cytoskeleton or indirectly affect cell functional state.
Altered cell shape upon ferromagnetic action could
also be caused by the reconstruction and the changed
orientation of main elements and proteins of cytoskel-
eton, first of all, actin that is the main component of
cell cytoskeleton and is responsible for cell shape,
migration and distribution [25].
Ultrastructural study of cells treated with ferro-
magnetic for 2 days allowed to detect its elevated
accumulation in the cells of all studied lines (Fig.
2, a). Ultrastructural patterns of cells were practically
unaltered except for the formation of much higher
numbers of phagolysosomes of larger size. It’s nec-
essary to note that in the cells of studied sublines
further increase of apical part of cytoplasm could be
a
c
b
d
Fig. 1. Ultrastructure of tumor cells after 1 day of exposure to stabilized Fe3O4 dispersion: a, — sensitive to antitumor drugs A2780 hu-
man ovarian cancer cells, X10000; b, — sensitive to antitumor drugs MCF-7 human breast cancer cells, X10000; c, — resistant
to doxorubicin A2780/Dox human ovarian cancer cells, X10000; d, — presence of single microfilament bunches in cytoplasm of
sensitive MCF-7 human breast cancer cells, X20000
240 Experimental Oncology 32, 237–242, 2010 (December)
observed, which could be explained by larger total
volume of nanoparticles accumulated by the cells. The
structure of mitochondria remained altered especially
in MCF-7/Dox cells (Fig. 2, b).
After 3 days of incubation of cells with ferromagnetic
dispersion, a gradual decrease of its accumulation in
the cells of all studied sublines has been detected
(Fig. 3, a). Ferromagnetic has been removed from the
cells by exocytosis of phagolysosomes in intercellu-
lar space, as well as by clasmacytosis (separation of
small parts of cytoplasm containing large quantities of
ferromagnetic) (see Fig. 2, b). At the third day of incu-
bation all studied sublines showed significant number
of blebs of various sizes with different quantity of
ferromagnetic located on cell membrane. The number
of blebs elevated along with the increase of incubation
period with nanoparticles.
a
b
Fig. 2. Ultrastructure of tumor cells after 2 days of exposure to
stabilized Fe3O4 dispersion: a, — resistant to doxorubicin human
ovarian cancer A2780 cells, X10000; b, — resistant to doxorubi-
cin human breast cancer MCF-7 cells, X10000
Among mechanisms of toxic action of small sized
nanoparticles one should mention their ability to
damage mitochondria that are indicators of cell func-
tional state most sensitive to the action of damaging
factors. It is known that among early signs of cell
damage there are alterations of mitochondrial ultra-
structure determined as formation of electron-dense
mitochondria with weakly contoured crists, and their
vacuolization. Exactly such structure of mitochondria
was observed by us in the cells treated with nanocom-
plexes (Fig. 3, c).
After 8 days of cultivation of MCF-7 cells in stan-
dard medium that replaced ferromagnetic after 3-days
incubation, such altered ultrastructure of mitochondria
still could be observed in some cases.
a
b
c
Fig. 3. Ultrastructure of tumor cells after 3 days of exposure to
stabilized Fe3O4 dispersion: a, — resistant to doxorubicin human
ovarian cancer A2780 cells, X10000; b, — sensitive to antitumor
drugs A2780 human ovarian cancer cells, X10000; c, — severe
damage of mitochondria structure in resistant to doxorubicin
human ovarian cancer A2780 cells, X15000
It is known that 90–97% of oxygen in cells is me-
tabolized by mitochondria [26]. Taking into account
that many complexes of mitochondrial respiratory
chain contain iron [27], we have studied an influence
of stabilized nanoferromagnetic on the rate of oxygen
uptake by MCF-7/S, MCF-7/ DDP and MCF-7/Dox
cells. It has been revealed that intact MCF-7/Dox cells
uptake oxygen somewhat more rapidly than original
MCF-7/S cells (0.05 < p < 0.1; Table). This fact is in
accordance with our earlier data obtained on rat tumor
cells [28]. Interestingly enough, 48 h incubation with
ferromagnetic resulted in decreased rate of oxygen
uptake by the cells, but at different degree in differ-
ent cell sublines (see Table). After incubation with
ferromagnetic the rate of oxygen uptake by MCF-7/S
cells significantly decreased (by 33%; p < 0.05), while
in MCF-7/DDP and MCF-7/Dox cells it decreased by
10 and 21%, respectively. This fact evidenced the re-
Experimental Oncology 32, 237–242, 2010 (December) 241
sistance of MCF-7/DDP and MCF-7/Dox cells not only
to some cytostatics, but also to some other agents,
for example, to ferromagnetics of certain composition
and size. These data are important for further studies
of effective antitumor nanocomposites designed for
use in vivo.
Table. Oxygen uptake rate in MCF-7/S, MCF-7/ DDP and MCF-7/Dox
cells after their incubation for 48 h with ferromagnetic stabilized with dex-
tran and phosphatidylcholine (n = 5). Oxygen uptake rate was expressed in
nanoatoms of О2/min/1 х 106 cells
Treatment Cell line
MCF-7/S MCF-7/DDP MCF-7/Dox
Сontrol 10.8 ± 0.2 10.3 ± 0.7 12.2 ± 1.0
After 48 h incubation with ferro-
magnetic
7.2 ± 0.4* 9.3 ± 1.2 9.6 ± 0.7
Note: *difference is significant compared with respective control (p < 0.05).
In conclusion, it has been shown in our study that
cultivation of cells with stabilized Fe3O4 dispersion
leads to intracellular accumulation of ferromagnetic
nanoparticles. The most active ferromagnetic uptake
by wild type cells have been observed after 24 h
and 48 h of incubation. Resistant cells accumulated
iron more slowly and its maximal concentration was
registered after 48 h. The presence of ferromagnetic
in culture medium has led to altered mitochondrial
structure which caused the decrease of oxygen up-
take rate. Also, the decrease of the oxygen uptake
rate by the cells that may also promote cytotoxic
damage upon treatment with stabilized iron occured.
In the large majority of cells after 72 h of incubation
ferromagnetic was released from nanoparticles via
exocytosis or clasmacytosis. One could detect such
ferromagnetic particles in intercellular space. After
72 h in significant number of cells no ferromagnetic
particles could be observed. The number of dead cells
or cells with severe damage was moderate enough,
so cytotoxic action of nanoparticles of stabilized iron
toward studied cell lines was minimal. The results of
our study allow us to conclude that the presence of
ferromagnetic in culture medium leads to alteration
of ultrastructural organization and decreased oxygen
uptake by mitochondria in the cells sensitive and re-
sistant to anticancer drugs.
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