International Journal of Biological Macromolecules 168 (2021) 722–732

Contents lists available at ScienceDirect

International Journal of Biological Macromolecules

journal homepage: http://www.elsevier.com/locate/ijbiomac

Xyloglucan-based hybrid nanocomposite with potential for

biomedical applications
Aiêrta Cristina Carrá da Silva a, Raimundo Rafael de Almeida b, Alexandre Carreira da Cruz Sousa a,c,
Fabián Nicolás Araneda Martínez d, Juliano Casagrande Denardin d,
Selene Maia de Morais e, Nágila Maria Pontes Silva Ricardo a,⁎
a
Laboratory of Polymers and Materials Innovation, Department of Organic and Inorganic Chemistry, Sciences Center, Federal University of Ceará, Campus of Pici, Zip Code 60440-760 Fortaleza,
CE, Brazil
b
Federal Institute of Education, Science and Technology of Ceará, Campus Camocim, Camocim, CE Zip Code 62400-000, Brazil
c
Federal Institute of Education, Science and Technology of Ceará, Campus Quixadá, Quixadá, CE, Zip Code 63902-580, Brazil
d
Department of Physics, University of Santiago and Cedenna, USACH-CEDENNA, Santiago Zip Code 9170124, Chile
e
Laboratory of Natural Products, Science and Technology Center, Ceará State University, Campus of Itaperi, Zip Code 60714-903 Fortaleza, CE, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Natural polymer-based hybrid nanocomposites have been proposed as one of the most promising tools for bio-
Received 24 July 2020 medical applications, including disease treatment and diagnosis procedures. Xyloglucan nanocapsules can simul-
Received in revised form 19 October 2020 taneously load magnetic iron oxide nanoparticles and bioactive for a specific tissue, reducing the processes of
Accepted 18 November 2020
degradation and metabolic inactivation of molecules with biological activity. In this work, magnetic nanocapsules
Available online 21 November 2020
of xyloglucan loaded with hydrophilic sulfated quercetin (MNXQ_SO3) were successfully synthesized by inverse
Keywords:
miniemulsion process through interfacial polymerization. The polymeric shell formation of nanocapsules was ev-
Magnetic nanocapsules of xyloglucan idenced by Fourier Transform Infrared spectroscopy and Transmission Electron Microscopy. The ferrofluid
Targeted drug delivery (Fe3O4@PAAS) incorporated into the xyloglucan nanocapsules was synthesized by hydrothermal method,
Biomedical applications using polyacrylic acid sodium salt as coating. Dynamic Light Scattering technique confirmed the nanomeric di-
mensions (202.3 nm) and the good colloidal stability (−40.2 mV) of MNXQ_SO3. The saturation magnetization
analyses pointed out the superparamagnetic behavior of Fe3O4@PAAS (48 emu/g) and MNXQ_SO3 (4.2 emu/g).
MNXQ_SO3 was able to modify the release profile of sulfated quercetin (67%) when compared to the free bioac-
tive (100%), exhibiting a release profile compatible with the zero-order kinetic model. The results showed that
the development of MNXQ_SO3 presents a new perspective for biomedical applications, including studies of
targeted drug delivery.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction ferrofluid with superparamagnetic behavior, which can be employed

Nowadays, many researchers use nanotechnology to try to develop
novel nanocarriers that are selective drug delivery systems [1]. The
drug encapsulation process promotes the protection of the bioactive
from degradation in vivo, which allows its specific targeting to the dis-
eased tissue [2]. Additionally, the incorporation of superparamagnetic
iron oxide nanoparticles (SPIONs) in these drug delivery systems, espe-
cially magnetite (Fe3O4), has been an alternative to obtain nanosystems
able to be guided by an external magnetic field to specific tissue [3,4].
The literature reports that polyacrylic acid sodium salt (PAAS) cov-
ered of magnetite nanoparticles (Fe3O4@PAAS) produces an aqueous
⁎ Corresponding author.
E-mail address: naricard@ufc.br (N.M.P.S. Ricardo).
in biomedical applications [5]. The coating improves the dispersion
and chemical stability of magnetic nanoparticles, avoids its aggregation
and air oxidation, preventing the loss of magnetic properties [6,7].
Currently, the FDA (Food and Drug Administration) already ap-
proved the use of magnetite (Fe3O4) as iron deficiency therapeutics
(Feraheme®) and as magnetic resonance imaging (MRI) contrast
agents (Feridex® and Gastromark®) [6]. Thus, the SPIONs and its asso-
ciation between drug delivery systems allows their use in many
theranostic applications, including trigger-controlled drug release and
magnetic hyperthermia for cancer treatment [8].
In recent years, the scientific community has dispensed attention in
publications about the magnetic loading in polymeric nanocontainers.
In this context, there are nanocapsules, which can be based on biocom-
patible polymers and emerge as an excellent nanocarrier for the admin-
istration of chemotherapeutic drugs [4]. The nanocapsules have a

https://doi.org/10.1016/j.ijbiomac.2020.11.128
0141-8130/© 2020 Elsevier B.V. All rights reserved.
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al.
polymeric shell, a hydrophilic or hydrophobic core and can be obtained
for many procedures. However, the interfacial polymerization is usually
employed for the preparation of aqueous core nanocapsules through in-
verse miniemulsion technique [9].
The use of natural polymers (polysaccharides) on drug delivery sys-
tems often occurs because they are biodegradable, biocompatible,
widely available, nontoxic and flexible to chemical modification [10].
In this research field, some authors published relevant works about
drug delivery vehicles based on polysaccharides, such as gum arabic,
chitosan, and maltodextrin for curcumin delivery [11]; salecan for doxo-
rubicin delivery [12]; the self-assembly of anionic (salecan) and cationic
(chitosan) polysaccharides into polyelectrolyte complex for release of
vitamim C [13] and green tea polyphenols [14].
In this sense, xyloglucan is also a natural polymer obtained from
tamarind (Tamarindus indica Linn.) seeds, a typical plant of tropical
region, which has been cultivated in Brazilian Northeast since the last
century. This polysaccharide is a neutral hemicellulose and contains a
β-(1 → 4)-linked D-glucan backbone chain, which is partly substituted
at O-6 position of D-glucopyranosyl residues with α-D-xylopyranose
or with 2-O-β-D-galactopyranosyl-α-D-xylopyranose [15,16]. Due to
its mucoadhesive and in situ gelling properties, xyloglucan has been re-
ported as an attractive and functional natural polymer in drug delivery
assays [10].
Xyloglucan has been widely employed in the pharmaceutical field,
including the investigation of drug delivery via nasal, ocular, pulmonary,
rectal and oral administration. Recently, a collection of works was pub-
lished about drug delivery systems based on xyloglucan, including
thermosensitive and thermoreversible in situ gel, nanoaggregates, nano-
spheres, films, tablets, patches, gel and hydrogel for biomedical applica-
tions [17]. Therefore, this polysaccharide presents a great versatility and
should be studied by the academy community. However, until now, no
polymeric nanocapsules based on xyloglucan have been synthesized.
Among many bioactives, there is quercetin (3,3′,4′,5′-7-penta-hy-
droxy-flavone), a flavonoid obtained from fruits and vegetables, which
presents many biological properties, including antiviral, antioxidant, an-
tibacterial, gastroprotective, anti-inflammatory and anti-carcinogenic
activities. This polyphenol (C15H10O7, 302.2 g/ mol) is a yellow solid,
which has a hydrophobic character with aqueous solubility of 0.5 g L−1
at 25 °C [18–20]. Thus, quercetin presents a low biodisponibility and
after its oral consumption, quercetin undergoes significant presystemic
elimination, which blocks its use as chemotherapeutic agent. In addition,
quercetin showed in vitro toxic effects on normal human cell lines.
Therefore, many synthetic compounds have been investigated in order
to develop a new quercetin derivative that also has similar biological
properties to the original molecule and be able to replace this chemo-
therapeutic bioactive. The literature reports that hydrophilic quercetin
sulfate is one of the candidates to replace quercetin [21].
In the present study, we describe the synthesis by inverse
miniemulsion of novel magnetic hybrid nanocomposites based on
xyloglucan loaded with Fe3O4@PAAS and hydrophilic quercetin, which
was used as drug-model for the release study of this bioactive. In this
work we developed nanocarriers from natural and renewable sources,
which represents new perspectives for biomedical applications.
2. Materials and methods
2.1. Materials
Ethanol (97%), acetone (99.5%), diethyl ether (98%), cyclohexane
(99%), N,N-dimethylformamide (99%) and sodium acetate (99%) were
purchased from Synth® and used as received. Ammonium hydroxide
(28–30% of ammonia) was acquired from Vetec®. Iron (II) chloride
tetra-hydrate (FeCl2·4H2O, ≥99.0%), iron (III) chloride hexa-hydrate
(FeCl3·6H2O, ≥99.0%) and isopropyl alcohol (99.5%) were purchased
from Sigma-Aldrich®. Sulfur trioxide pyridine complex (98%), tolylene-
2,4-diisocyanate (TDI), (95%), sodium dodecyl sulfate (99%), phosphate
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International Journal of Biological Macromolecules 168 (2021) 722–732
buffered saline (PBS, pH 7.4), deuterium oxide (99.9 atom % D) and poly-
acrylic acid sodium salt (PAAS) were obtained from Aldrich® and were
used as received. Polyglycerol polyricinoleate (Grindsted® PGPR super)
was donated from DuPont Danisco® (Brazil) and quercetin was acquired
from PVP-Anonymous Society (Brazil). Distilled and ultrapure water
(produced by Milli-Q Advantage A-10 system, Millipore®) were used
in this research. Seeds of tamarind (Tamarindus indica L.) were obtained
from fruit pulp acquired at the local market. All the solvents and reagents
were analytical grade and used directly without further purification.
2.2. Experimental
2.2.1. Extraction and molar mass determination of Tamarindus indica Linn.
xyloglucan
The seeds of tamarind fruit were manually separated from pulp,
washed with running water and stirred (400 rpm) with distilled
water at 100 °C during 30 min for enzyme inactivation and softening
of the seeds coats. After the separation of the cotyledons from seeds cov-
ering, tamarind kernels were frozen at −20 °C and dried using a freeze
dryer (Model Martin Christ Alpha 1–2 LDplus) under the follow condi-
tions: pressure of 0.12 mbar and condenser temperature at −55 °C for
48 h. Xyloglucan was obtained through exhaustive aqueous extraction
of tamarind kernels, which was performed to the previously reported
method [22].
The aqueous xyloglucan solution was exposed to the same afore-
mentioned freeze drying process and the sample yield was calculated
and characterized by Nuclear Magnetic Resonance spectroscopy. Ther-
mal analysis was evaluated. The molar mass was estimated by Gel
Permeation Chromatography (GPC), using a Shimadzu LC-10AD chro-
matograph with a refractive index detector (Model RID-10A) at 40 °C.
The chromatograph was equipped with an Ultrahydrogel linear column
(7.8 mm × 300 mm) and used a flow rate of 1 mL/min. The analysis was
carried out with 20 μL of polysaccharide solution 0.1% (w/v), dissolved
in ultrapure water, and 0.1 mol/L of sodium nitrate was used as eluent
[23]. All the solutions were filtered in cellulose acetate membranes
(Sigma-Aldrich, St. Louis, USA). A calibration curve of Pullulan was
used as standard, with different molecular weights (range: 5.9 × 103 a
7.88 × 105 g/mol). The equation obtained from this calibration plot
was: log Mw = 13.677–0.954 Ve, where Ve was the elution volume in
mL. The linear correlation coefficient was 0.99.
2.2.2. Synthesis and characterization of hydrophilic quercetin sulfate
(Q_SO3)
Hydrophilic quercetin sulfate was obtained from adapted method by
Nair & Bernstein, 1983 [24]. Briefly, 1.22 g of quercetin was stirred
(350 rpm) in 20 mL of N,N-dimethylformamide and 3.34 g of sulfur tri-
oxide pyridine complex was added at 65–70 °C for 5 h. The solution was
cooled at room temperature and isopropyl alcohol was placed to form a
brown precipitate which was separated by centrifugation. The brown
solid was washed with diethyl ether and dried using a desiccator.
Then the precipitate was dissolved in deionized water with 10 mL of so-
dium acetate 30% (w/v) using a magnetic stirring for 20 min. Finally,
100 mL of isopropyl alcohol was added to separate the solid by decanta-
tion. The mixture was filtered, and the precipitate was washed with
diethyl ether again and dried. Then, Q_SO3 was analyzed by Fourier
Transform Infrared spectroscopy and Thermogravimetry.
2.2.3. Synthesis of magnetic nanocapsules based on xyloglucan loaded with
hydrophilic quercetin sulfate (MNXQ_SO3)
The sample (MNXQ_SO3) was prepared in a water-in-oil
miniemulsion system similarly to the method previously reported by
Kang et al. [1]. The aqueous phase was formed by 4 mL of an aqueous so-
lution of xyloglucan 1% (w/v) containing 20 mg of Q_SO3 and 12 mg of
superparamagnetic nanoparticles (Fe3O4@PAAS). The organic phase
contained 14.5 g of cyclohexane with a varying amounts of polyglycerol
polyricinoleate (100, 120 or 160 mg) as surfactant and TDI (42.5 or
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al.
Table 1
Experimental formulations for the synthesis of MNXQ_SO3 sample.
Sample Organic phase
PGPR (mg) TDI (mg)
S1 100 80
S2 120 80
S3 160 80
S4 100 42.5
S5 120 42.5
S6 160 42.5
80 mg) as crosslinker agent. Table 1 shows the composition of the or-
ganic phase, which forms the samples S1–S6.
Initially, 8.0 g of organic phase was homogenized with the aqueous
phase using a Benchmark™ vortex mixer (Model BV-1000). Then, this
pre-emulsion was sonicated in an ultrasound (Branson Sonifier W-
450-Digital and a 1/2″ tip) at 70% amplitude for 3 min with a pulse of
20 s on and 10 s off (cooling the mixture with an ice bath). Afterwards,
4.5 g of organic phase was mixed with the miniemulsion again and
placed at the ultrasound under the same conditions as for the last
step. Then, tolylene-2,4-diisocyanate was added (42.5 or 80 mg) in 2 g
of the oil phase and dripped slowly into the sample (Table 1). The inter-
facial polymerization was carried out at 25 °C for 24 h, using a mechan-
ical stirring (Model RW 20 digital, IKA®) at 450 rpm. Finally, a
purification process was carried out: the MNXQ_SO3 nanocapsules dis-
persion in cyclohexane were centrifuged at 4000 rpm for 20 min, and
the precipitate was redispersed in the same amount of fresh cyclohex-
ane. Afterwards, it was homogenized by vortex. This procedure was re-
peated three times. After drying, 2 mg of these samples (S1–S6, Table 1)
were investigated by Fourier Transform Infrared spectroscopy to con-
firm the crosslinking reaction.
To obtain the MNXQ_SO3 aqueous samples from S1 to S6, the puri-
fied nanocapsules dispersion in cyclohexane was added dropwise into
sodium dodecyl sulfate solution 0.1% (w/v) using a sonication bath
(Quimis®, Q335D) during 4 min. This dispersion was mechanical stirred
(450 rpm) overnight, in an open vial, to allow evaporation of cyclohex-
ane. The aqueous samples were analyzed by Dynamic light scattering
(DLS) technique.
After analyzing these data, the most appropriate formulation was
used to continue this research. The selection of the best sample was
based on three parameters: the colloidal stability and the average parti-
cle size, which should be compatible with nanocarriers for biomedical
applications, as well as the Fourier Transform Infrared spectroscopy
analysis, that was performed to assess the interfacial polymerization re-
action. Then the purified nanocapsules dispersion in cyclohexane was
analyzed by Transmission electron microscopy. Thermal Analysis and
Magnetic properties were performed using the powder obtained from
drying the nanocapsules dispersion in cyclohexane.
The magnetic nanoparticles (Fe3O4@PAAS) used in this procedure
were synthesized using a hydrothermal method [25] and were investi-
gated by Transmission electron microscopy, Thermogravimetry, X-ray
powder diffraction and Magnetic properties.
2.3. General characterization procedures
2.3.1. Nuclear magnetic resonance (NMR) spectroscopy
The Nuclear magnetic ressonance (NMR) spectrum of the
xyloglucan sample was recorded in a 600 MHz Agilent DD2 spectrome-
ter equipped with an inverse detection 5-mm One-Probe (H-F/15N-31P)
and Z-gradient coils. Xyloglucan was prepared by dissolving 10 mg of
the material in 600 μL of D2O (deuterium oxide). For 1H NMR analysis
was applied 32 scans, 32 k of points in the time dominium with a spec-
tral window of 16.0 ppm, an acquisition time of 3.328 s and the time be-
tween each acquisition was 10 s. The 13C NMR spectrum was recorded
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International Journal of Biological Macromolecules 168 (2021) 722–732
with 13 k transients, spectral window of 251.3 ppm, an acquisition
time of 0.865 s and a time between each acquisition of 1 s [26].
2.3.2. Infrared spectroscopy
The Fourier Transform Infrared spectra (FT-IR) were obtained with
Shimadzu IRTracer-100 Spectrophotometer (Model 8300) using KBr
pellets in the wave number range of 400 and 4000 cm−1 [27]. The sam-
ples spectra were recorded from 100 scans.
2.3.3. Dynamic light scattering (DLS) technique
The polydispersity index (PdI), particle size and zeta potential of
the sample were investigated using a Zetasizer Nano Series Malvern
W-ZS90. The samples were diluted 50 times with ultrapure water
and analyzed in an optical grade polystyrene cuvette at 25 °C [28].
The intensity-weighted hydrodynamic diameters and z-average
were based on three measurements, each one originated from 11
scans.
2.3.4. Transmission electron microscopy (TEM)
Transmission electron microscopy (TEM) images of MNXQ_SO3
sample (cyclohexane) were obtained using a Hitachi®HT7700 TEM sys-
tem operating at an accelerating voltage of 120 kV. In order to perform
the TEM investigation, the sample was prepared according to the meth-
odology previously reported [29].
2.3.5. Thermal analysis
The thermal properties of the samples were evaluated by
thermogravimetry analysis (TGA). TGA analysis were conducted on a Si-
multaneous Thermal Analyzer (PerkinElmer, Model STA 6000) instru-
ment, using nitrogen atmosphere with flow of 50 mL/min, heating
rate of 10 °C/min and temperature range of 25–800 °C [26].
2.3.6. X-ray powder diffraction (XRD)
X-ray patterns diffraction of the synthesized sample was collected
using a PANalytical (X'pert Pro MPD) X-ray powder diffractometer op-
erating in Bragg-Brentano reflection geometry with Co-Kα radiation
(40 Kv, 40 mA) over the range 20° < 2θ < 100° and scan speed of
0.013°/s [3].
2.3.7. Magnetic properties
The magnetic behavior of the samples was evaluated using a home-
made vibrating sample magnetometer (VSM) at 300 K in the magnetic
field range from −10 to 10 kOe [3]. In order to assure the magnetic mo-
ments values acquired, the equipment was previously calibrated using a
standard reference material (yttrium Iron Garnet Sphere) from the Na-
tional Institute of Standards and Technology (NIST). For all measure-
ments, the magnetic moment obtained for each applied field was
normalized by the mass of the samples.
2.4. Release study and encapsulation efficiency of hydrophilic quercetin
sulfate
The release profile of quercetin sulfate into magnetic xyloglucan
nanocapsules was investigated using a previously reported methodol-
ogy [3]. The experiment was conducted at 37 °C and the donor compart-
ment of the system contained 1.5 mL of MNXQ_SO3 sample
(0.333 mg/mL of sulfate quercetin), furthermore the acceptor compart-
ment was prepared with 50 mL of PBS (pH 7.4). The release assay was
also carried out with an aqueous solution of active ([Q_SO3] =
0.333 mg/mL), which was placed in the donor compartment (1.5 mL)
for data comparison. Aliquots (2 mL) were collected after 30 min of ex-
periment and at intervals of 1 h for the first 8 h of assay. Then, more al-
iquots were collected each 24 h until completing 48 h of experiment.
The resulting aliquots were analyzed using a UV–Vis Spectrophotome-
ter (ThermoScientific®, model: Genesis 10S) at 265 nm. The cumulative
percentage of dissolved Q_SO3 was calculated using a regression
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al.
equation generated from the standard data. Usually, the most important
mechanisms for the transport of drugs or bioactives from polymeric ma-
trices are diffusion, erosion and degradation. However, the in vitro data
dissolution was fitted to the more important mathematical models
(zero and first order, Higuchi and Korsmeyer-Peppas, which were de-
fined for Eqs. (1)–(4), respectively) to evaluate the kinetic mechanism
of quercetin sulfate release in the MNXQ_SO3.
Zero Order Model : Q t ¼ Kt
First Order Model : ln Q t ¼ Kt
Higguchi Model : Q t ¼ Kt1=2
Korsmeyer−Peppas : Q t ¼ Ktn
where Qt is the amount of drug/bioactive released at time t; K is the
release constant for the corresponding kinetic model and n is the re-
lease exponent that specifies the drug/bioactive release. The litera-
ture reports that the mechanism of release in Higguchi Model
involves a diffusion process (Fickian Model), while the mechanism
of release for Korsmeyer-Peppas Model can occur by diffusion, when
n = 0.5; by anomalous transport (Non Fickian Model, which presents
both process: diffusion and polymeric chain relaxation), when
0.5 < n < 1.0; and by case-II transport, when n = 1.0, indicating that
the mechanism of release is purely controlled by the polymeric chain
relaxation [3,30–32].
The MNXQ_SO3 formulation was subjected to the magnetic separa-
tion for determination of the free bioactive compound amount [3]. The
aqueous fraction without magnetic properties was analyzed by UV–
Vis spectrometry (265 nm). The Q_SO3 entrapped in the sample was
Fig. 1. 1H NMR spectrum of T. indica xyloglucan.
International Journal of Biological Macromolecules 168 (2021) 722–732
determined by the difference between the initial amount of bioactive
added to the MNXQ_SO3 formulation and the free amount observed.
In this way, the encapsulation efficiency (%EE) was determined through
the following equation:
%EE ¼ ½ðB−AÞ=B  100
ð1Þ where:
ð2Þ A = free amount of bioactive in MNXQ_SO3
B = initial amount of bioactive in MNXQ_SO3
ð3Þ
3. Results and discussion
ð4Þ
3.1. Extraction and characterization of Tamarindus indica L. xyloglucan
Xyloglucan was efficiently obtained with extracted yield of 43.11 wt
% (based on the dry cotyledon mass of T. indica seeds). The yield values
reported in the literature for xyloglucan of T. indica range from 10.1 to
50% [15,33–35].
The GPC chromatogram for xyloglucan of T. indica is shown in Fig. S1
(Appendix A – Supplementary data). The number average molecular
weight (Mn) was 233 kDa, average molecular weight (Mw) was
1227 kDa, higher average molecular weight (Mz) was 4362 kDa and
polydispersity index was 5.26. The value of Mw for the xyloglucan sam-
ple was similar to other researches published in the literature.
Periasamy et al. (2018) obtained xyloglucan of kernel powder from
T. indica seeds with high molecular weight (Mw = 1331 kDa). This
value depends on the source and on the extraction method of polysac-
charide [31].
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A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al. International Journal of Biological Macromolecules 168 (2021) 722–732

Fig. 2. 13C NMR spectrum of T. indica xyloglucan.

The 1H NMR (Fig. 1) and 13C NMR (Fig. 2) analyses were performed
to investigate the xyloglucan structure of T. indica. The 1H spectrum
shows signals of β-D-glucopyranosyl (Glu) residues at 3.42 ppm and
three signals in the anomeric region: at 5.13 ppm, which is compatible
with 2-linked α-D-xylopyranosyl residues (Xyl 1); at 4.95 ppm corre-
sponds to the terminal α-D-xylopyranosyl units (Xyl 2) and at
4.57 ppm refers to an overlapped of β-glucopyranosyl and β-
galactopyranosyl residues [15,31,33–36]. The ratio of the carbohydrate
residues for xyloglucan sample is calculated by the relative areas of
the signal 1H (Glu), 1H (Gal) and 1H(Xyl), resulting in a molar ratio of
3:1:2 for the xyloglucan monomer Glu:Gal:Xyl [32]. As illustrated by
Fig. 1, the area under glucose (Glu), galactose ([Glu + Gal] – Glu) and
xylose (Xyl 1 + Xyl 2) provides a ratio of 2.83:0.95:1.99. These results
are in accordance with other works previously published [33,37,38].
As verified in Fig. 2, the signals at 104.95, 102.93, 99.66 and
99.41 ppm of xyloglucan 13C NMR spectrum correspond to the anomeric
carbons of β-D-galactopyranose (Gal), β-D-glucopyranose (Glu), and α-
D-xylopyranose (Xyl 2 and Xyl 1), respectively. The signal at 60.57 is
assigned to C-6 units of free β-D-galactopyranoses and the signal at
61.71 ppm corresponds to C-5 of α-D-xylopyranose [39,40].
The nanocapsule size of the samples measured by DLS is in the range
of 202.3 to 552.0 nm. The literature reports that some parameters must
be within a range to be compatible with nanocarriers for biomedical
purposes. For example, zeta potential of dispersions above −30 mV
was considered to have good colloidal stability, while the PdI can
range from 0 (monodisperse) to 1 (polydisperse) [41]. Moreover, the
average particle size of nanocapsules must be in the range of 50 to
500 nm [29].
It can be seen through Table 2 that the samples S1, S3 and S6 showed
an average particle size and a good colloidal stability compatible with
the literature data. Therefore, the samples mentioned above were sub-
jected to FT-IR analysis.
The FT-IR analysis was performed to assess the crosslinking reaction.
The absence of the band in 2275 cm−1 indicates that all the crosslinking
agent was consumed during the reaction of nanocapsules surface for-
mation [42]. Furthermore, a better biocompatibility of the final
nanocapsules depends on reducing the amount of excess TDI [29].
Fig. 3 shows the FT-IR spectra from the samples S1, S3 and S6.
Through Fig. 3 it was possible to verify that only the sample S6 did
not present the band in 2275 cm−1. This means that all crosslinker

Table 2
3.2. General characterization procedures Obtained results of average size, zeta potential and polydispersity index.

3.2.1. Influence of surfactant (PGPR) and crosslinker agent (TDI) amounts Samplea Average particle size (nm) Zeta potential (mV) PdI

in the formulation obtained for MNXQ_SO3 samples (S1–S6) S1 422.7 −32.5 0.254
At this stage, the amounts of PGPR and TDI were varied (100, 120 or S2 552.0 −14.1 0.374
S3 515.5 −37.5 0.474
160 mg and 42.5 or 80 mg, respectively) to investigate and obtain the
S4 359.7 −23.3 0.348
most appropriated formulation of MNXQ_SO3. The synthesized S5 497.2 −12.4 0.596
nanocapsules in aqueous dispersion (SDS 0.1%) were characterized by S6 202.3 −40.2 0.417
DLS to determine the average nanocapsule size, the surface charge a
Samples S1, S2 and S3 were synthesized using: 80 mg of TDI; 100, 120 and 160 mg of
(zeta potential) and the size distribution values (polydispersity index PGPR, respectively. Samples S4, S5 and S6 were synthesized using: 42.5 mg of TDI; 100,
– PdI). These results are presented in Table 2. 120 and 160 mg of PGPR, respectively.

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A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al.
Fig. 3. FT-IR spectra obtained of the samples from optimization study.
agent was consumed during the polymerization process. However, only
the sample S6 was selected to proceed with the experiments. Thus, the
sample S6 was called of MNXQ_SO3 and was subjected to more
characterizations.
3.2.2. Infrared spectroscopy
FT-IR analysis of MNXQ_SO3 (Fig. 4a) was recorded to investigate the
shell composition of nanocapsules and to confirm the chemical reaction
between NCO groups of TDI with OH groups from xyloglucan and surfac-
tant molecules. The effectiveness interfacial polymerization was evalu-
ated by crosslinked of xyloglucan nanocapsules, resulting on the
presence of urea and urethane groups. Bands at 1734 cm−1 (C_O vibra-
tion) and 1544 cm−1 (N\\H vibration) evidence the formation of ure-
thane groups. Furthermore, the band at 1645 cm−1 represents C_O
vibration of urea formed through the reaction between isocyanate with
water. The absence at 2275 cm−1 indicates that all crosslinker isocyanate
(NCO) was consumed [9,42]. A strong band at 3400 cm−1 is characteris-
tic of an oxygen-bonded O\\H stretching vibration. Other bands are also
expected in this spectral region (valence vibrations of N\\H and C\\H at
3300 and 3000 cm−1, respectively), but probably are overlapped by the
O\\H vibration band. The literature reports the presence of a band at
1600 cm−1 which refers to C_C vibration valence from aromatic sys-
tems [29]. Furthermore, it is possible to see a band around 584 cm−1,
also present in Fe3O4@PAAS spectrum (Fig. 4b), which refers to Fe\\O vi-
bration of the magnetite (Fe3O4) formation, probably indicating that
magnetite was incorporated into nanocapsule sample [5].
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International Journal of Biological Macromolecules 168 (2021) 722–732
Fig. 4b also shows infrared bands of Fe3O4@PAAS sample, which can
be assigned to the presence of polyacrylate sodium salt on the surface of
Fe3O4 (1400 and 1550 cm−1 represent symmetric and asymmetric
stretch of COO−, respectively; 1450 cm−1 is designated for bending vi-
bration of C\\H and 1650 cm−1 refers to C_O stretching vibration of
carboxylate) [5].
The FT-IR spectrum of xyloglucan (Fig. 4c) is in good agreement with
the one reported in the literature. The absorption at 3408 and
2922 cm−1 is assigned for stretching vibrations of O\\H and C\\H, re-
spectively [34]. Bands at region spectral between 1600 and 800 cm−1
exhibit highly coupled C–C–O, C–O–C and C–OH stretching modes of
polymer backbone [32]. The band at 1039 cm−1 is reported for C\\H
bond of the anomeric carbon (C1) and at 896 cm−1 indicates the α-
bond between D-xylopyranose units [43].
As shown in Fig. 4d, the FT-IR spectrum of Q_SO3 illustrates three
bands, which refer to the asymmetric stretching vibration of the S_O
bond (1050, 1144 and 1248 cm−1), indicating that the sulfated deriva-
tive of quercetin was successfully synthesized. These results are similar
to those published in the literature [44].
3.2.3. Dynamic light scattering (DLS) and transmission electron
microscopy (TEM)
The average particle size (202.3 ± 2.3 nm) and polydispersity index
(0.417 ± 0.045) of MNXQ_SO3 were obtained by DLS analysis. Recently,
gelatin capsules loaded with an aqueous dispersion of magnetic nano-
particles were produced by inverse miniemulsion and the DLS analysis
revealed an average size in the range of 500–700 nm [42]. On the
other hand, starch nanocapsules with encapsulated dsDNA produced
by miniemulsion technique had a size measured in the range of 320 to
920 nm and the polydispersity index varied from 0.26 to 0.36, indicating
a broad size distribution of the capsules [29].
Furthermore, the MNXQ_SO3 sample shows a good stability (zeta
potential value of −40.2 mV) and no precipitation or coagulation was
observed during three months of storage. The negative zeta-potential
value is due to the presence of sodium dodecyl sulfate (negatively
charged stabilizing agent) [45].
Fig. 5a and b shows the TEM images of the sample. Fig. 5c shows the
distribution curve of particle size, in which it is possible to see that the
average diameter of MNXQ_SO3 was approximately 126 ± 31 nm. In
this case, the particle size obtained by TEM analysis for MNXQ_SO3 is
smaller than that obtained by DLS. Probably, the difference between
the average sizes obtained from DLS and TEM analyses occurs because
the TEM analysis was performed under vacuum atmosphere [46].
Baier et al. [29] obtained starch nanocapsules with encapsuled dsDNA
in which the average size determined by TEM micrograph was in the
range of 286 to 381 nm.
Furthermore, the TEM images of MNXQ_SO3 show the core-shell
structure, confirming the nanocapsule morphology. It also could be
seen the presence of dark contrasts around the nanocapsules, indicating
the successful synthesis of magnetic nanocapsules via inverse
miniemulsion.
3.2.4. Thermal analysis: TGA/DTG of the samples
The thermogram curve of the xyloglucan sample (Fig. S2 in Appen-
dix A – Supplementary data) shows two steps of weight loss, with
total weight loss of around 84%. The first region ranges from 27 °C to
106 °C and represents up to about 9% of the weight loss, which is
assigned to the residual and structural water evaporation previously
present in the sample. Some publications attribute the occurrence of
this thermal degradation to the hydrophilic nature of the polysaccharide
(presence of hydroxyl functional groups in the chemical structure) [40].
The second step appears in the temperature range of 239–468 °C and is
related to the thermal decomposition of xyloglucan chain [47], which
corresponds to 75% of the weight loss. Furthermore, the Derivative
Thermogravimetric analysis (DTG) shows a maximum degradation at
a temperature of 300 °C, which occurs in the second main step thermal
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al.
Fig. 4. FT-IR spectra of the samples (a) MNXQ_SO3, (b) Fe3O4@PAAS, (c) xyloglucan and
(d) Q_SO3.
decomposition. This result is consistent with other papers previously
published [26,48].
TGA/DTG curves of Fe3O4@PAAS (Fig. S2) exhibit three weight loss
steps. The first one (around 4%) is observed in the temperature range
of 31–103 °C and corresponds to the sample dehydratation. The second
thermal step (approximately 10%) occurs in the range of 182–415 °C
and represents the exothermic decomposition of organic capping
agent (PAAS). Finally, the third weight loss (about 16%) happens in
the temperature range of 458–730 °C and is related to further degrada-
tion of the resultant carbonic residues, as well as the partial reduction of
Fe3O4 surface [25]. Thus, the total weight loss (30%) indicates the per-
centage of coating formed by polyacrylic acid sodium salt in the
Fe3O4@PAAS sample.
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International Journal of Biological Macromolecules 168 (2021) 722–732
Fig. S2 also illustrates the thermal behavior of Q_SO3. Three main
steps of weight loss are observed in the TGA/DTG curves. The first region
starts at 26 °C and ends at 113 °C, which corresponds to the water loss
(11%). The second weight loss (around 16%) occurs in the temperature
range of 193–411 °C and is attributed to overlapping of several pro-
cesses according to the DTG curve profile. Woznicka et al. [44] report
this degradation process generates H2O, SO2, CO2 and CO. The third
step of decomposition (weight loss up to about 36%) begins at 603 °C
and ends at 794 °C, in which it is related to production of CO and CO2
[44].
The thermogravimetric analysis (Fig. S2) of MNXQ_SO3 sample was
performed to investigate the thermal stability. The TGA profile of
MNXQ_SO3 exhibits a stepwise weight-loss curve and the total weight
loss is around of 78%. The first step appears in the range of 26–97 °C
and probably corresponds to endothermic desorption of physically
absorbed water. The second thermal event occurs in the temperature
range of 138–276 °C, which can be associated to degradation processes
of xyloglucan. The thermal stability of xyloglucan in the sample
MNXQ_SO3 is lower than the polysaccharide alone due to the reduction
of hydrogen bonds along the polymer chain, which occurs by the reac-
tion with the crosslinking agent [49]. This reduction of the thermal sta-
bility can be a relevant result to drug delivery process, which occurs in
the presence of magnetic field because the temperature increase caused
by magnetic hyperthermia should accelerate the drug release process.
Therefore, the maximum degradation for this sample is also lower
than polysaccharide and occurs at 214 °C. The last degradation step hap-
pens between 288 °C and 483 °C and perhaps can be attributed to the
thermal decomposition of the hydrophilic quercetin sulfate. The in-
creased thermal stability of bioactive in the sample, when compared
to bioactive alone, can indicate the successfully loaded Q_SO3 into the
magnetic nanocapsules.
3.2.5. X-ray powder diffraction (XRD)
The Fe3O4@PAAS sample was subject to XRD technique, which is
displayed in Fig. 6. All the peaks of the sample spectrum exhibited
very similar pattern to magnetite (JCPDS card # 19-0629) phase,
which possesses an inverse cubic spinel structure [50]. No other hema-
tite (JCPDS card # 01-086-0550) or maghemite (JCPDS card # 39-1346)
peaks were found in the sample, revealing a pure phase of magnetite
(Fe3O4) [51,52]. This result is in accordance with the data in the litera-
ture [25].
Fig. 7a and b exhibits the TEM micrographs of magnetic nanoparti-
cles coated with PAAS (Fe3O4@PAAS) and shows the morphology, size
and structural defects of the synthesized sample. It is possible to observe
the faceted shape of magnetic nanoparticles and the absence of nano-
particles clusters. Moreover, the sample corresponds to nanosized mag-
netite as described in the literature [25]. Through Fig. 7c is possible to
see the size histogram for Fe3O4@PAAS, which the mean particle size
was determined (approximately 8 nm).
3.2.6. Magnetic properties
Fig. 8 shows the hysteresis loops as a function of the magnetic field at
room temperature (300 K). Through Fig. 8(a) it is possible to evaluate
the influence of the coating on the magnetization in the sample
Fe3O4@PAAS. The sample Fe3O4 with the coating (PAAS) reduces the
saturation magnetization from 56 emu/g to 48 emu/g (Fe3O4@PAAS).
This decrease does not change the superparamagnetic behavior and
the coercivity and remanence values remain practically zero. Different
values of saturation magnetization can be attributed to the different
amounts of coating and preparation techniques [53,54]. In this paper
we obtained the sample Fe3O4@PAAS with 30% of coat (determined
by TGA).
The magnetization of MNXQ_SO3 is shown in Fig. 8(b) and a satura-
tion magnetization value of 4.2 emu/g is obtained. The reduction in
magnetization of the sample was expected due to the presence of poly-
mer and organic molecules, which contribute to the increase in the total
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al. International Journal of Biological Macromolecules 168 (2021) 722–732

Fig. 5. (a) and (b) TEM micrographs of MNXQ_SO3; (c) particle size distribution curve of MNXQ_SO3.

mass of the nanocapsules, reducing the saturation magnetization [3].

This result is similar to that published by Kavousi et al. [55], in which
the authors synthesized a magnetic polymer nanocomposite for the re-
lease of metoprolol with the saturation magnetization value of 3.5 emu/
g [55]. Furthermore, the VSM analysis of MNXQ_SO3 indicates the prom-
ising use of this nanomaterial in future studies for biotechnological and
theranostic applications, such as its use in magnetic hyperthermia as-
says and diagnostic imaging tests as a contrast agent.

3.3. Release study and efficiency encapsulation of hydrophilic quercetin

sulfate

The release behavior of hydrophilic quercetin sulfate (Q_SO3) free

Fig. 6. XRD pattern diffraction of magnetic nanoparticles coated with polyacrylic acid
sodium salt (Fe3O4@PAAS).
and encapsulated within MNXQ_SO3 sample was performed in contact
with phosphate buffered saline at pH 7.4 and can be seen in Fig. 9.
After of the first 30 min of experiment about 22% of Q_SO3 was released
from nanocapsules, while the percentage concentration of free bioactive
was 34%. The total amount of free Q_SO3 (100%) in the PBS medium was
obtained after 48 h of release assay. However, at the end of the delivery
study, the rate released of Q_SO3 from MNXQ_SO3 sample was 67%. It is
already known in the literature that the delivery of the encapsulated
material into polymeric nanocapsules shows a drug release of more
than 50% [29].
Through Fig. 9, it is possible to verify that MNXQ_SO3 shows a signif-
icant increase of the drug rate release (burst effect) in the first 8 h and
until 24 h, the percentage rate of Q_SO3 release increased slowly. The lit-
erature reports that polymer-based nanocapsules are biphasic systems
and have a release behavior of apparent zero order kinetics. Therefore,
these systems have a fast initial phase of drug released and a second
slower phase: in the fast step the desorption of the bioactive on the

729
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al. International Journal of Biological Macromolecules 168 (2021) 722–732

Fig. 7. (a) and (b) TEM images of Fe3O4@PAAS; (c) particle size distribution curve of Fe3O4@PAAS.

nanocapsule surface or the degradation of the polymeric nanocapsules
wall can occur, while the slower step is attributed to diffusion of the en-
capsulated drug [45].
Table 3 shows the results of the kinetic study of mathematical
models, such as zero and first order, Higuchi and Korsmeyer-Peppas,
which were employed to evaluate the in vitro quercetin sulfate release
from MNXQ_SO3. The results indicate that the sample is in accordance
with the mathematical model of zero order and, in other words, this
profile releases the same amount of bioactive per unit of time, being
one of the best ways of deliver drugs in a prolonged release [30].
Recent studies demonstrate that the presence of magnetic nanopar-
ticles in drug delivery vehicles can be able to ablate cancer cells by mag-
netic hyperthermia. Additionally, the heat formed by this process can
modify the release profile of bioactives, increasing the release rate.
Therefore, the combination of both techniques can increase the effi-
ciency of cancer treatment and reduce the secondary effects of non-
targeted nanocarriers [56]. In this study, the presence of Fe3O4@PAAS
into MNXQ_SO3 can be enlarge the rate release of quercetin sulfate, im-
proving the response of this hybrid nanocomposite to targeted drug
delivery.

Fig. 8. Magnetic behavior of (a) Fe3O4, Fe3O4@PAAS and (b) MNXQ_SO3, at 300 K.

730
A.C.C. da Silva, R.R. de Almeida, A.C. da Cruz Sousa et al.
Fig. 9. Release behaviors of Q_SO3 free and MNXQ_SO3 at pH 7.4 during 48 h.
Table 3
Kinetic study of data obtained by Q_SO3 release profile at pH 7.4.
Sample Correlation coeficiente (r2)
Zero-order First-order Higuchi
Q_SO3 free 0.8995 0.5627 0.9826
MNXQ_SO3 0.9986 0.5768 0.9494
The encapsulation efficiency of QSO3 in the sample MNXQ_SO3 was
determined and showed a value of 56%. Studies published previously
by other authors indicate that nanocapsules consisting of an aqueous
core and polymer shell have encapsulation efficiency varying in the
range of 46% until close to 100%. The difference between the encapsula-
tion efficiency values is assigned to the crosslinking degree [9,57].
4. Conclusion
In this work, magnetic nanoparticles (Fe3O4@PAAS) were obtained
by hydrothermal synthesis. The analyses of magnetic properties and
X-ray powder diffraction reveal, respectively, a superparamagnetic be-
havior and a pure-phase of magnetite for Fe3O4@PAAS. The obtaining
of Q_SO3 allowed its incorporation in hydrophilic-core nanocapsules,
increasing the application potential of this bioactive. Magnetic
nanocapsules of xyloglucan loaded with hydrophilic quercetin sulfate
(MNXQ_SO3) were successfully synthesized by inverse miniemulsion
polymerization. The nanocapsule shell formation and magnetite incor-
poration in the sample were corroborated by FT-IR and TEM
micrography. After the incorporation of Fe3O4@PAAS in the xyloglucan
nanocapsules loaded with Q_SO3, the superparamagnetic behavior
was consistent, being an attractive nanomaterial for drug delivery to
specific tissues without damaging healthy cells. The sample achieved a
promising encapsulation efficiency and was able to modify the release
profile of hydrophilic quercetin sulfate (Q_SO3), when compared with
the free hydrophilic bioactive. This work allows for the development
of the novel multifunctional tool that has promising potential for vari-
ous biomedical applications, such as drug delivery, magnetic hyperther-
mia and agent contrast in MRI.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ijbiomac.2020.11.128.
CRediT authorship contribution statement
Aiêrta Cristina Carrá da Silva: Conceptualization, Investigation, For-
mal analysis, Writing – Original Draft. Writing – review & editing.
Alexandre Carreira da Cruz Sousa: Investigation. Fabián Nicolás
International Journal of Biological Macromolecules 168 (2021) 722–732
Araneda Martínez: Investigation. Raimundo Rafael de Almeida: Con-
ceptualization, Supervision, Writing – review & editing. Juliano
Casagrande Denardin: Investigation. Writing – review & editing.
Selene Maia de Morais: Funding acquisition. Nágila M. P. S. Ricardo:
Conceptualization, Writing – review & editing, Supervision, Funding
acquisition.
Acknowledgments
This study was financed in part by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance
Code 001, Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq) and Fundação Cearense de Apoio ao
Desenvolvimento Científico e Tecnológico (FUNCAP), Edital No 03/
2019. The authors thank CNPq for their grants (N.M.P.S.R. – Project No
307837/2017-3 and A.C.C.S. Project No 140256/2017-2) and FUNCAP
(R.R.A (Project No 88887.162539/2017-00)). We also want to acknowl-
edge the analyses and data acquisition provided by Embrapa
Agroindústria Tropical, X-ray Laboratory of Federal University of Ceará
(LRX-UFC), Fondecyt 1200782, CEDENNA AFB180001 (USACH) and
Central Analítica-UFC/CT-INFRA/MCTI-SISNANO/CAPES.
Data availability statement
Korsmeyer-Peppas The raw/processed data required to reproduce these findings cannot
be shared at this time as the data also forms part of an ongoing study.
0.9789
0.9551
Declaration of competing interest
The authors declare no conflict of interest.
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