REACTIVE

&
FUNCTIONAL
Reactive & Functional Polymers 66 (2006) 944–951
POLYMERS
www.elsevier.com/locate/react

Preparation and characterization of magnetic

PLA–PEG composite nanoparticles for drug targeting
Jie Ren *, Haiyan Hong, Tianbin Ren, Xinrong Teng
Institute of Nano and Bio-Polymeric Materials, School of Material Science and Engineering, Tongji University,
1239 Siping Road, Shanghai 200092, People’s Republic of China

Received 20 June 2005; accepted 5 January 2006

Available online 20 February 2006

Abstract

A series of biodegradable block copolymers of poly-D,L-lactide-co-polyethylene glycol (PLA–PEG) was prepared by ring-
opening polymerization of D,L-lactide with stannous caprylate (Sn(Oct)2) as catalyst, then composite particles were prepared
using PLA–PEG copolymers and magnetic Fe3O4 by a phase separation method. The average molecular weight and structure
of PLA–PEG were determined by gel permeation chromatography (GPC), nuclear magnetic resonance (1H NMR) and dif-
ferential scanning calorimeter (DSC). The sizes and its distributions of the composite particles were investigated by laser par-
ticle size analyzer. The morphologies of prepared particles were observed by transmission electron microscopy (TEM). The
contents of Fe in the composite particles were determined by inductively coupled plasma-atomic emission spectrometry (ICP-
AES). The magnetic susceptibilities were measured by nephelometery. The magnetic particles prepared were spherical with
size range of 100–200 nm. The sizes of spheres were influenced by PLA, PEG chain length and block ratio. The magnetic prop-
erties of composite particles increased with increasing PEG chain length and PEG content. Particles with Fe content ranging
from 0.5% to 5.2% were prepared. The properties of magnetic composite particles were controlled by altering the block ratio
and the length of PLA–PEG copolymer to meet more requirements. The prepared Fe3O4/PLA–PEG particles with magnetic
properties and biodegradable properties would provide practical applications in drug targeting and controlled drug release.
Ó 2006 Published by Elsevier B.V.

Keywords: Poly-lactide-co-polyethylene glycol (PLA–PEG); Magnetic particle; Phase separation; Drug targeting

1. Introduction magnetic part and a polymer part. The magnetic

Magnetic polymer particles are a new type of
functional material that has been recently applied
to enzyme immobilization [1], drug targeting [2], cell
separation [3] and immunoassay [4], etc. The mag-
netic polymer particles are usually composed of a
*
Corresponding author. Tel./fax: +86 21 65989238.
E-mail address: renjie@mail.tongji.edu.cn (J. Ren).
part is often an inorganic magnetic nanoparticle,
such as Fe2O3, Fe3O4, etc. The polymer part, such
as polyethylene [5], polystyrene [6], poly(vinyl alco-
hol) [7], albumin [8], starch [9], chitosan [10], etc.
provides favorable function to magnetic particles.
The possible adverse effects of the presence in the
body of inorganic particles must be taken into con-
sideration. Experiments [11] performed in vivo on
the toxicity of magnetite and magnetic polymer par-
ticles have indicated that the latter have rather low

1381-5148/$ - see front matter Ó 2006 Published by Elsevier B.V.

doi:10.1016/j.reactfunctpolym.2006.01.002
 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951
toxicity, and magnetite itself has also little adverse
effects. Nevertheless, care must be taken with the
particle size and distribution of magnetic polymer
particles: any fraction of particles with sizes larger
than 5 lm must be avoided in order to prevent
forming capillary blocks. Small particles with nar-
row particle size distribution are required to make
targeting more efficient.
Many studies have described methods to prepare
particles containing inorganic magnetic nanoparti-
cles either by monomer polymerization methods:
emulsion polymerization [12], dispersion polymeri-
zation [13], suspension polymerization [14], micro-
emulsion polymerization [15] or by polymer hybrid
methods: emulsion technology [16] and solvent
evaporation [17].
Gómez-Lopera et al. [16] prepared mixed colloi-
dal particles (average diameter 0.16 ± 0.06 lm) with
approximately spherical geometry by double-emul-
sion technique. The particles were composed of a
magnetite nucleus and a biodegradable poly (D,L-lac-
tide). They found that the new synthetic material dis-
plays a behavior intermediate between that of
magnetite and that of poly (D,L-lactide) spheres. In
this paper, biodegradable PLA–PEG block copoly-
mers were used as magnetite carriers. And the mag-
netic Fe3O4/PLA–PEG composite particles were
prepared by a phase separation method, furthermore
adequate control of magnetic properties, such as
particle size and magnetic responsibility were studied
in this paper. This paper also deals with the synthesis
and characterization of PLA–PEG block copoly-
mers with different block ratios and different block
lengths synthesized by a ring-opening polymeriza-
tion of D,L-lactide and PEG. The structure of the
copolymer played an important role in the proper-
ties of the magnetic composite particles.
We attempted to control the properties of
magnetic composite particles by altering the block
ratio and length of PLA–PEG copolymer. The pre-
pared Fe3O4/PLA–PEG particles with magnetic
properties and biodegradable properties would pro-
vide useful applications in drug targeting and for
controlled drug release.
2. Experimental
2.1. Materials
Poly(ethylene glycol)s (PEGs) with weight aver-
age molecular weights (g mol1) of 2000, 4000,
6000, 8000, and 10,000 were used after being dried
945
under vacuum at 80 °C for over 10 h. D,L-lactide
was used after further purification. Fe3O4 with
particle size of 20-30 nm, which were provided by
Huaming group, Shanghai, China, were modified
by KH-570 (CH2@C(CH3)C(O)OCH2CH2CH2Si-
(OCH3)3). PEGs, Stannous caprylate (Sn(Oct)2),
acetone, ethyl acetate, n-heptane and other solvents
(analytical purity) were purchased from Shanghai
Chemical Industry (China).
2.2. Preparation of PLA–PEG block copolymers
Block copolymers were synthesized as described
in the following section, and copolymers obtained
are referred to as PLAx–PEGy (Table 1), where x
represents weight ratio of LA/PEG in the polymer-
ization, y represents weight averaged molecular
weight of PEG in kDa.
PLAx–PEGy was synthesized from D,L-lactide
and poly(ethylene glycol) of various molecular
weight using stannous caprylate as a catalyst. The
molecular weights of PEGs were 2000(PEG2),
4000(PEG4), 6000(PEG6), 8000(PEG8) and
10000(PEG10), respectively.
To obtain desired copolymers, D,L-lactide and
PEG were placed into an one-neck flask with a pre-
determined amount of stannous caprylate. Nitrogen
was directed through the reaction flask for 30 min
by a syringe. Then the flask was sealed and put into
a 120–130 °C oil bath for 8 h to react. The product
obtained was dissolved in ethyl acetate, then precip-
itated by n-heptane and finally washed with distilled
water, followed by drying in a vacuum oven at room
temperature for 4–5 days.
2.3. Preparation of magnetite/PLAx–PEGy
composite particles
The phase separation method was used for
preparation of magnetic PLA–PEG composite par-
ticles. In a typical procedure, 0.010 g Fe3O4 and
0.200 g PLA–PEG were dispersed in 20 ml acetone,
and a 50-kHz ultrasonic device (Branson, Ameri-
can) was used to make a good dispersion. Then
the well-dispersed suspension was dropped into
20 ml distilled water through a burette. Then the
resulting suspension was put into a ventilated cab-
inet to let acetone evaporate. After acetone was
completely evaporated, the suspension was centrif-
ugalized at 500 rpm for 5 min by a centrifuge, then
the well-distributed composite dispersion were
obtained.
946 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951

Table 1
Survey on the synthesis of PLA–PEG copolymer
PLAx–PEGy Weight average molecular LA/PEG (g/g) Mw Mn PI Block ratio M n
weight of PEG (PLA/PEG)
PLA2–PEG4 4000 2 10,137 7530 1.35 nd nd
PLA3–PEG4 4000 3 nd nd nd nd nd
PLA4–PEG4 4000 4 18,967 12,592 1.51 3.73 18,923
PLA5–PEG4 4000 5 17,646 11,271 1.57 4.59 22,366
PLA8–PEG4 4000 8 30,665 26,248 1.17 6.96 31,853
PLA10–PEG4 4000 10 33,387 18,818 1.77 9.26 41,045
PLA12–PEG4 4000 12 42,972 25,500 1.69 11.65 50,621
PLA15–PEG4 4000 15 nd nd nd 14.53 62,148
PLA5–PEG2 2000 5 14,625 11,263 1.30 nd nd
PLA5–PEG6 6000 5 45,681 28,912 1.58 nd nd
PLA5–PEG8 8000 5 48,105 31,600 1.52 nd nd
PLA5–PEG10 10,000 5 48,625 31,281 1.55 nd nd
x represents the weight ratio of LA/PEG in polymerization. y represents the weight averaged molecular weight of PEG in kDa. Weight
averaged molecular weight (Mw), number averaged molecular weight (Mn) and polydispersity indexes (PI = Mw/Mn) of the PLA–PEGs as
determined by GPC. The block ratio and number averaged molecular weight ðM n Þ of PLA–PEGs were calculated from 1H NMR data.
nd, not done.

2.4. Measurements volume of polystyrene standards with narrow

2.4.1. Nuclear magnetic resonance (1H NMR)
Chemical compositions of prepared PLA–PEG
multi-block copolymers and the block ratios of
PLA and PEG in multi-block copolymers were
characterized by 1H NMR. PLA–PEG copolymer
was dissolved in CDCl3 and 1H NMR spectra were
taken with trimethyl silane (TMS) as internal refer-
ence standard using a Bruker DMX500 spectrome-
ter (Bruker, Rheinstetten, Germany).
2.4.2. Differential scanning calorimetry (DSC)
To further analyze the structure of the copolymer
block, glass transition temperature (Tg) of the
copolymers was determined by DSC using a DSC
Q100 (TA, American). Polymer samples of
5-12 mg were taken for the determination. The ther-
mograms covered temperature range of 90–150 °C
in a nitrogen atmosphere at a 5° min1 heating rate.
2.4.3. Gel permeation chromatography (GPC)
Average molecular weight and its distribution of
the polymers were determined by GPC with a
Waters 150C GPC coupled with a Waters Differen-
tial Refractometer. Polymer samples were dissolved
in tetrahydrofuran (THF) (analytical purity) at a
concentration of 1–2 mg/ml. THF was eluted at
1.0 ml min1 through two Waters Styragel HT col-
umns and a linear column. The internal and column
temperatures were kept constant at 35 °C. The
molecular weights were calculated from the elution
molecular weight distributions.
2.4.4. Laser particle size analyzer
The particle sizes and its distributions of the pre-
pared magnetic composite particles were determined
by LS230 Laser particle analyzer (Coulter,
American).
2.4.5. Transmission electron microscopy (TEM)
TEM was used to investigate morphology of the
composite particles. The particles were dyed by 4%
(wt%) phosphotungstic acid. The morphology of
the prepared particles was examined using H-600
TEM (Hitachi, Tokyo, Japan).
2.4.6. Inductively coupled plasma-atomic emission
spectrometry (ICP-AES)
ICP-AES was used to determine Fe content in
the composite particles. The prepared well-dispersed
dispersion was accurately weighed and dried, and
then the copolymers were removed by HClO4. The
contents of Fe in the composite particles were deter-
mined by an IRIS Advantage 1000 ICP (Thermo
Jarrell Ash, American).
2.4.7. Nephelometery
The magnetic susceptibilities of the prepared com-
posite particles was analyzed by nephelometery
method in which the sedimentation ratio was used
to characterize the magnetic properties. The sedimen-
tation ratios (S) were calculated by absorbency of
 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951
sedimentation under natural condition (A0) and mag-
netic field (A) after 10 min (S = (A0  A)/A0). The
absorbency was measured by a U-1800 ultraviolet
spectrophotometer (HITACHI, Japan) at 800 nm.
3. Results and discussion
3.1. Composition of PLA–PEG copolymers
Table 1 is the summary of properties of the PLA–
PEGs synthesized. The PEG/LA weight ratio of
these polymers varies from 2 to 15. Fig. 1 shows
the 1H NMR spectrum of PEG4–PLA5, which is
representative for all synthesized PEG-PLAs. As
shown in the figure 1.56, 5.17 and 3.64 ppm can
be attributed to CH, CH3 at PLA blocks and CH2
at PEG blocks, respectively [18]. These signals can
be used to calculate the chain ratio of PLA to
PEG. The results of this analysis are summarized
in Table 1, which shows that the LA/PEG weight
ratio before copolymerization is similar to the
PLA/PEG ratio calculated by 1H NMR. The exis-
tence of a covalent bond between LA and PEG
block is evident from a low-intensity multiplet at
4.25 ppm representing methylene protons of the
acylated end unit of PEG chain (–CH2–O–CO–),
this shows that copolymerization of LA and PEG
really takes place. Furthermore, in Table 1 the
molecular weight data obtained from GPC analysis
are also included. The values of molecular weight
Fig. 1. 1H NMR spectrum of PLA5–PEG4.
947
obtained from GPC are in good agreement with
the results calculated from 1H NMR. These data
indicate the feasibility of preparing well defined
PLA–PEG block copolymer under controlled con-
ditions. It also can be seen from Table 1 that the
concentration and molecular weight of PEG affects
the copolymerization of LA and PEG significantly.
The molecular weight of PEG–PLA copolymers
increases with the increase of LA/PEG ratio and
PEG molecular weight. This must be attributed to
the fact that the –OH groups in PEG are involved
in chain transfer reactions. With higher LA/PEG
ratio, the content of –OH groups in polymerization
system is less, giving less chance to chain transfer
reaction. And for the PEG with higher molecular
weight, the –OH groups is also less, giving also less
chance to chain transfer reaction.
The quantitative evaluation of the thermal transi-
tions of PLA–PEG copolymers, such as the glass
transition can be made based on DSC. The shift
in the glass transition temperature of PLA–PEG
copolymers with different block ratio are found.
The signals for the glass transition appear in the
reversing heat flow signal on the DSC thermograms
as shown in Fig. 2. For all copolymers, the DSC fig-
ure only shows the single glass transition tempera-
ture, which further proves that the PLA–PEG
copolymers, not mixture of PLA and PEG homo-
polymer, were synthesized. This indicates that the
copolymers are well-distributed, with no significant
phase separation. The glass transition temperature
of PLA–PEGs is lower compared to pure PLA,
and it shifts to lower temperatures with increase of
Exothermic
PLA
PLA8-PEG4
PLA5-PEG4
PLA4-PEG4
PLA3-PEG4
-60 -40 -20 0 20 40 60
Temperature (°C)
Fig. 2. DSC thermograms of PLA–PEG copolymers.
948 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951
PEG content in copolymers. In a word, the DSC
analysis surely shows that there is a high degree of
phase mixing in the block copolymers.
3.2. Morphology
Fig. 3A shows the particle morphology of modi-
fied Fe3O4 by TEM. It is seen that the particles are
well dispersed with particle size about 20-30 nm.
The prepared magnetic particles are spherical with
a size range of 100–200 nm as shown in Fig. 3B.
The particles in Fig. 3B can be divided into three
kinds: PLA–PEG copolymer particles (white parti-
cles), PLA–PEG magnetic composite particles with
Fe3O4 adsorbed on the surface (black particles and
white particles circled by black ring) and enwrapped
PLA–PEG magnetic composite particles (black core
and white shell). Only a small amount of Fe3O4 par-
ticles were enwrapped in a PLA–PEG matrix. A
large amount of Fe3O4 might be adsorbed on the
surface of PLA–PEG matrix, which cannot be rec-
ognized in the TEM image because they have been
concealed by phosphotungstic acid. The mechanism
of formation of the magnetic nanoparticles is
thought to be something like this: As Fe3O4 was
modified by silicone coupling agent – KH-570, the
surface of Fe3O4 particles and KH-570 were cou-
pled by Si–O bond (formed by reaction of KH-570
with absorbed water on Fe3O4 surface). When the
copolymer – Fe3O4/acetone dispersion was added
to water, acetone mixes with water as it is miscible
with water and at the same time it evaporates.
Fig. 3. TEM photographs of magnetic particles.
Fe3O4 was adsorbed on the surface of copolymer
or enwrapped by copolymer. Because the prepared
composite dispersion shows good dispersibility, the
modified inorganic Fe3O4 particles and the copoly-
mer chain may be linked by some chemical bond
or physical interaction, such as the Van der Waals
force, polar interaction, etc.
3.3. Effect of LA/PEG feed ratio on the properties of
magnetic polymer composite particles
Copolymers of LA/PEG-4000 with different feed
ratio varying from 2 to 15 were used as matrix for
magnetite composite particles. The properties of
the magnetic copolymer composite particles, such
as particle size, Fe content and magnetic properties
were investigated. These properties are important
for the application as drug targeting particles. Figs.
4–6 show the effects of the LA/PEG ratio on the
particle size, Fe3O4 content and magnetic proper-
ties, respectively.
As shown in Fig. 4, the particle size of the pre-
pared magnetic particles increases with increase of
the LA/PEG ratio, which is due to the surface inter-
action between polymer and water. The decrease of
PEG content leads to decline in hydrophilicity,
which makes interfacial tension between polymer
and water increase, also particle sizes larger. Fig. 5
shows the Fe contents of particles with different
LA/PEG-4000 ratio. It can be seen that all the com-
posite particles with copolymers synthesized by
PEG-4000 have Fe content larger than 1.264%.
 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951 949

14
Fig. 6 shows that with increasing LA/PEG-4000
4:1
5:1
ratio from 2 to 15, the magnetic properties of the
12 composite particles weaken first, and when LA/
8:1
10 10:1 PEG-4000 ratio is larger than 8, the sedimentation
12:1
Number (%)

ratio remains constant. The magnetic property of

8
the Fe3O4 weakens when it is adsorbed or
6 enwrapped by copolymers. Copolymers with higher
4
LA/PEG-4000 ratio have larger molecular weights
that can give rise to improved conjunction to
2 Fe3O4 particles by causing adsorption or enwrap-
0 ping of large particles. These factors make the
0.1 1 decrease of magnetic property more remarkably.
Particle Diameter (μm) On the other hand, particles prepared by high LA/
Fig. 4. Effect of PLA/PEG ratio on particle size and size PEG-4000 ratio are larger. So they give less
distribution. response when magnetic field is applied.

3.4. Effect of molecular weight of PEG for

polymerization on the properties of magnetic polymer
2.0
composite particles
1.8
1.6
The molecular weight of PEG for the polymer-
1.4
Content of Fe (%)

izations affects the hydrophilicity of the prepared

1.2 copolymers, which is a parameter important to
1.0 copolymers as well as to magnetic particles.
0.8 Fig. 7 shows the effect of molecular weight of
0.6 PEG on the particle size of composite particles.
0.4 With increasing PEG molecular weight, particle
0.2 size of composite particles decreases. This can be
0.0 explained as discussed above. With fixed PLA/
1 2 3 4 5 11 12 13
PEG block ratio of 5:1, with increase of PEG
LA/PEG feed ratio in the polymerization of copolymer molecular weight the hydrophilicity of synthesized
Fig. 5. Effect of LA/PEG feed ratio on content of Fe in copolymer enhances, which leads to smaller inter-
composite particle. facial tension between polymer solution and water,
and give rise to smaller particle size. Fig. 8 shows

0.9

0.8 14
PEG-10000
0.7 12 PEG-8000
0.6 PEG-6000
Sedimentation ratio

10 PEG-4000
Number (%)

0.5 PEG-2000
8
0.4
6
0.3
4
0.2

0.1 2

0.0 0
0 2 4 6 8 10 12 14 16 0.1 1
LA/PEG4000 ratio Particle Diameter (μm)

Fig. 6. Sedimentation ratio of microspheres as a function of LA/ Fig. 7. Effect of PEG molecular weight on particle size and
PEG ratio. distribution.
950 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951

1.8 magnetic properties of composite particles do not

change significantly with Fe content.
1.6
To summarize briefly, the formation of particles
1.4 was influenced by the difference of hydrophilicity
between PEG chain and PLA chain. Stable disper-
Content of Fe (%)

1.2
1.0
0.8
0.6
0.4
0.2
0.0
4000 6000 8000
PEG molecular weight
Fig. 8. Effect of PEG molecular weight on content of Fe.
the effect of molecular weight of PEG on Fe
content. It can be seen that all the composite par-
ticles with copolymers synthesized with LA/PEG
of 5:1, have Fe content larger than 1.0%, and it
does not change linearly with the change of PEG
molecular weight. As shown in Fig. 9, the magnetic
property of the composite particles enhances
greatly when the PEG molecular weight increases
from 2000 to 6000. The weakening of magnetic
property may be dominantly attributed to the
hydrophobic block (i.e., PLA block) in copolymer.
Longer hydrophobic blocks lead to severe weaken-
ing of magnetic property. The Fe contents of all
composite particles show little difference, and the
sion cannot be formed with particles prepared by
pure PEG or PLA. With proper feed ratio of
PLA/PFG, small particles with strong magnetic sus-
ceptibilities were obtained.
3.5. Effect of copolymer concentration on the
properties of magnetic polymer composite particles
10000 Fig. 10 shows that the particle sizes of mag-
netic composite particles increase with increasing
polymer concentration. The high polymer concen-
tration gives rise to a high viscosity in the oil
phase, the high viscosity solution containing
Fe3O4 has more chances to the conglutination
between particles when they are dropped into
water, so larger particles are obtained. The Fe
content in composite particles decreases with
increasing polymer concentration as shown in
Fig. 11. In the experiment, when polymer concen-
tration is higher than 0.15 g/20 ml, the dispersion
is unstable, no particles but films were formed
after acetone is evaporated completely. The
magnetic properties of the composite particles
weaken with increasing polymer concentration as
shown in Fig. 12. Just as explained above, the
particle size determines the magnetic properties
of particles.

0.7

0.6 18
16 0.0649g/20ml
0.5 0.1009g/20ml
Sedimentation ratio

14 0.1522g/20ml
0.4 0.2045g/20ml
12
0.3029g/20ml
Number (%)

0.3 10
8
0.2
6
0.1 4

0.0 2
0
2 4 6 8 10 0.1 1
PEG molecular weight (x1000) Particle parameter (μm)
Fig. 9. Sedimentation ratio of microspheres as a function of PEG Fig. 10. Effect of polymer concentration on size and size
molecular weight. distribution.
 J. Ren et al. / Reactive & Functional Polymers 66 (2006) 944–951 951

6 separation method. The magnetic properties of

prepared composite particles are strengthened with
5 increasing PEG chain length and PEG ratio and
decreased with increasing polymer concentration.
Content of Fe (%)

4 The prepared Fe3O4/PEG–PLA nanoparticles with

magnetic properties and biodegradable properties
3 would provide useful application in drug targeting
and controlled drug release.
2

1
Acknowledgements

0 This work is supported by Development Founda-

0.05 0.10 0.20 0.25 tion of Science and Technology of Shanghai (No.
Polymer concentration (g/20ml) 002312024), Key Basic Research Foundation for
Development of Science and Technology of Shang-
Fig. 11. Effect of polymer concentration on content of Fe. hai (No. 05DJ14006), the Track Plan Project of Ris-
ing Star for Youthful Scholar of Shanghai (No.
04QMH1406) and the Project of Nano Science
and Technology of Shanghai (No. 0452nm059).
0.6
References
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