In this paper the authors develop the concept of using solid-phase nanoscale inclusions in biological structures, as the concentrators of acoustic energy for ultrasound therapy of oncological diseases. Particu-lar attention is paid to possibility of synthesis of these inclusions directly in the tumor tissue. The validity of the hypothesis of solid-phase sonosensitization has been confirmed in vitro on bacterial cultures. Super-additive effect of combined action of ultrasound and solid-phase sonosensitizer on bacterial cultures was shown. Experimental studies on animals showed that the ultrasound exposure of malignant tumors con-taining nanoparticles of gold and some complex compounds (e.g. theraphthal) results in a significant ther-apeutic effect, which is expressed in a considerable inhibition of tumor growth.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/3541

Bozhevolnov, V.E.

Dezhkunov, N.V.

Gopin, A.V.

Mazina, S.E.

Nikolaev, A.L.

Treschalina, E.M.

SocioEconomic Challenges Journal (Sumy State University)

PROCEEDINGS OF THE INTERNATIONAL CONFERENCE  
NANOMATERIALS: APPLICATIONS AND PROPERTIES 
Vol. 2 No 4, 04NABM04(3pp) (2013) 
 
 
2304-1862/2013/2(4)04NABM04(3) 04NABM04-1  2013 Sumy State University 
Ultrasonic Nanomedicine in the Therapy of Oncological Diseases 
 
A.L. Nikolaev1, A.V. Gopin1,*, V.E. Bozhevolnov1, S.E. Mazina1, E.M. Treschalina2, N.V. Dezhkunov3 
 
1 Lomonosov Moscow State University, Faculty of Chemistry, 1-3, Leninskiye Gory, 119991 Moscow, Russian Federation 
2 N.N. Blokhin Cancer Research Center RAMS, 23, Kashirskoe Ave., 115448 Moscow, Russian Federation 
3 Belarusian State University of Informatics and Radioelectronics, 6, P. Browki Str., 220013 Minsk, Belarus 
 
(Received 17 May 2013; published online 30 August 2013) 
 
In this paper the authors develop the concept of using solid-phase nanoscale inclusions in biological 
structures, as the concentrators of acoustic energy for ultrasound therapy of oncological diseases. Particu-
lar attention is paid to possibility of synthesis of these inclusions directly in the tumor tissue. The validity 
of the hypothesis of solid-phase sonosensitization has been confirmed in vitro on bacterial cultures. Super-
additive effect of combined action of ultrasound and solid-phase sonosensitizer on bacterial cultures was 
shown. Experimental studies on animals showed that the ultrasound exposure of malignant tumors con-
taining nanoparticles of gold and some complex compounds (e.g. theraphthal) results in a significant ther-
apeutic effect, which is expressed in a considerable inhibition of tumor growth. 
 
Keywords: Oncological diseases, Tumor, Ultrasound, Sonosensitization, Solid phase sonosensitizers. 
 
 PACS numbers: 87.50.yt 
 
 
                                                        
* alexgopin@gmail.com 
1. INTRODUCTION 
 
Studies in which nanoparticles (micelles, liposomes, 
nanoemulsion, bubbles, etc.), introduced into the blood-
stream, are the means of delivering drugs to the tumor, 
and ultrasound is a factor stimulating drug release, can 
be attributed to the ultrasonic nanomedicine. 
The method of ultrasonic nanotherapy of malignant 
tumors, developed in this study, differs from those de-
scribed in the literature by two statements: (i) nano-
particles and their aggregates are formed immediately 
in the tumor from a nontoxic and non-medicinal sub-
stance introduced into the bloodstream as a solution; 
(ii) the ultrasound exposure on a tumor containing na-
noparticle aggregates causes effects leading to inhibi-
tion of its growth and, in some cases, to its total remis-
sion. 
As a result of the metabolic atypia, physicochemical 
conditions in the tumor (decreased pH, an increased 
content of calcium ions in intercellular liquid, etc.) dif-
fer from conditions in normal tissues surrounding the 
tumor. These differences result in the possibility of 
solid phase formation mostly in the tumor. The solid 
phase segregates in the tumor after intravenous intro-
duction of solutions of compounds whose calcium salts 
or acidic forms are insoluble under tumor conditions. 
Thus, the selectivity of the formation of nanoparticles 
and their aggregates mostly in the tumor can be 
achieved using the least specific, hence, most stable 
symptoms of its atypia. 
The ultrasound-induced therapeutic effect on the 
biological systems modified by nanoparticle aggregates 
is achieved due additional acoustic energy release in 
regions where these aggregates are localized. This oc-
curs due to the fact that aggregates locally change the 
ultrasound absorbance, increasing the heat release and 
intensity of cavitation processes [1]. 
The above considerations were put into the basis of 
the development of the method of ultrasonic tumor de-
struction in the presence of solid nanoparticles and 
their aggregates. We called the phenomena underlying 
this method and associated with the presence of the 
solid phase as the solid-phase sonosensitization, and 
nanoparticles and their aggregates as solid-phase sono-
sensitizers (SPSs). The effect of solid-phase sonosensi-
tization was tested in experiments in vitro on bacterial 
cells and in vivo on mice. 
 
2. EXPERIMENTAL 
 
2.1 Solid-Phase Modifiers 
 
Theraphathal™ – octasodium salt of cobalt octacar-
boxyphthalocyanine. Theraphthal is soluble in water 
compound. It was synthesized in Organic Intermedi-
ates and Dyes Institute (Moscow, Russia). In proper 
conditions it forms insoluble in water calcium salt of 
theraphthal. 
 
2.2 In Vitro Experiments 
 
2 mL of the suspension of bacterial cells and 2 mL of 
theraphthal solution (10 – 5 mol/L) or 2 mL of gold nano-
particles suspension (10 – 5 g/mL) were introduced into 
the thermostated vessel with an ultrasonic transparent 
bottom and were exposed to ultrasonic treatment 
(0.88 MHz, 1 W/cm2) for 10 minutes at 38 °C. Then, 
1 mL of the suspension was transferred to a sterile Petri 
dish. Bacterial cultures were grown on a PCA Standard 
Methods agar medium. The result of seeding was esti-
mated after 24 hours by counting the number of colony-
forming units. 
 
2.3 In Vivo Experimens 
 
Melanoma B16 was inoculated intramuscularly into 
BDF1 mice in the right paw according to the standard 
procedure [2, 3]. The initial tumor volume at 8th day 
after inoculation was V0  1.1  0.1 cm3. Sonosensitizers 
were injected intravenously 1 hour prior to ultrasonic 
 A.L. NIKOLAEV, A.V. GOPIN, V.E. BOZHEVOLNOV, ET AL. PROC. NAP 2, 04NABM04 (2013) 
 
 
04NABM04-2 
treatment. Ultrasonic treatment of inoculated tumors 
was performed simultaneously with two frequencies 
(0.88 MHz 1 W/cm2 and 2.64 MHz 2 W/cm2) for 
10 minutes at 40 °C. The dynamics of tumor growth was 
assessed by the change in its volume. 
 
3. RESULTS 
 
3.1 In Vitro Experiments 
 
Fig. 1 shows scanning electron micrographs of bacte-
ria after the action of ultrasound and theraphthal. 
 
 
 
 
 
 
 
Fig. 1 – Electron micrographs of Enterococus spp. Cells: un-
treated cells (a), after ultrasonic treatment (b) and after com-
bined action of ultrasound and theraphthal (c) 
 
It is evident that as a result of ultrasonic treatment 
some of the bacteria exposed to destruction apparently 
accompanied by the leakage of cytoplasm (Fig. 1b). 
However, most of the cells keep normal form. Bacteria 
pretreated with theraphthal show a change in the shape 
and the destruction of the membranes that cover almost 
all the treated cells (Fig. 1c). Thus combined action of 
theraphthal and ultrasound leads to the destruction of 
cell membranes and organelles. In our opinion, theraph-
thal reacts with calcium ions contained in the cells and 
forms a solid phase of nanoparticles of calcium salts. 
This phase provides sonosensitizing action, stimulating 
the destruction of the cells under the action of ultra-
sound. 
Data on destruction of bacterial cells are in accord-
ance with data on their survival. Thus ultrasound expo-
sure leads to about 10 % decrease of bacteria viability. 
Bacteria treated with theraphthal or gold nanoparticles 
show no change in viability. Combined action of ultra-
sound and sonosensitizer (theraphthal or gold nanopar-
ticles) leads to significant decrease of viability (30-
60 %). Hence this combined action results in a super-
additive effect. 
 
3.2 In Vivo Experimens 
 
At the N.N. Blokhin Cancer Research Center, Rus-
sian Academy of Medical Science, the experimental pos-
sibility of applying the solid-phase sonosensitization 
effect to ultrasonic therapy of oncological diseases is pre-
clinically studied over several years [4]. The experiments 
are performed on animals with various tumor types, 
different therapy schemes, and include estimation of the 
therapeutic efficiency, harmlessness, and the effect on 
metastatic disease. These studies showed a high thera-
peutic efficiency of the method, i.e., tumor regression by 
75-80 % on average with an increase in the animal life-
time by two times, good exposure tolerance, and the ab-
sence of the effect on metastatic disease. 
 
0 2 4 6 8 10
0
2
4
6
8
10
4
5
3
2

SPS

US
V
 /
 V
0
t, days

C
1
 
 
Fig. 2 – Growth dynamics of tumors containing SPS after 
ultrasound exposure for BDF1 mice and melanoma В16 tu-
mor. Conditions: simultaneous exposure to ultrasound of two 
frequencies: 0.88 MHz, 1 W/cm2 and 2.64 MHz, 2 W/cm2; the 
exposure time is 10 minutes at 40 °С; V0 is the tumor volume 
to the beginning of ultrasound exposure, t is the time of obser-
vation of tumor volume V growth after ultrasound exposure. 
(1) control; (2) ultrasound; (3) theraphthal, 30 mg/kg + ultra-
sound; (4) gold nanoparticles, 7 mg/kg + ultrasound; (5) ZnPc, 
12 mg/kg + ultrasound 
 
Fig. 2 shows the tumor growth dynamics in several 
experimental series using octasodium salt of cobalt octa-
carboxyphthalocyanine (theraphthal), octasodium salt of 
zinc octacarboxyphthalocyanine (ZnPc), and gold nano-
a 
b 
c 
 ULTRASONIC NANOMEDICINE IN THE THERAPY OF ONCOLOGICAL DISEASES PROC. NAP 2, 04NABM04 (2013) 
 
 
04NABM04-3 
particles as SPS. We can see in Fig. 2 that the time of 
tumor size doubling in the experiments using SPS (SPS) 
increases ten times in comparison with the control group 
(C) and five times in comparison with the case of only 
ultrasound exposure (US). This means that the thera-
peutic efficiency of ultrasound exposure in the presence 
of SPS significantly increases. Similar results were also 
obtained for other tumor types (carcinoma Ca755, Ehr-
lich carcinoma, and Lewis carcinoma). In therapeutic 
efficiency, these results were comparable to the results 
of treatment using optimum chemotherapeutic schemes. 
Tumor growth inhibition and its complete remission 
in certain cases probably result from destruction of tumor 
cell membranes and cellular organelles. Fig. 3 compares 
the electron micrographs of mitochondria of melanoma 
B16 tumor cells unexposed and exposed to ultrasound 
(0.88 MHz, 1 W/cm2 + 2.64 MHz, 2 W/cm ) in the pres-
ence of SPS nanoparticles (theraphthal). The experiment 
was performed on BDF1 mice. In the micrograph of tu-
mor exposed to combined action of ultrasound and 
theraphthal (Fig. 3b), we can clearly see mitochondria 
with destructed membrane structures (cristae). Similar 
defects of mitochondria were almost absent when using 
the same ultrasound exposure parameters without 
theraphthal (Fig. 3a). 
 
     
 
Fig. 3 – Electron micrographs of mitochondria of melanoma В16 tumor cells. Control (a) and ultrasound exposure in the presence 
of theraphthal nanoparticles (b) 
 
4. CONCLUSION 
 
Analysis of the results shows that nanoparticles of 
various substances are effective "amplifiers" of anti-
tumor action of ultrasound. The results of these studies 
formed the basis of the method of ultrasonic therapy of 
cancer with the use of solid-phase nanoinclusions syn-
thesized directly in the tumor. Clinical trials of this 
method are carried out at the N.N. Blokhin Cancer 
Research Center, Russian Academy of Medical Sci-
ence. 
 
 
REFERENCES 
 
1. A.L. Nikolaev, A.V. Gopin, V.E. Bozhevolnov, 
E.M. Treshchalina, N.V. Andronova, I.V. Melikhov, 
Acoust. Phys. 55, 575 (2009). 
2. N.V. Andronova, D.V. Filonenko, V.E. Bozhevolnov, 
A.L. Nikolaev, I.M. Treshalin, E.M. Treshalina, 
G.K. Gerasimova, O.L. Kaliya, G.N. Vorozhtsov, Russ. J. 
Biother. 4 No 3, 101 (2005). 
3. N.V. Andronova, B.Yu. Bokhyan, A.L. Nikolaev, 
E.M. Treschalina, M.D. Aliev, E.E. Kovalevskiy, 
D.V. Filonenko, A.V. Gopin, V.E. Bozhevolnov, 
B.Ya. Kogan, G.N. Vorozhtsov, Sarcoma of bone, soft tissue 
and skin tumors 1, 28 (2011). 
4. A.L.Nikolaev, A.V. Gopin, V.E. Bozhevolnov, 
N.V. Andronova, E.M. Treschalina, G.K. Gerasimova, 
E.V. Khorosheva, O.L. Kaliya, G.N. Vorozhtsov, 
N.V. Dezhkunov, Materials of III Euro-asian congress on 
Medical Physics 1, 150 (2010). 
 
a b 


English

Ultrasonic Nanomedicine in the Therapy of Oncological Diseases

Electronic Sumy State University Institutional Repository

PROCEEDINGS OF THE INTERNATIONAL CONFERENCE  NANOMATERIALS: APPLICATIONS AND PROPERTIES Vol. 2 No 4, 04NABM04(3pp) (2013)   2304-1862/2013/2(4)04NABM04(3) 04NABM04-1  2013 Sumy State University Ultrasonic Nanomedicine in the Therapy of Oncological Diseases  A.L. Nikolaev1, A.V. Gopin1,*, V.E. Bozhevolnov1, S.E. Mazina1, E.M. Treschalina2, N.V. Dezhkunov3  1 Lomonosov Moscow State University, Faculty of Chemistry, 1-3, Leninskiye Gory, 119991 Moscow, Russian Federation 2 N.N. Blokhin Cancer Research Center RAMS, 23, Kashirskoe Ave., 115448 Moscow, Russian Federation 3 Belarusian State University of Informatics and Radioelectronics, 6, P. Browki Str., 220013 Minsk, Belarus  (Received 17 May 2013; published online 30 August 2013)  In this paper the authors develop the concept of using solid-phase nanoscale inclusions in biological structures, as the concentrators of acoustic energy for ultrasound therapy of oncological diseases. Particu-lar attention is paid to possibility of synthesis of these inclusions directly in the tumor tissue. The validity of the hypothesis of solid-phase sonosensitization has been confirmed in vitro on bacterial cultures. Super-additive effect of combined action of ultrasound and solid-phase sonosensitizer on bacterial cultures was shown. Experimental studies on animals showed that the ultrasound exposure of malignant tumors con-taining nanoparticles of gold and some complex compounds (e.g. theraphthal) results in a significant ther-apeutic effect, which is expressed in a considerable inhibition of tumor growth.  Keywords: Oncological diseases, Tumor, Ultrasound, Sonosensitization, Solid phase sonosensitizers.   PACS numbers: 87.50.yt                                                           * alexgopin@gmail.com 1. INTRODUCTION  Studies in which nanoparticles (micelles, liposomes, nanoemulsion, bubbles, etc.), introduced into the blood-stream, are the means of delivering drugs to the tumor, and ultrasound is a factor stimulating drug release, can be attributed to the ultrasonic nanomedicine. The method of ultrasonic nanotherapy of malignant tumors, developed in this study, differs from those de-scribed in the literature by two statements: (i) nano-particles and their aggregates are formed immediately in the tumor from a nontoxic and non-medicinal sub-stance introduced into the bloodstream as a solution; (ii) the ultrasound exposure on a tumor containing na-noparticle aggregates causes effects leading to inhibi-tion of its growth and, in some cases, to its total remis-sion. As a result of the metabolic atypia, physicochemical conditions in the tumor (decreased pH, an increased content of calcium ions in intercellular liquid, etc.) dif-fer from conditions in normal tissues surrounding the tumor. These differences result in the possibility of solid phase formation mostly in the tumor. The solid phase segregates in the tumor after intravenous intro-duction of solutions of compounds whose calcium salts or acidic forms are insoluble under tumor conditions. Thus, the selectivity of the formation of nanoparticles and their aggregates mostly in the tumor can be achieved using the least specific, hence, most stable symptoms of its atypia. The ultrasound-induced therapeutic effect on the biological systems modified by nanoparticle aggregates is achieved due additional acoustic energy release in regions where these aggregates are localized. This oc-curs due to the fact that aggregates locally change the ultrasound absorbance, increasing the heat release and intensity of cavitation processes [1]. The above considerations were put into the basis of the development of the method of ultrasonic tumor de-struction in the presence of solid nanoparticles and their aggregates. We called the phenomena underlying this method and associated with the presence of the solid phase as the solid-phase sonosensitization, and nanoparticles and their aggregates as solid-phase sono-sensitizers (SPSs). The effect of solid-phase sonosensi-tization was tested in experiments in vitro on bacterial cells and in vivo on mice.  2. EXPERIMENTAL  2.1 Solid-Phase Modifiers  Theraphathal™ – octasodium salt of cobalt octacar-boxyphthalocyanine. Theraphthal is soluble in water compound. It was synthesized in Organic Intermedi-ates and Dyes Institute (Moscow, Russia). In proper conditions it forms insoluble in water calcium salt of theraphthal.  2.2 In Vitro Experiments  2 mL of the suspension of bacterial cells and 2 mL of theraphthal solution (10 – 5 mol/L) or 2 mL of gold nano-particles suspension (10 – 5 g/mL) were introduced into the thermostated vessel with an ultrasonic transparent bottom and were exposed to ultrasonic treatment (0.88 MHz, 1 W/cm2) for 10 minutes at 38 °C. Then, 1 mL of the suspension was transferred to a sterile Petri dish. Bacterial cultures were grown on a PCA Standard Methods agar medium. The result of seeding was esti-mated after 24 hours by counting the number of colony-forming units.  2.3 In Vivo Experimens  Melanoma B16 was inoculated intramuscularly into BDF1 mice in the right paw according to the standard procedure [2, 3]. The initial tumor volume at 8th day after inoculation was V0  1.1  0.1 cm3. Sonosensitizers were injected intravenously 1 hour prior to ultrasonic  A.L. NIKOLAEV, A.V. GOPIN, V.E. BOZHEVOLNOV, ET AL. PROC. NAP 2, 04NABM04 (2013)   04NABM04-2 treatment. Ultrasonic treatment of inoculated tumors was performed simultaneously with two frequencies (0.88 MHz 1 W/cm2 and 2.64 MHz 2 W/cm2) for 10 minutes at 40 °C. The dynamics of tumor growth was assessed by the change in its volume.  3. RESULTS  3.1 In Vitro Experiments  Fig. 1 shows scanning electron micrographs of bacte-ria after the action of ultrasound and theraphthal.        Fig. 1 – Electron micrographs of Enterococus spp. Cells: un-treated cells (a), after ultrasonic treatment (b) and after com-bined action of ultrasound and theraphthal (c)  It is evident that as a result of ultrasonic treatment some of the bacteria exposed to destruction apparently accompanied by the leakage of cytoplasm (Fig. 1b). However, most of the cells keep normal form. Bacteria pretreated with theraphthal show a change in the shape and the destruction of the membranes that cover almost all the treated cells (Fig. 1c). Thus combined action of theraphthal and ultrasound leads to the destruction of cell membranes and organelles. In our opinion, theraph-thal reacts with calcium ions contained in the cells and forms a solid phase of nanoparticles of calcium salts. This phase provides sonosensitizing action, stimulating the destruction of the cells under the action of ultra-sound. Data on destruction of bacterial cells are in accord-ance with data on their survival. Thus ultrasound expo-sure leads to about 10 % decrease of bacteria viability. Bacteria treated with theraphthal or gold nanoparticles show no change in viability. Combined action of ultra-sound and sonosensitizer (theraphthal or gold nanopar-ticles) leads to significant decrease of viability (30-60 %). Hence this combined action results in a super-additive effect.  3.2 In Vivo Experimens  At the N.N. Blokhin Cancer Research Center, Rus-sian Academy of Medical Science, the experimental pos-sibility of applying the solid-phase sonosensitization effect to ultrasonic therapy of oncological diseases is pre-clinically studied over several years [4]. The experiments are performed on animals with various tumor types, different therapy schemes, and include estimation of the therapeutic efficiency, harmlessness, and the effect on metastatic disease. These studies showed a high thera-peutic efficiency of the method, i.e., tumor regression by 75-80 % on average with an increase in the animal life-time by two times, good exposure tolerance, and the ab-sence of the effect on metastatic disease.  0 2 4 6 8 1002468104532SPSUSV / V0t, daysC1  Fig. 2 – Growth dynamics of tumors containing SPS after ultrasound exposure for BDF1 mice and melanoma В16 tu-mor. Conditions: simultaneous exposure to ultrasound of two frequencies: 0.88 MHz, 1 W/cm2 and 2.64 MHz, 2 W/cm2; the exposure time is 10 minutes at 40 °С; V0 is the tumor volume to the beginning of ultrasound exposure, t is the time of obser-vation of tumor volume V growth after ultrasound exposure. (1) control; (2) ultrasound; (3) theraphthal, 30 mg/kg + ultra-sound; (4) gold nanoparticles, 7 mg/kg + ultrasound; (5) ZnPc, 12 mg/kg + ultrasound  Fig. 2 shows the tumor growth dynamics in several experimental series using octasodium salt of cobalt octa-carboxyphthalocyanine (theraphthal), octasodium salt of zinc octacarboxyphthalocyanine (ZnPc), and gold nano-a b c  ULTRASONIC NANOMEDICINE IN THE THERAPY OF ONCOLOGICAL DISEASES PROC. NAP 2, 04NABM04 (2013)   04NABM04-3 particles as SPS. We can see in Fig. 2 that the time of tumor size doubling in the experiments using SPS (SPS) increases ten times in comparison with the control group (C) and five times in comparison with the case of only ultrasound exposure (US). This means that the thera-peutic efficiency of ultrasound exposure in the presence of SPS significantly increases. Similar results were also obtained for other tumor types (carcinoma Ca755, Ehr-lich carcinoma, and Lewis carcinoma). In therapeutic efficiency, these results were comparable to the results of treatment using optimum chemotherapeutic schemes. Tumor growth inhibition and its complete remission in certain cases probably result from destruction of tumor cell membranes and cellular organelles. Fig. 3 compares the electron micrographs of mitochondria of melanoma B16 tumor cells unexposed and exposed to ultrasound (0.88 MHz, 1 W/cm2 + 2.64 MHz, 2 W/cm ) in the pres-ence of SPS nanoparticles (theraphthal). The experiment was performed on BDF1 mice. In the micrograph of tu-mor exposed to combined action of ultrasound and theraphthal (Fig. 3b), we can clearly see mitochondria with destructed membrane structures (cristae). Similar defects of mitochondria were almost absent when using the same ultrasound exposure parameters without theraphthal (Fig. 3a).        Fig. 3 – Electron micrographs of mitochondria of melanoma В16 tumor cells. Control (a) and ultrasound exposure in the presence of theraphthal nanoparticles (b)  4. CONCLUSION  Analysis of the results shows that nanoparticles of various substances are effective "amplifiers" of anti-tumor action of ultrasound. The results of these studies formed the basis of the method of ultrasonic therapy of cancer with the use of solid-phase nanoinclusions syn-thesized directly in the tumor. Clinical trials of this method are carried out at the N.N. Blokhin Cancer Research Center, Russian Academy of Medical Sci-ence.   REFERENCES  1. A.L. Nikolaev, A.V. Gopin, V.E. Bozhevolnov, E.M. Treshchalina, N.V. Andronova, I.V. Melikhov, Acoust. Phys. 55, 575 (2009). 2. N.V. Andronova, D.V. Filonenko, V.E. Bozhevolnov, A.L. Nikolaev, I.M. Treshalin, E.M. Treshalina, G.K. Gerasimova, O.L. Kaliya, G.N. Vorozhtsov, Russ. J. Biother. 4 No 3, 101 (2005). 3. N.V. Andronova, B.Yu. Bokhyan, A.L. Nikolaev, E.M. Treschalina, M.D. Aliev, E.E. Kovalevskiy, D.V. Filonenko, A.V. Gopin, V.E. Bozhevolnov, B.Ya. Kogan, G.N. Vorozhtsov, Sarcoma of bone, soft tissue and skin tumors 1, 28 (2011). 4. A.L.Nikolaev, A.V. Gopin, V.E. Bozhevolnov, N.V. Andronova, E.M. Treschalina, G.K. Gerasimova, E.V. Khorosheva, O.L. Kaliya, G.N. Vorozhtsov, N.V. Dezhkunov, Materials of III Euro-asian congress on Medical Physics 1, 150 (2010).  a b 

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