Surfaces and Interfaces 20 (2020) 100523

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Surfaces and Interfaces

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Design of polyester structure in amphiphilic copolymer coated on magnetite T

nanoparticle: Effect on loading and sustaining release of indomethacin
Sujittra Paenkaew, Supachai Mekkapat, Chatchai Bunthip, Nunthiya Deepuppha,
⁎
Boonjira Rutnakornpituk, Uthai Wichai, Metha Rutnakornpituk
Department of Chemistry and Center of Excellence in Biomaterials, Faculty of Science, Naresuan University, Phitsanulok, 65000, Thailand

A R T I C LE I N FO A B S T R A C T

Keywords: This works presented the surface modification of magnetite nanoparticles (MNPs) with the copolymers con-
Magnetite taining hydrophilic mPEG and hydrophobic polyester for use in drug controlled release applications. Polyester
Nanoparticle moieties in the copolymers were adsorbed on MNPs to form hydrophobic layer for entrapment of a hydrophobic
Amphiphilic indomethacin model drug, while hydrophilic mPEG provided their good water dispersibity. Three different
Polyester
polyester structures in the copolymer for MNP coating were; 1) saturated, 2) unsaturated and 3) crosslinked
Sustainable drug release
polyesters. The copolymer structures were characterized via 1H NMR and their coatings were confirmed by FTIR.
These water dispersible MNPs contained 53–61% copolymer in the complexes with the size ranging between 8
and 14 nm. The MNPs containing saturated polyester showed higher drug entrapment and loading efficiencies
than the other two samples. Interestingly, those containing crosslinked polyester exhibited a potential to sustain
the release of the entrapped drug. These complexes might be suitable for use as vehicles for entrapment of
hydrophobic drugs with tunable and controllable release rate.

1. Introduction amphiphilic polyester-containing copolymers such as poly(D,L-lactide-

The magnetic responsive ability of magnetite nanoparticles (MNPs)
with the use of external magnetic fields has recently attracted much
attention for use in various biomedical applications [1,2] such as hy-
perthermia [3,4] and targeted drug delivery [5] for cancer diagnosis/
treatment. These applications take advantages of specific properties of
MNPs in nanoscale including their easy surface modification, exotic and
superparamagnetic properties, nontoxic, biocompatibility and proces-
sability [6,7]. Particularly, the design of MNP surface with functional
polymers has been prevalently studied for the development in drug
delivery because coating MNPs with long chain polymers provided both
steric repulsion stabilization and decorating versatility with functional
groups on their surfaces [8–10]. Numerous methods have been used for
coating polymers on MNP surface such as “grafting to” [11], “grafting
from” [12,13], and emulsion [14,15], polymerizations as well as phy-
sical adsorption [16].
Interestingly, amphiphilic copolymers containing both hydrophilic
and hydrophobic blocks are especially of interest for applications in
drug delivery systems because they can molecularly self-assemble to
form polymeric micelles in a selective solvent [17–19]. Previous works
have presented the stabilization of MNPs with various types of
co-glycolide)-st-poly(ethylene glycol) (st-PLGA-PEG) copolymer [20],
poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA)
copolymer [21] and cholesterol-grafted poly(ethylene glycol) methyl
ether-Dlabile-poly(β-amino ester)-Dlabile-poly(ethylene glycol) methyl
ether (mPEG-Dlabile-PAE-g-Chol) [22], in an attempt to obtain dis-
persible MNPs in water and potential uses for drug delivery. In aqueous
system, hydrophobic drugs/molecules can hypothetically be embedded
into hydrophobic polyester layers through physical adsorption, while
hydrophilic moiety played a role in particle steric stabilization in water
[23]. Aliphatic polyesters considered as hydrophobic portion have been
generally prepared by two methods including the stepwise poly-
condensation and the ring-opening polymerization (ROP) of cyclic es-
ters [24]. Especially, the stepwise polycondensation has been mostly
used to prepare polyester from commercially available diol and di-
carboxylic acid compounds [25] to obtain degradable and biocompa-
tible polymers [26,27]. They can also be applied for hydrophobic drug
reservoirs and also enhance cytotoxicity and cell viability of the drug
[28,29].
This work focused in the design and synthesis of polyester-con-
taining copolymer for coating on MNP surface and its potential appli-
cations for sustainable drug release. The copolymers were synthesized

⁎
Corresponding author.
E-mail address: methar@nu.ac.th (M. Rutnakornpituk).

https://doi.org/10.1016/j.surfin.2020.100523
Received 6 December 2019; Received in revised form 17 March 2020; Accepted 2 April 2020
Available online 23 May 2020
2468-0230/ © 2020 Elsevier B.V. All rights reserved.
S. Paenkaew, et al. Surfaces and Interfaces 20 (2020) 100523

Fig. 1. Schematic illustration of MNPs coated with polyester-containing copolymers; (A) mPEG-saturated polyester-coated MNPs (“sat-coated MNPs”), (B) mPEG-
unsaturated polyester-coated MNPs (“unsat-coated MNPs”) and (C) mPEG-crosslinked polyester-coated MNPs (“crosslinked-coated MNPs”).

Fig. 2. Chemical structures of (A) mPEG-saturated polyester copolymer, (B) mPEG-unsaturated polyester copolymer and (C) mPEG-crosslinked polyester copolymer.

Fig. 3. 1H NMR spectra of (A) mPEG-saturated polyester copolymer and (B) mPEG-unsaturated polyester copolymer.

from the esterification of malonic acid, 1,6-hexane diol and mPEG with addition, the effect of polyester structures (saturated, unsaturated and
the molecular weight of 5000 g/mol [30]. Three types of the copoly- crosslinked structures) coated on the MNP surface on loading and en-
mers used in this work included mPEG-saturated polyester copolymer, trapment efficiencies as well as releasing behavior of entrapped in-
mPEG-unsaturated polyester copolymer and mPEG-crosslinked polye- domethacin was investigated.
ster copolymer (Fig. 1). They were synthesized using a well-designed
strategy to gain those with hydrophilic mPEG block and hydrophobic
polyester block. Polyester parts can hypothetically be adsorbed on MNP
surface, while hydrophilic mPEG moiety can serve as a stabilized outer
layer to render good dispersibility for MNPs in aqueous media. In

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S. Paenkaew, et al. Surfaces and Interfaces 20 (2020) 100523

Fig. 4. FTIR spectra of (A) sat-coated MNPs, (B) unsat-coated MNPs and (C) crosslinked-coated MNPs.

Fig. 5. TEM images of (A) sat-coated MNPs, (B) unsat-coated MNPs, (C) crosslinked-coated MNPs and (D) a representative TEM image of unsat-coated MNPs showing
the formation of nanoclusters.

Table 1 2. Experimental
Dh of the copolymers, the copolymer-coated MNPs and drug-loaded copolymer-
coated MNPs in water. 2.1. Materials
Dh (nm)
(Types of mPEG-polyester copolymers used) mPEG with the molecular weight of 5000 g/mol (Acros) was dried
saturated Unsaturated crosslinked in vacuo before used. Iron(III) chloride anhydrous (FeCl3, Carlo Erba),
iron(II) chloride tetrahydrate (FeCl2•4H2O, Carlo Erba), ammonium
Copolymer solutions in watera 263 ± 4 289 ± 5 –
Copolymer-coated MNPsb 215 ± 3 211 ± 3 168 ± 2 hydroxide (NH4OH, 28–30%, J.T. Baker), oleic acid (Fluka), malonic
Drug-loaded copolymer-coated 182 ± 4 172 ± 4 121 ± 1 acid (99%, Acros), 1,6-hexane diol (99%, Acros) and maleic acid (99%,
MNPsc Acros) were used without purification. Potassium persulfate (KPS,
a
K2S2O8) was kept in a dessicator until used.
0.1 mg/ml of the copolymers was used for PCS measurements.
b
The samples were dialyzed before the measurements.
c
The samples were centrifuged to remove aggregated drugs before the
measurements.

Fig. 6. TGA thermograms of bare MNPs (black), oleic acid-coated MNPs (red), sat-coated MNPs (blue), unsat-coated MNPs (green) and crosslinked-coated MNPs
(orange).

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S. Paenkaew, et al. Surfaces and Interfaces 20 (2020) 100523

Table 2
The percentages of each composition calculated from TG.
Weight remaining (wt Percentages in the complexes (wt
%)a %)d
Fe3O4b Oleic acid Copolymer

Bare particle 93 100 – –

Oleic acid-coated 66 71c 29c –
MNPs
Sat-coated MNPs 31 33 14 53
Unsat-coated MNPs 27 29 12 59
Crosslinked-coated 26 28 11 61
MNPs

a
Assuming that the weight remaining was the weight percentage of iron
oxide from oxidized MNPs at 600 °C.
b
Assuming that all iron oxides were in Fe3O4 form at room temperature and
percent Fe3O4 was the percent weight remaining normalized with 0.93 (%wt Fig. 8. M-H curves of (a) bare MNPs, (b) sat-coated MNPs, (c) unsat-coated
remaining of bare MNPs). MNPs and (d) crosslinked-coated MNPs showing their magnetic responsiveness
c
Ratio of Fe3O4 to oleic acid was 2.4:1. properties.
d
Total compositions of all components in the complexes was 100%.

Fig. 9. Stability of sat-coated MNPs (⬛), unsat-coated MNPs (⬛) and cross-
linked-coated MNPs (⬜) in water at room temperature.

under reduced pressure for 18 h to continuously remove water. Upon

cool down, the mixture was repeatedly extracted with diethyl ether to
neutralize the product, dried with anh.MgSO4 and evaporated to re-
move the solvent until dryness. According to the endgroup analysis via
1
H NMR, the molecular weights of the copolymers were ca.6,700 g/mol
[28]. The unsaturated copolymer was prepared using a similar proce-
dure with the use of 5 mol% of unsaturated diacid (5% maleic acid and
95% malonic acid) in transesterification.

2.2.2. Synthesis of MNPs coated with the copolymers containing saturated-,

Fig. 7. XRD patterns of (A) sat-coated MNPs, (B) unsat-coated MNPs and (C)
crosslinked-coated MNPs and (D) an XRD pattern from the standard Fe3O4
powder diffraction data.
2.2. Syntheses
2.2.1. Synthesis of mPEG-saturated polyester copolymer and mPEG-
unsaturated polyester copolymer
mPEG (10.00 g, 2 mmol), malonic acid (4.78 g, 46 mol), 1,6-hex-
anediol (5.20 g, 44 mmol) and sulfuric acid (0.5 M, 0.50 ml) were
mixed in a reaction flask. The reaction temperature was set at 180 °C
unsaturated- and crosslinked polyesters
Synthesis of oleic acid-coated MNPs has been previously reported
[28]. Briefly, an iron(III) chloride solution (1.66 g in 20 ml DI water)
and an iron(II) chloride solution (1.00 g in 20 ml DI water) were stirred
and added with 25% NH4OH (20 ml) to form an MNP aqueous dis-
persion. After centrifugation, an oleic acid solution (2.0 ml in 20 ml
hexane) was mixed with the particle dispersions to form an oleic acid-
coated MNP. Oleic acid-coated MNP dispersion (1.0 ml) was added into
2% of mPEG-saturated polyester copolymer or mPEG-unsaturated
polyester copolymer in water (10 ml). They were sonicated for 4 h and
then centrifuged to remove large aggregate. The copolymer-coated
MNPs in aqueous phase were dialyzed against DI water and refreshed
repeatedly to remove excess copolymers. To prepare the MNPs coated
with crosslinked polyester, a certain amount of KPS was added to the
dispersions of the MNPs coated with mPEG-unsaturated polyester co-
polymer during the drug loading process. The crosslinking reaction was
accomplished at 60 °C for 4 h under N2 atmosphere.

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S. Paenkaew, et al. Surfaces and Interfaces 20 (2020) 100523

Fig. 10. (A) Drug entrapment efficiency (%EE) and (B) drug loading efficiency (%DLE) of copolymer-coated MNPs.

Fig. 11. (A) Indomethacin-release profiles of (a) sat-coated MNPs, (b) unsat-coated MNPs and (c) crosslinked-coated MNPs, and (B) proposed released behavior of
entrapped indomethacin from copolymer-coated MNPs.

2.3. Characterization sample magnetometer (VSM, a Standard 7403Series, Lakeshore vi-

The copolymers were characterized via proton nuclear magnetic
resonance spectroscopy (1H NMR, a 400 MHz Bruker NMR spectro-
meter using CDCl3 as a solvent). MNPs were characterized using fourier
transform infrared spectroscopy (FTIR, Perkin-Elmer Model 1600 Series
FTIR Spectrophotometer), thermogravimetric analysis (TGA, SDTA 851
Mettler-Toledo at a heating rate of 20 °C/min under air atmosphere),
transmission electron microscope (TEM, a Philips Tecnai 12 operated at
120 kV equipped with a Gatan model 782 CCD camera) and vibrating
brating sample magnetometer). Hydrodynamic diameter (Dh) of MNPs
and the copolymer were measured via photon correlation spectroscopy
(PCS, NanoZS4700 nanoseries Malvern instrument). They were redis-
persed by an ultrasound bath (S 70 H elmasonic) without filtration
before each measurement and separated using a permanent magnet. X-
ray diffraction (XRD) patterns were obtained on Phillips X'pert X-ray
diffractometer using Cu-Kα radiation (λ=1.540598 angstrom) oper-
ated at 30 kV).

5
S. Paenkaew, et al.
2.4. Studies in indomethacin entrapment, loading efficiencies and releasing
behavior of the copolymer-coated MNPs
The indomethacin solution (1 ml, 100 ppm in THF) was slowly
dropped into copolymer-coated MNP dispersion (6 ml) and stirred for
30 min in an attempt to embed indomethacin into the hydrophobic
polyester coated on the MNPs. The indomethacin-entrapped MNPs were
separated out from the mixture by a permanent magnet and then wa-
shed with water. To study the indomethacin entrapment and loading
efficiencies, the drug entrapped in the particles was repeatedly ex-
tracted in an EtOH/THF solution (1:1 v/v) and then centrifuged to
discard aggregated MNPs. After determining amounts of drug in the
supernatant via UV/Vis spectrophotometry, drug loading efficiency (%
DLE) and entrapment efficiency (%EE) were calculated from the fol-
lowing equations:
Drug loading efficiency (%DLE)
Weight of the entrappeddruginnanoparticles
= x100
Weightofmagnetitenanoparticles
Entrapment efficiency (%EE)
Weightoftheentrappeddruginnanoparticles
= x100
Weightoftheloadeddrug
To investigate in vitro release of the entrapped indomethacin in
copolymer-coated MNPs, the MNP dispersions (5 ml) loaded in a dia-
lysis membrane bag were immerged in phosphate buffer (pH 7.45,
300 ml) and then continuously stirred at room temperature. During the
experiment, aliquot solutions (5 ml) were withdrawn from the release
media at the predestined time interval and then refilled with fresh
phosphate buffer (5 ml) in the mixture. After the MNPs were separated
by a permanent magnet, the amounts of the released drug in the su-
pernatants were determined via UV/Vis spectrophotometry at 320 nm
wavelength.
3. Results and discussion
The originality of this study was that we here demonstrated a design
of polyester-containing copolymer coated on MNP surface for sus-
taining the release of an indomethacin model drug. Hypothetically,
hydrophobic indomethacin was partially partitioned in the hydro-
phobic polyester on MNP surface, whereas hydrophilic mPEG offered
steric repulsion stabilization and good water dispersibility to the par-
ticles. It was interesting to investigate the influence of saturated and
unsaturated polyesters in the copolymer structure on the drug entrap-
ment and loading efficiencies of the particles. Crosslinked structure of
the unsaturated polyester was anticipated to sustain the release of the
entrapped drug from the particle surface. Three types of mPEG-polye-
ster copolymers used in this work were based on the copolymer syn-
thesized from malonic acid, 1,6-hexanediol and mPEG [28] (Fig. 2).
MNPs coated with saturated polyester copolymer was designated as
“sat-coated MNPs”, while the particles coated with the unsaturated
polyester copolymer (5% maleic acid and 95% malonic acid in the
polyester structure) was designated as “unsat-coated MNPs” (Fig. 1).
The unsaturated polyester moiety on the particle surface can be radi-
cally crosslinked; the particles were thus designated as “crosslinked-
coated MNPs”.
3.1. Characterization of mPEG-polyester copolymers and copolymer-coated
MNPs
1
H NMR spectra of mPEG-saturated polyester copolymers and
mPEG-unsaturated polyester copolymer are shown in Fig. 3. The ex-
istence of ester linkages was evidenced by the signal at δ 4.13 ppm
(signal a) of methylene protons next to the ester linkages. In the spec-
trum of mPEG-unsaturated polyester copolymer, the weak signal at δ
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Surfaces and Interfaces 20 (2020) 100523
6.27 ppm (signal f) corresponding to the vinylic protons indicated the
presence of 2% of unsaturated moiety in the copolymer. An expanded
1
H NMR spectrum of mPEG-unsaturated polyester copolymer is shown
in Figure A1 in Appendix.
The as-synthesized mPEG-polyester copolymers, both saturated and
unsaturated ones, were then used as steric stabilizers for MNPs to ob-
tain sat-coated MNPs and unsat-coated MNPs and the unsaturated
moiety in the unsaturated polyester can be chemically crosslinked to
obtain crosslinked-coated MNPs. FTIR spectra of these three types of
the particles showed the signals of carbonyl groups of esters at
1729–1724 cm−1 and Fe-O bond of MNP at 558 cm−1 (Fig. 4).
Fig. 5 showed representative TEM images of sat-coated MNPs,
unsat-coated MNPs and crosslinked-coated MNPs. They showed the
averaged particle size of 10 nm in the range of 8–14 nm in diameter.
After crosslinking, the particles remained good dispersibility in water
without noticeable aggregation. According to PCS measurements, Dh of
the copolymers (without MNP) in water was in the range of
263–289 nm and this was attributed to the size of amphiphilic copo-
lymer aggregated in water (Table 1). Interestingly, after coating MNPs
with the copolymers, their Dh (168 and 215 nm) seemed to be smaller
than those of the copolymers in water probably owing to the formation
of MNP nanoclusters. The existence of MNP nanoclusters was also ob-
served in TEM experiments (Fig. 5D). It should be noticed that Dh of
crosslinked-coated MNPs (168 nm) was smaller than those of the other
two complexes. This was probably due to the contraction of the cross-
linked structure of the copolymers, resulting in the decrease in Dh of the
complexes. Upon loading indomethacin into the complexes, their Dh
decreased as compared to the ones before drug loading. This was
probably owing to the enhancement of the structural contraction upon
addition of the hydrophobic drug into the complexes.
Percent compositions of the copolymers and MNPs in these three
samples were determined via TGA. According to the results in Fig. 6, the
residual weight corresponded to the iron oxide completely oxidized at
600 °C, while the observed loss weight corresponded to the degraded
organic and volatile contents. Bare MNPs showed a slight weight loss at
200–230 °C with 93 wt% remaining of the oxidized iron; the percent
residual weight of other compositions was thus normalized with 0.93
(Table 2). To calculate the percentage of oleic acid in each composition,
the ratio of MNPs to oleic acid in oleic-coated MNPs was calculated and
then this ratio was applied to estimate the percentage of oleic acid in
other compositions (an example of the calculations was shown in Ap-
pendix). Sat-coated MNPs exhibited a consistent weight loss in the
range of 130–550 °C due to the decomposition of organic contents (e.g.
oleic acid and the copolymers) presenting on the MNP surface. Unsat-
coated MNPs and crosslinked-coated MNPs showed an initial weight
loss ranging from 100 to 200 °C attributed to the degradation of maleic
contents in the complex. Their second major weight loss (ca.
250–350 °C) was due to oleic acid remaining in the complexes, which
were also observable in the same range as those of oleic acid-coated
MNPs. The weight loss at high temperature ranging between 370 and
470 °C was attributed to the decomposition of mPEG in the copolymer.
The crystal structures of all MNP samples were studied by XRD
analysis with the comparison with the standard Fe3O4 powder diffrac-
tion data obtained from Hailstone, R., Rochester Institute of
Technology, NY, USA (Fig. 7). Due to the presence of Fe3O4 core, all
samples showed the similar patterns of Fe3O4 crystals with the relative
intensities and positions that matched well with the characteristic peaks
of the standard Fe3O4 crystals (2θ = 30.2, 35.4, 43.2, 53.6, 57.2, 62.8,
71.3, 74.4, 79.2°).
3.2. Determination of magnetic properties of copolymer–coated MNPs via
VSM
According to M-H curves shown in Fig. 8, saturation magnetization
values (Ms) of bare MNPs was 70 emu/g, and those of the MNPs coated
with the polymers ranged between 50–64 emu/g (Fig. 8). The decrease
S. Paenkaew, et al.
of the Ms values of these three samples as compared to bare MNPs was
attributed to the presence of the non-magnetic polymers on the particle
surface. Although the Ms values slightly dropped, they still well re-
sponded to an external permanent magnet (Figure A2 in Appendix).
3.3. Effect of the polyester structure on stability of MNPs in water
The concentrations of MNPs remaining in aqueous dispersions after
settling for four weeks were investigated to study their stability in water
(Fig. 9). The initial concentrations of the dispersible particles in water
were strongly dependent on the structure of polyesters in the copoly-
mers. In general, the concentrations of MNPs in water decreased about
10–35% in the first week and continuously dropped to remain about
50% after four weeks, depending on the types of the copolymers used.
The dispersions containing high MNP concentrations exhibited high
tendency of particle aggregation (about 35% particle aggregation in the
first week) due to the close proximity of each particle in the dispersions,
resulting in a significant drop of the percentage of the particles. The
dispersions with diluted particle concentrations showed a good stability
in water with less than 10% of particle aggregation after one week.
However, about 50% of particle aggregation was observed after four
weeks upon their preparation, indicating that these particles might be
suitable for short-term uses.
3.4. Indomethacin entrapment and loading efficiencies and the releasing
behavior of copolymer-coated MNPs
Indomethacin was used as a model drug in this work because it can
somewhat diffuse to the hydrophobic polyester layer of the complexes
in the aqueous media.%EE in these three samples ranged between 48
and 82% (48–82 mg indomethacin entrapped/100 mg indomethacin
loaded), while%DLE ranged between 61 and 97% (610–970 µg/1 mg
MNP used) (Fig. 10). It was interesting that both%EE and%DLE of sat-
coated MNPs were significantly higher than those of unsat-coated
MNPs. The lower values of%EE and%DLE in unsat-coated MNPs were
attributed to the relatively high polarity of double bonds in unsaturated
polyester. Due to its poor solubility in water (0.937 mg/L at 25 °C)
[31–32], indomethacin was more preferable to be entrapped in hy-
drophobic or non-polar portion than in hydrophilic moiety [33]. Thus,
in the present work, hydrophobic indomethacin should somewhat be
partitioned in sat-coated MNPs more than in unsat-coated MNPs. To
verify this rationale, the partition coefficients (Kow) of mPEG-saturated
polyester copolymer and mPEG-unsaturated polyester copolymer were
determined. Kow is defined as a concentration ratio of a sample in two
immiscible solvents, in the present work, hexane and water [34]. A high
Kow value of a sample implies that it tends to be more preferable in
organic environment (nonpolar) than in water (polar). In other words,
the sample with high Kow signifies its less polarity than the one having
high Kow. It was found that Kow of mPEG-saturated polyester was
0.11 ± 0.04 and Kow of mPEG-unsaturated polyester was 0.05 ± 0.01,
signifying that mPEG-saturated polyester copolymer has lower polarity
than those of the unsaturated one. This result indicated that the dif-
ference in polarity of the copolymers coated on MNPs might play an
important role in the indomethacin entrapment and loading effi-
ciencies.
Interestingly,%EE and%DLE in the case of crosslinked-coated MNPs
showed higher values than those of unsat-coated MNPs (before cross-
linking reaction). It should be noted that the drug loading process was
carried out prior to the crosslinking step; the drug might be entrapped
in the network structure during the crosslinking, resulting in the in-
crease in the drug loading and entrapment efficiencies (Fig. 10).
However, the entrapped drug might be somewhat locked in the network
as indicated by the less drug release (Fig. 11) discussed in the later
section.
Releasing behavior of indomethacin entrapped in copolymer-coated
MNPs was investigated in phosphate buffer solution (PBS). Suspension
7
Surfaces and Interfaces 20 (2020) 100523
of the MNPs in water was dialyzed against PBS releasing media with pH
7.4. The concentrations of indomethacin released were analyzed at a
given time until the release percentages reached their equilibriums. The
percentages of the drug release at equilibrium of sat- and unsat-coated
MNPs were 88% and 62%, respectively (Fig. 11A). These two samples
reached their equilibriums within 3 h of dialysis, whereas that of
crosslinked-coated MNPs was ca. 8 h of dialysis, implying that cross-
linking of the polyester layer was able to sustain the release of the
entrapped drug from the particles (Fig. 11B). Its low percent drug re-
lease at equilibrium (45%) was again attributed to the crosslinked
structure of polyester, which might somewhat inhibit the release effi-
ciency of the entrapped drug.
4. Conclusions
MNPs were surface modified with the copolymers containing hy-
drophobic polyester and hydrophilic mPEG to gain the particles with a
rapid magnetic separation and good water dispersibility for use in drug
sustainable release applications. Unsat-coated MNPs showed lower%EE
and%DLE than those of sat-coated and crosslinked-coated MNPs, in-
dicating that the structural design of the polymers can influence their
drug entrapment and loading efficiencies. In addition, crosslinked-
coated MNPs exhibited a potential to sustain the release of the en-
trapped drug. Hence, these complexes might be used as a platform for
embedding other hydrophobic drugs and modified to obtain desirable
releasing properties.
Declaration of Competing Interest
The authors declare no competing financial interest.
Acknowledgement
The authors acknowledge the financial support from the Thailand
Research Fund (TRF) (RSA6280048) and the Research, Development
and Engineering (RD&E) fund through the National Nanotechnology
Center (NANOTEC), The National Science and Technology
Development Agency (NSTDA), Thailand (Project P-10-10816) to
Naresuan University. SP thanks the Royal Golden Jubilee PhD Program
(PhD/0210/2556) for the scholarship.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.surfin.2020.100523.
References
[1] X. Zhang, X. Zhang, S. Wang, M. Liu, L. Tao, Y. Wei, Surfactant modification of
aggregation-induced emission material as biocompatible nanoparticles: facile pre-
paration and cell imaging, Nanoscale 5 (2013) 147–150 https://doi.org/10.1039/
c2nr32698a.
[2] X. Zhang, X. Zhang, L. Tao, Z. Chi, J. Xub, Y. Wei, Aggregation induced emission-
based fluorescent nanoparticles: fabrication methodologies and biomedical appli-
cations, J. Mater. Chem. B. 2 (2014) 4398–4414 https://doi.org/10.1039/
C4TB00291A.
[3] G. Kandasamy, A. Sudame, T. Luthra, K. Saini, D. Maity, Functionalized hydrophilic
superparamagnetic iron oxide nanoparticles for magnetic fluid hyperthermia ap-
plication in liver cancer treatment, ACS Omega 3 (2018) 3991–4005 https://doi.
org/10.1021/acsomega.b00207.
[4] Z. Shen, X. Chen, Iron oxide nanoparticle based contrast agents for magnetic re-
sonance imaging, Mol. Pharmaceutics. 14 (2017) 1352–1364 https://doi.org/10.
1016/j.jmbbm.2017.10.015.
[5] B. Shen, Y. Ma, S. Yu, C. Ji, Smart multifunctional magnetic nanoparticle-based
drug delivery system for cancer thermo-chemotherapy and intracellular imaging,
ACS Appl. Mater. Interfaces. 8 (2016) 24502–24508 https://doi.org/10.1021/
acsami.6b09772.
[6] P. Tartaj, M.P. Morales, T.G. Carreno, S.V. Verdaguer, et al., Biomedical applica-
tions of magnetic nanoparticles, in: K.H. Jürgen Buschow, R.W. Cahn,
M.C. Flemings, B. Ilschner, E.J. Kramer, S. Mahajan, et al. (Eds.), Encyclopedia of
materials: Science and Technology, Elsevier Inc., 2007, pp. 1–7 https://doi.org/10.
S. Paenkaew, et al.
1016/B978-0-12-803581-8.02251-7.
[7] E.M. Denkba¸ E. Celik, E. Erdal, D. Kavaz, O. Akbal, G. Kara, C. Bayram,
Magnetically based nanocarriers in drug delivery, in: A.M. Grumezescu (Ed.),
Nanobiomaterials in Drug Delivery, Elsevier Inc., 2016, pp. 285–331 https://doi.
org/10.1016/B978-0-323-42866-8.00009-5.
[8] S.P. Hooshyar, R.Z. Mehrabian, H.A. Panahi, M.H. Jouybari, H. Jalilian, Synthesis
and characterization of magnetized- PEGylated dendrimer anchored to thermo-
sensitive polymer for letrozole drug delivery, Colloid. Surface. B. 176 (2019)
404–411 https://doi.org/10.1016/j.colsurfb.2019.01.014.
[9] S. Paenkaew, M. Rutnakornpituk, Effect of alkyl chain lengths on the assemblies of
magnetic nanoparticles coated with multi-functional thiolactone-containing copo-
lymer, J. Nanopart. Res. 20 (2018) 193–205 https://doi.org/10.1007/s11051-018-
4295-2.
[10] A. Gupta, A. Ahmad, H. Singh, S. Kaur, N.K. M, M.M. Ansari, G. Jayamurugan,
R. Khan, Nanocarrier composed of magnetite core coated with three polymeric
shells mediates LCS-1 delivery for synthetic lethal therapy of BLM-defective col-
orectal cancer cells, Biomacromolecules 19 (2018) 803–815 https://doi.org/10.
1021/acs.biomac.7b01607.
[11] M. Banaei, M.S. Kalajahi, A “Grafting to” approach to synthesize low cytotoxic poly
(aminoamide)-dendrimer-grafted Fe3O4 magnetic nanoparticles, Adv. Polym. Tech.
37 (2018) 21741–21747 https://doi.org/10.1002/adv.21741.
[12] E. Naeemikhah, A.A. khaneghah, A. Heydari, H. Behniafar, Magnetic crosslinked
polyester with hydrophilic nature prepared through surface-initiated ATRP tech-
nique, Colloid. Surface. A. 582 (2019) 123866–123873 https://doi.org/10.1016/j.
colsurfa.2019.123866.
[13] M. Kampferbeck, T. Vossmeyer, H. Weller, Cross-linked polystyrene shells grown on
iron oxide nanoparticles via surface-grafted AGET−ATRP in microemulsion,
Langmuir 35 (2019) 8790–8798 https://doi.org/10.1021/acs.langmuir.9b01060.
[14] H.S. Chae, S.H. Piao, W.J. Han, H.J. Choi, Core/shell polystyrene/magnetite hybrid
nanoparticles fabricated by pickering emulsion polymerization and their magne-
torheological response, Macromol. Chem. Phys. 219 (2018) 1700408–1700415
https://doi.org/10.1002/macp.201700408.
[15] A. Mahdieh, A.R. Mahdavian, H.S. Mobarakeh, Chemical modification of magnetite
nanoparticles and preparation of acrylic-base magnetic nanocomposite particles via
miniemulsion polymerization, J. Magn. Magn. Mater. 426 (2017) 230–238 http://
dx.doi.org/10.1016/j.jmmm.2016.11.091.
[16] I.S. Unver, Z. Durmus, Magnetic and microwave absorption properties of magnetite
(Fe3O4)@conducting polymer (PANI, PPY, PT) composites, IEEE. T. Magn. 53
(2017) 2001708-2001716 http://dx.doi.org/10.1109/TMAG.2017.2716349.
[17] P. Ni, F.N. Jones, S. Fu, Synthesis of amphiphilic copolymers based on acrylates by
free-radical polymerization and their application in alkyd emulsions, J.M.S.-Pure.
Appl. Chem. 37 (2000) 1391–1406 http://dx.doi.org/10.1081/MA-100101161.
[18] P. Alexandridis, Amphiphilic copolymers and their applications, Curr. Opin.
Colloid. In. 1 (1996) 490–501 https://doi.org/10.1016/S1359-0294(96)80118-X.
[19] S. Imai, M. Takenaka, M. Sawamoto, T. Terashima, Self-sorting of amphiphilic co-
polymers for self-assembled materials in water: polymers can recognize themselves,
J. Am. Chem. Soc. 141 (2019) 511–519 http://dx.doi.org/10.1021/jacs.8b11364.
[20] G. Ma, C. Zhang, L. Zhang, H. Sun, C. Song, C. Wang, D. Kong, Doxorubicin-loaded
micelles based on multiarm star-shaped PLGA–PEG block copolymers: influence of
arm numbers on drug delivery, J. Mater. Sci: Mater. Med. 27 (2016) 17–32 https://
Surfaces and Interfaces 20 (2020) 100523
doi.org/10.1007/s10856-015-5610-4.
[21] H. Danafar, K. Rostamizadeh, S. Davaran, M. Hamidi, Drug-conjugated
PLA–PEG–PLA copolymers: a novel approach for controlled delivery of hydrophilic
drugs by micelle formation, Pharm. Dev. Technol. 22 (2017) 947–957 https://doi.
org/10.3109/10837450.2015.1125920.
[22] M. Xu, C.Y. Zhang, J. Wu, H. Zhou, R. Bai, Z. Shen, F. Deng, Y. Liu, J. Liu, PEG-
detachable polymeric micelles self-assembled from amphiphilic copolymers for
tumor-acidity-triggered drug delivery and controlled release, ACS Appl. Mater.
Interfaces. 11 (2019) 5701–5713 https://doi.org/10.1021/acsami.8b13059.
[23] S. Meerod, G. Tumcharern, U. Wichai, M. Rutnakornpituk, Magnetite nanoparticles
stabilized with polymeric bilayer of poly(ethylene glycol) methyl ether-poly(ɛ-ca-
prolactone) copolymers, Polymer 49 (2008) 3950–3956 https://doi.org/10.1016/j.
polymer.2008.07.003.
[24] O.D. Cabaret, B.M. Vaca, D. Bourissou, Controlled ring-opening polymerization of
lactide and glycolide, Chem. Rev. 104 (2004) 6147–6176 https://doi.org/10.1021/
cr040002s.
[25] T. Karthik, R. Rathinamoorthy, Sustainable synthetic fibre production, in:
S.S Muthu (Ed.), Sustainable Fibres and Textiles, Elsevier Inc., 2017, pp. 191–240
https://doi.org/10.1016/B978-0-08-102041-8.00008-1.
[26] M. Vert, Aliphatic polyesters: great degradable polymers that cannot do everything,
Biomacromolecules 6 (2005) 538–546 https://doi.org/10.1021/bm0494702.
[27] Y. Qin, A Brief Description of Textile fibers, Medical textile Materials, Elsevier Inc.,
2016, pp. 23–42 https://doi.org/10.1016/B978-0-08-100618-4.00003-0.
[28] B. Yameen, C. Vilos, W. Cho, A. Whyte, J. Huang, L. Pollit, O.C. Farokhzad, Drug
delivery nanocarriers from a fully degradable PEG conjugated polyester with a
reduction-responsive backbone, Chem. Eur. J. 21 (2015) 11325–11329 https://doi.
org/10.1002/chem.201502233.
[29] Y.Y. Li, X.Z. Zhang, H. Cheng, G.C. Kim, S.X. Cheng, R.X. Zhuo, Novel stimuli-
responsive micelle self-assembled from Y-shaped P(UA-Y-NIPAAm) copolymer for
drug delivery, Biomacromolecules 7 (2016) 2956–2960 https://doi.org/10.1021/
bm060080k.
[30] S. Mekkapat, B. Thong-On, B. Rutnakornpituk, U. Wichai, M. Rutnakornpituk,
Magnetic core–bilayer shell complex of magnetite nanoparticle stabilized with
mPEG–polyester amphiphilic block copolymer, J. Nanopart. Res. 15 (2013)
2051–2063 https://doi.org/10.1007/s11051-013-2051-1.
[31] S.H. Yalkowsky, R.M. Dannenfelser, Aquasol Database of Aqueous Solubility,
College of Pharmacy, University of Arizona-Tucson, AZ, 1992 Version 5PC Version.
[32] J.T. Rubino, J. Swarbrick, J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical
Technology, 3 Marcel Dekker, Inc., New York, 1988, https://doi.org/10.1081/E-
EPT-120041601.
[33] S.Y. Kim, I.G. Shin, Y.M. Lee, C.S. Cho, Y.K. Sung, Methoxy poly(ethylene glycol)
and ε-caprolactone amphiphilic block copolymeric micelle containing
indomethacin.II. Micelle formation and drug release behaviours, J. Control. Release
51 (1998) 13–22 https://doi.org/10.1016/S0168-3659(97)00124-7.
[34] S.J. Hayward, Y.D. Lei, F. Wania, Comparative evaluation of three high perfor-
mance liquid chromatography–based Kow estimation methods for highly hydro-
phobic organic compounds: polybrominated diphenyl ethers and hex-
abromocyclododecane, Environ. Toxicol. Chem. 25 (2016) 2018–2027 https://doi.
org/10.1897/05-675R.1.