Journal of Magnetism and Magnetic Materials 252 (2002) 378380

Magnetic uid hyperthermia of the mouse experimental tumor

Nikolai A. Brusentsova,*, Lev V. Nikitinb, Tatiana N. Brusentsovac, Anatoly
A. Kuznetsovd, Felix S. Bayburtskiye, Leonid I. Shumakovf, Nikolai Y. Jurchenkoa
a

Blokhin Oncological Research Center RAMS, Moscow 115478, Russia

b
Moscow State University, Moscow 119899, Russia
c
Institute of Mechanics Moscow State University, Moscow 117192, Russia
d
Institute of Biochemical Physics RAS, Moscow, 117977, Kosygina 4 Russia
e
Mendeleev University Chemical Technology Russia, Moscow 125047, Russia
f
Russian Radiotechnical Research Institute, Moscow, Russia

Abstract
Four of the water-based dextran-ferrite (DF) magnetic uids (MF) were prepared. Their saturation magnetization
was from 0.9 to 7.5 kA/m; specic power absorption rates were 210 W/g Fe; pH was from 6 to 9 and Zeta-potential (f)
was from +18 to 12 mV. After nine magnetic uid tumor hyperthermia at +441C to +451C, 30 min with waterltered AC magnetic eld (0.88 MHz, 9.3 kA/m, 0.15 kW), while using DF MF (saturation magnetization 7.5 kA/m, pH
6.6, f +15 mV), a complete tumor regression sarcoma MX11 in C57Bl/6j mice was 33%, life span increase achieved was
150%.
r 2002 Elsevier Science B.V. All rights reserved.
Keywords: Sarcoma; Magnetic uid hyperthermia; Dextran-ferrite targetinginhomogeneous permanent magnetic eld (PMF); AC
magnetic eldwater-ltered

1. Introduction
We have developed magnetic dextran-ferrite #363
(DF) nanoparticles for an externally applied AC
magnetic eld hyperthermia [1,2]. DF magnetic uids
(MFs), that had been prepared, were less toxic for
experimental animals [3], so that they may be ideal
magnetic carriers [4]. The particles of DF dissipate
of AC magnetic eld energy through various kinds of
losses and therefore cause hyperthermia in the area of
their connement [1,2, 47]. The survival of MX11 cells
as the function of the exposure time at +441C when
heating DF #363 MFs was achieved by AC magnetic
*Corresponding author.
E-mail addresses: nikitin@magn.ru (L.V. Nikitin), gogosov@imec.msu.ru (T.N. Brusentsova), akuz@sky.chph.ras.ru
(A.A. Kuznetsov), akuz@sky.chph.ras.ru (A.A. Kuznetsov),
akuz@sky.chph.ras.ru (A.A. Kuznetsov), akuz@sky.chph.ras.ru (A.A. Kuznetsov), akuz@sky.chph.ras.ru (A.A. Kuznetsov),
bayburt@mail.ru (F.S. Bayburtskiy).

eld (0.88 MHz, 7.2 kA/m, 0.15 kW) or water bath was
the same [2].
The inevitable technical problem with hyperthermia in
vivo is the difculty of the uniform heating of only the
tumor region until the required temperature without
damaging normal tissue.
The purpose of this work was to evaluate DF #363
MFs for the site-specic AC magnetic eld hyperthermia
of sarcoma MX11 in vivo.

2. Materials and methods

We tested the four water-based DF #363 MFs which
were prepared by the procedure modied from Ref. [2].
The sample of the initial DF MF was lyophilized. Zetapotential (f) was xed by electrophoresis. The methods of initial magnetic susceptibility (vinit ), specic
power absorption rates (SAR) of MFs [2]; saturation magnetization (Ms ) of 10%, 20%, 30%, and 40%

0304-8853/02/$ - see front matter r 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 3 0 4 - 8 8 5 3 ( 0 2 ) 0 0 6 3 4 - 0

N.A. Brusentsov et al. / Journal of Magnetism and Magnetic Materials 252 (2002) 378380

3. Results and discussion

M s of evaluated DF MFs was from 0.9 to 7.5 kA/m,
pH 69, f from +18 to 12 mV, SAR 210 W/g Fe.
From 3% to 6% of the injected DF was observed
accumulated in the tumor tissue after the rst injection
was given to mice of the second group; from 18% to
30% of DF was PMF targeted in the tumor tissue after
the rst injection with following PMF targeting in
groups 3 and 4. The temperature of the tumors in mice
of group 2 was elevated slowly. In groups 3 and 4, the
temperature of the tumor was elevated rapidly and
reached +441C after 15 min by the AC magnetic eld.
The tumor temperature at the outside of the skin
continued to increase gradually over +451C, and in

some of the mice an obvious burn was observed on the

skin covering the tumor when AC magnetic eld
treatment was extended beyond 33 min, and therefore
the treatment was applied for 30 min in the following
experiments. In contrast, the temperature in the rectum
or in the tumor remained between +331C and +361C
without DF.
The tumor volume in each mouse of groups 1 and 2
steadily increased; in contrast, complete tumor regression was observed in some mice of 3 and 4 groups. In
most cases, in groups 3 and 4 the tumor volume
increased up to the 12th15th day, after which it began
to decrease and in some of group 4 mice disappeared
nally. Over a period of 3 months following complete
regression, no regrowth of tumor was observed. A spot
remained on the tumor place after regression.
At the application techniques of tumor hyperthermia
with water-ltered AC magnetic eld (0.88 MHz, 9.3 kA/
m, 0.15 kW), the temperatures at the outer skin covering
the tumor increased to about +441C, and was maintained with an accuracy of at least 711C. They
increased higher inside the tumor. The cells at these
areas would become necrotic. However, when AC
magnetic eld treatment was done three times, the
histological observations of tumor tissues containing
extra and intracellular DF particles showed that single
tumor cells in the peripheral area of tumors had
survived. Complete tumor regression was observed 5
weeks after the last AC magnetic eld treatment.
PMF DF targeting demonstrated signicant tumor
responses over 36 days in groups 3 and 4 compared to
the control (group 1) or to treatment with no PMF
targeting in group 2 (DF was given, but no PMF eld
was attached to the tumor, Fig. 1, Table 1).

tumor volume [mm3]

DF-water-based MFs and other physical, chemical and

biological characterizations of DF MFs determined are
presented in Refs. [3, 811].
To prepare tumor-bearing animals, mouse sarcoma
MX11 was implanted subcutaneously into the right
femoral region of 36 female C57Bl/6j mice, 69 weeks
old, by injection of 106 viable tumor cells in 0.05 ml of
saline, pH 7.4, according to the procedures [12]. These
mice were then separated into four equal groups. The
volume of each tumor was calculated as: V 0:5ln2 ;
where V is the tumor volume, l the length, and n2 the
width. The experiments were performed 69 days later
when tumor volumes were in the range from 21 to
30 mm3. Then 300 ml of DF MF (net g-Fe2O3 weight:
36 mg; pH 6.6; f +15 mV; M s 7.5 kA/m; SAR 210 W/g
Fe) was slowly injected into multiple tumor sites of mice
groups 24, and moreover in groups 3 and 4 injected
MFs were concentrated in the tumor tissue in an
inhomogeneous permanent magnetic eld (PMF) the
mice which were placed within 36 min in the center of
the permanent SmCo magnet (50  50  20 mm, 0.2 T
induction, 0.015 T/cm gradient). Interstitial concentration of DF was determined by the procedure [8]. The
rst mice group was control.
Administered in tumor tissues, DF mice of groups 24
were restrained in a non-conductive cover and placed in
glass water bolus [4] that was positioned inside the coil
(inner diameter: 60 mm; length: 200 mm), and the AC
magnetic eld generator was switch on. A continuous
water ow was maintained through the bolus by a ow
thermostat (temperature +361C). The hyperthermia
treatment was carried out for 30 min with 3 days
interval. Tumor and rectum temperature were measured
by electrical thermometer before and at once after the
AC magnetic eld treatment; the tumor temperature
measuring at the same time with the AC magnetic eld
treatment was done by alcohol thermometer that was
xed on the shaven skin covering the tumor. Statistical
analysis was done as described in Ref. [12].

379

treatment
start

45
40
35
30
25
20
15
10
5
0
0

treatment
finish

10 20 30 40 50 60 70 80 90
growth time [days]

group 1,

group 2,

group 3,

group 4

Fig. 1. Volume of mouse sarcoma MX11 after treatment by

intratumorally injected DF (group 2), after treatment with
injected and PMF DF targeted (groups 3 and 4) and in control
animals (group 1). Results represent the mean from four
independent experiments.

N.A. Brusentsov et al. / Journal of Magnetism and Magnetic Materials 252 (2002) 378380

380

Table 1
Antitumor effect of water-ltered AC magnetic eld treatment on solid MX11 sarcoma tissue that was formed subcutaneously over 36
days after the rst DF #363 MF injection and increase life span (ILS) of female C57Bl/6j mice
Group

Treatment time

Average tumor volume 7SD (mm3)

Relative tumor volume*

Complete regression (%)

(ILS) (%)

1
2
3
4

0
3
3
9

33 4207180
30 0517150
10 242763
9073

1.000
0.899
0.306
0.003

0
0
11
33

0
107
130
150

*Relative tumor volume=(average tumor volume of each group)/(average tumor volume of group 1).

Table 1 shows the average and relative tumor

volumes, ratios of complete regression on the 36th day
after the last DF injection and increase life span
(ILS). In group 2, the decrease of the average tumor
volume was not signicant, ILS107%. In the cases of
groups 3 and 4 the average tumor volumes decreased
markedly, ILS was 130% and 150%, accordingly
(P > 0:05). In one of the nine mice of group 3 and three
of the nine mice of group 4 complete regression was
observed.

4. Conclusions
Multiple injections of DF MF and PMF DF targeting
in tumor tissues with the following AC magnetic eld
treatment may be necessary in such a case, to achieve
tumor complete regression. The 30% rise of dextranferrite concentration in the tumor tissue, the 33%
complete tumor regression sarcoma MX11 and 150%
increase life span in female C57Bl/6j mice were
shown at the application of the developed DF MF
hyperthermia.

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