European Polymer Journal 120 (2019) 109263

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European Polymer Journal

journal homepage: www.elsevier.com/locate/europolj

Synthesis and characterization of poly(N-isopropylacrylamide-co-N,N′- T

methylenebisacrylamide-co-acrylamide) core – Silica shell nanoparticles by
using reactive surfactant polyoxyethylene alkylphenyl ether ammonium
sulfate
⁎
Ngoc-Hanh Cao-Luua, Quoc-Thai Phamb, Zong-Han Yaoc, Fu-Ming Wangb, Chorng-Shyan Cherna,
a
Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan
b
Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan
c
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan

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

Keywords: We report a novel approach based on using polyoxyethylene alkylphenyl ether ammonium sulfate (HS10) as an
Poly(N-isopropylacrylamide) anion reactive surfactant, which greatly reduced the size of poly(N-isopropylacrylamide-co-acrylamide-co-N,N′-
Temperature-responsive methylenebisacrylamide) [P(NIPAM/AM/MBA)] microgel core – silica shell particles. First, the microgel cores
Silica were synthesized by copolymerization of N-isopropylacrylamide (NIPAM), N,N′-methylenebisacrylamide (MBA)
Reactive surfactant
with a variation of acrylamide (AM) and HS10 concentration in water. It followed by silica encapsulation of the
Coupling agent
Hybrid core – shell nanoparticles
microgel cores via the addition of 3-glycidyloxypropyltrimethoxysilane (GLYMO) and tetraethyl orthosilicate
(TEOS) at alkaline environment (pH 12). It is interesting to note that the size of both PNIPAM-based microgel
cores and PNIPAM-based microgel core – silica shell particles were well-controlled by using a small level of
HS10. Furthermore, SEM images of the hybrid core – shell particles show the well-defined spherical morphology
with monodisperse particle size distribution. As expected, HS10-containing samples are covered by the porous
silica shell layer, instead of continuous silica shell obtained from HS10-free samples observed in TEM images.
This novel incorporation not only well controls the core size and shell morphology, leading to increase their
specific surface area but also does not greatly affect the thermo-sensitivity of final products. The resultant
thermo-responsive microgel core – silica shell particles with controlled particle morphology and physico-
chemical properties are useful for biomedical application fields.

1. Introduction single gold nanoparticle, followed by in situ polymerization and

Thermo- and/or pH-sensitive materials based on poly(N-iso-
propylacrylamide) (PNIPAM) play an important role in biomedical
applications due to the different thermal and pH conditions within
various tissue and cellular compartments along the endo- cytic pathway
[1–6]. For example, Kuckling et al. [5] prepared thermosensitive na-
nogels from photo-crosslinkable copolymers of NIPAM and 2-di-
methylmaleinimido ethylacrylamide (DMIAAm) in water at 45 °C and
extensively characterized their physicochemical properties. It was
shown that the colloidal size of nanogels was dependent on the con-
centrations of photopolymer and sodium dodecyl sulfate and the
amount of chromophore DMIAAm in the photopolymer chains. Zhao
et al. [6] successfully synthesized photothermo-responsive Au@IPN-
PNIPAM nanogels by growing an acrylamide (AM) monolayer on a
crosslinking of NIPAM and AM. The hybrid nanogels were characterized
by biocompatibility at relatively low concentration (< 200 mg ml−1),
the unique scattering properties of AuNP core and the reversible
thermo-responsive volume phase transition of IPN-PNIPAM shell. Thus,
these nanogels may find potential applications such as simultaneous
optical temperature-sensing, cell imaging and combined chemo-pho-
tothermal treatment.
Inorganic silica nanoparticles show great potential in applications
such as drug carriers, chemical sensors, catalysis, adsorption, chroma-
tography, microelectronics and electro-optics [7,8]. For instance, it was
illustrated that silica nanoparticles with the size range of 10–200 nm
showed rather limited cytotoxicity and, therefore, these colloidal pro-
ducts can be used as drug carriers [9–11]. It is noteworthy that Wang
et al. [12] recently prepared novel lipase-powered mesoporous silica

⁎
Corresponding author.
E-mail address: cschern@mail.ntust.edu.tw (C.-S. Chern).

https://doi.org/10.1016/j.eurpolymj.2019.109263
Received 26 June 2019; Received in revised form 17 September 2019; Accepted 19 September 2019
Available online 21 September 2019
0014-3057/ © 2019 Elsevier Ltd. All rights reserved.
N.-H. Cao-Luu, et al.
nanomotors for degradation of triglyceride. These nanomotors were
capable of promoting their Brownian motion in triglyceride solution
over a long period of time. Furthermore, they could effectively degrade
triglyceride droplets that mimic blood lipids as well. This unique ex-
ample demonstrates the versatile features of silica nanoparticles in
biomedical applications.
PNIPAM core-silica shell particles have attracted great attention due
to the unique physicochemical properties and potential applications in
biomedical fields such as drug delivery system. However, most hybrid
particles reported in the literature are rather limited in drug delivery
applications because of the micron-sized characteristic originating from
micron-sized PNIPAM core particles [13–20]. It is very difficult for
micron-sized particles (as a drug carrier) to penetrate tissues and then
enter cells, thereby leading to inefficient delivery of drug molecules to
target sites of action [21–26]. Recently, Hegazy et al. [27] used the
photo-induced electron/energy transfer-reversible addition fragmenta-
tion chain transfer polymerization technique, mediated by a ruthenium-
based photoredox Ru(bpy)3Cl2 catalyst, to effectively graft PNIPAM
chains (as the shell) onto the magnetic mesoporous silica nanoparticles
(as the core). Doxorubicin (as a model anticancer drug) was facilely
encapsulated into the nanocarriers with a quite high loading capacity,
and rapidly released in response to the triple-responsive mechanisms
(i.e., the magnetic, reductive and thermo-). This unique drug delivery
system is not only magnetically guided but also of great value in the
formulation of targeted delivery of therapeutic agents to tumors and
inflammatory sites.
In our previous report [28], P(NIPAM/AM) core-silica shell nano-
particles (< 100 nm in diameter) were successfully synthesized by
using PNIPAM-based mesoglobule cores as the template for subsequent
silica encapsulation thereon. In contrast, in the presence of N,N′-me-
thylenebisacrylamide (MBA, as a crosslinking agent), the diameter of P
(NIPAM/AM/MBA) microgel core – silica shell particles were much
larger (ca. 500–600 nm) [29]. Therefore, it is crucial for the dimension
of hybrid particles to be well controlled within the nano-sized range via
minimizing the microgel core size. One approach involves adjustment
of the size of PNIPAM microgel cores by addition of surfactants
[16,18,30,31]. However, conventional surfactants may impart some
negative effects to key product properties because the physically ad-
sorbed surfactant species can be easily desorbed from the colloidal
particle surface due to the weak hydrophobic interaction between
surfactant and polymer particles [32]. A promising alternative to re-
solve this critical issue is to use surfmers (i.e., polymerizable surfactants
containing one carbon-carbon double bond) [33]. Besides emulsion
polymerization, surfmers can be used for more sophisticated purposes
(e.g., for drug delivery systems, hydrogels, nanomaterials and en-
capsulation) [33].
There are few studies related to preparation of polymeric hydrogels
based on NIPAM and surfmers. For example, Chen et al. [34] used n-
dodecyl glyceryl itaconate (DGI, a polymerizable nonionic surfactant)
to form bilayer membranes in water. PNIPAM gel was then synthesized
in the space of the compartments between the bilayer membranes to
form hybrid PDGI-PNIPAM hydrogel, which shows very rapid shrinking
behavior during the lower critical solution temperature (LCST) phase
transition. Friedrich et al. [35] prepared thermo-responsive hydrogels
via radiation-induced copolymerization of NIPAM and cationic surfmer
11-(acryloyoxy)undecyl)trimethylammonium bromide (AUTMAB) in
aqueous solutions. It was shown that the LCST of PNIPAM hydrogels
containing AUTMAB could be manipulated by varying the surfmer
concentration. Atta et al. [36] synthesized a new bifunctional surfmer
via the reaction of polyoxyethylene 4-nonyl-2-propylene-phenol (a re-
active nonionic surfactant) with maleic anhydride, followed by ester-
ification with poly(ethylene glycol). This surfmer was used as a stabi-
lizer to prepare amphiphilic crosslinked copolymer nanogel of NIPAM
and 2-acrylamido-2-methylpropane sulfonic acid (P(NIPAM/AMPS)) in
toluene and formamide. The P(NIPAM/AMPS) dispersions exhibited
high surface activity, and used as stabilizers to prepare crosslinked
2
European Polymer Journal 120 (2019) 109263
styrene-co-divinylbenzene-co-AMPS microgel particles. Dyab et al. [37]
prepared poly(NIPAM/AMPS) microgel particles functionalized with a
polymerizable nonionic surfactant (polyoxyethylene 4-nonyl-2-propyl-
phenyl maleate ester) in non-aqueous media. The resultant microgel
particles were greatly effective to reduce the oil–oil interfacial tension
and were strongly adsorbed on the oil–oil interface to prevent droplet
coalescence. Recently, Kraus et al. [38] studied copolymerization of
NIPAM, acrylic acid (AA) and ω-methoxy [poly(ethyleneoxide)40] un-
decyl-α-methacrylate (PEO-R-MA-40). The hydrogels prepared by γ-ir-
radiation were transparent and stable. In the presence of high surfmer
concentration, both the LCST and the crosslinked network density in-
crease, while the gel permeability decreases.
The objective of this study was to use a commercially available
polymerizable anionic surfactant, polyoxyethylene alkylphenyl ether
ammonium sulfate with 10 units of ethylene oxide (HS10), to effec-
tively reduce the sizes of both P(NIPAM/MBA/AM) microgel cores and
the corresponding hybrid microgel core – silica shell particles. The
major parameters chosen for study are the concentrations of acrylamide
(AM) and HS10 used to synthesize microgel cores. Note that the silica
encapsulation process was conducted in the presence of 3-glycidylox-
ypropyltrimethoxysilane (GLYMO, as the coupling agent), which con-
tains one epoxide group and three methoxysilyl groups. In this manner,
the amide groups of AM, MBA and NIPAM units can react with the
epoxide group of GLYMO, while the four ethoxysilyl groups of tetra-
ethyl orthosilicate (TEOS (silica precursor)) and the three methoxysilyl
groups of GLYMO can simultaneously undergo the sol-gel reaction to
form tiny silica nanoparticles right on the PNIPAM-based microgel core
surfaces in an attempt to form desirable ideal core – shell particle
morphology. The resultant microgel cores and the hybrid microgel core
– shell particles were then extensively characterized by FE-SEM, TEM,
DLS, DSC, TGA, FTIR, 1H NMR, surface area and pore size distribution.
2. Experimental
2.1. Materials
The chemicals used in this work include N-isopropylacrylamide
(NIPAM, 99%, Acros), acrylamide (AM, 99%, Sigma-Aldrich), N,N′-
methylenebisacrylamide (MBA, 99%, Acros), polyoxyethylene alkyl-
phenyl ether ammonium sulfate (HS10, 98%, Dai-Ichi Kogyo Seiyaku),
potassium persulfate (KPS, 99%, Acros), 3-glycidyloxypropyl-
trimethoxysilane (GLYMO, 98%, Evonik), tetraethyl orthosilicate
(TEOS, 98%, Acros), dimethylsulfoxide‑d6 (DMSO‑d6, +99%, Acros),
and potassium bromide (KBr, +99%, Acros). Deionized water
(Barnsted, Nanopure Ultrapure Water System, specific conductance <
0.057 µS cm−1) was used throughout this work. All chemicals were
reagent grade and used as received.
2.2. Synthesis of microgel core particles
Polymeric core particles were synthesized via free radical copoly-
merization of 1 g of NIPAM, 0.05 g of MBA and 0.04 g of KPS in the
presence of 0.02 or 0.05 g of AM along with 0, 0.001, 0.005, 0.01 or
0.02 g of HS10 in 70 g of water. Before polymerization, the resultant
solution was deoxygenated with nitrogen purge for 10 min. The reac-
tion was then carried out at 70 °C over a period of 6 h. It should be
noted that the reaction temperature was set at 70 °C (> LCST) in this
study. This is because the major monomer unit (e.g., NIPAM unit in this
work) in NIPAM-based copolymer must be relatively water-insoluble at
the reaction temperature in order to achieve successful nucleation,
growth and aggregation (if present) of polymer particles involved in
heterogeneous emulsion copolymerization [39]. In this manner,
PNIPAM-based chains become relatively water-insoluble at 70 °C and
are capable of promoting the desirable emulsion copolymerization that
is characterized by producing a large population of very small polymer
particles. After polymerization, the crude microgel core particles were
N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Table 1 and measured for three times. In addition, zeta potential (ζ) of microgel
Recipes for preparation of microgel core particles. core particles and hybrid microgel core – silica shell particles were
Microgel cores NIPAM (g)a MBA (g) AM (g) HS10 (g) KPS (g) determined by a Brookhaven 90 Plus instrument.

2AM/0HS10 1 0.05 0.02 0 0.04 2.4.2. Thermal properties

2AM/0.1HS10 1 0.05 0.02 0.001 0.04
DLS was also used to study the thermo-sensitivity of microgel cores
2AM/0.5HS10 1 0.05 0.02 0.005 0.04
2AM/1HS10 1 0.05 0.02 0.01 0.04
and hybrid microgel core – silica shell particles in the temperature
2AM/2HS10 1 0.05 0.02 0.02 0.04 range 25–50 °C with an interval of 1 °C. The thermo-responsive beha-
5AM/0HS10 1 0.05 0.05 0 0.04
vior of these samples with a total solids content of 10 wt% was further
5AM/0.1HS10 1 0.05 0.05 0.001 0.04 investigated by Differential Scanning Calorimetry (DSC, TA Instruments
5AM/0.5HS10 1 0.05 0.05 0.005 0.04 Q20) in the same temperature range at a heating rate of 2 °C min−1.
5AM/1HS10 1 0.05 0.05 0.01 0.04 The thermal decomposition of dried samples was determined by
5AM/2HS10 1 0.05 0.05 0.02 0.04
thermogravimetric analysis (TGA, Perkin-Elmer Diamond TG/DTA) at a
a
These samples were synthesized in 70 g water. heating rate of 10 °C min−1 under an air flow rate of 20 mL min−1 in
the temperature range 100–700 °C.
purified by dialysis with molecular weight cutoff
(MWCO = 12,000–14,000 Da) for 5 days to remove unreacted mono- 2.4.3. FTIR and 1H NMR analysis
mers and other species. Table 1 summarizes the recipes used to prepare Fourier transform infrared (FTIR, FTS-3500, Bio-Rad) was used to
the microgel core particles. verify the presence of silica in hybrid microgel core – silica shell par-
ticle structure. FTIR spectrum was recorded in the wavenumber range
4000–400 cm−1 with a total of 32 scans and a resolution of 4 cm−1
2.3. Synthesis of hybrid microgel core – silica shell particles under nitrogen flow to remove the moisture. The sample was dried at
90 °C for 24 h in a vacuum oven and then mixed with spectroscopically
Microgel core particles were encapsulated by silica via the sol-gel pure KBr for FTIR measurements.
reaction of TEOS in the presence of GLYMO. In brief, 20 g of aqueous Chemical incorporation of reactive surfactant into polymer chains
polymer dispersion (0.5 wt%) was adjusted to pH 12 by sodium hy- was verified by proton nuclear magnetic resonance spectroscopy (1H
droxide (0.5 M). This was followed by adding GLYMO and TEOS into NMR, Bruker AVIII HD-600, Bruker, Billerica, MA). Synthesis of P
the dispersion with the weight ratio of polymer:GLYMO:TEOS = 1:1:1. (NIPAM/AM/HS10) [10/0.2/1 (w/w/w)] and P(NIPAM/AM) [10/0.2
The reaction was carried out at 50 °C over a period of 10 h. The crude (w/w)] initiated by KPS in water (10 wt% solids content) was carried
product was first precipitated by centrifugation (20,000 rpm, 50 min) out at 70 °C for 24 h. This was followed by washing the resultant pro-
and then washed with water three times. The resultant dispersion of duct three times with hot water (70 °C) and drying it in a vacuum oven
microgel core-silica shell particles is denoted as the nomenclature of at 90 °C for 24 h. The dried polymer was then dissolved in DMSO‑d6 for
microgel core (Table 1) in combination with three digits “111” that 1
H NMR measurements.
represents the weight ratio of polymer:GLYMO:TEOS. For example, the
recipe comprising 0.1 g of microgel core (2AM/0.5HS10), 0.1 g of TEOS 2.4.4. Surface area and pore size distribution
and 0.1 g of GLYMO in 20 g water is denoted as 2AM/0.5HS10-111. Nitrogen adsorption-desorption isotherm of hybrid microgel core –
It is noteworthy that the sol-gel reaction of TEOS in the presence of silica shell particles was measured at −196 °C by using a Surface Area
GLYMO was conducted at 50 °C (> LCST) in order to allow the reaction and Porosimetry Analyzer (BEL Belsorp-Max, Japan). The specific sur-
to proceed to a significant extent. If the reaction temperature is below face area was determined by the Brunauer-Emmett-Teller (BET) method
the LCST of the polymeric core (e.g., 25 °C), the condensation reaction and the average pore size and pore size distribution were calculated
of TEOS and GLYMO will become quite slow. Furthermore, the ring from the adsorption isotherm using the Barrett-Joyner-Halenda (BJH)
opening reaction between the epoxide group of GLYMO and the pri- method. All samples were freeze-dried and then degassed at 100 °C for
mary or secondary amine groups of AM will be greatly retarded. As a 4 h under vacuum prior to measurements.
result, the hybrid core-shell particles could not be successfully attained.
3. Results and discussion
2.4. Characterization
3.1. Synthesis and characterization of microgel cores
2.4.1. Morphology, particle size and zeta potential
The morphology and dried particle size of hybrid polymeric core – Formation of P(NIPAM/AM/HS10) microgel core – silica shell par-
silica shell particles were characterized by field emission scanning ticles is schematically shown in Scheme 1. First, microgel cores were
electron microscopy (FE-SEM, JEOL JSM-6500F) and transmission synthesized by copolymerization of NIPAM, MBA, AM and HS10 con-
electron microscopy (TEM, H-7100 TEM, Hitachi). The sample was taining one carbon-carbon double bond per molecule. The surface-ac-
dispersed in water with the total solids content of ca. 0.05%, dropped tive HS10 species are predominantly adsorbed on the surface of mi-
on the copper foil (SEM) or coated on the copper grids (TEM), followed crogel cores, thereby acting as an effective stabilizer to effectively limit
by drying for 24 h under ambient condition. The number average par- their particle size [40]. This was followed by encapsulation of microgel
ticle diameter (dn), weight average particle diameter (dw) and poly- cores by silica particle nuclei in the presence of a coupling agent
dispersity index (PDI = dw/dn) were determined by SEM or TEM by (GLYMO) to facilitate formation of the desirable perfect core – shell
measuring at least 150 particles. structure. This is simply because GLYMO contains one epoxide group
The hydrodynamic diameters of microgel core particles (dc) and and three methoxysilyl groups and, therefore, it can greatly enhance the
hybrid microgel core – silica shell particles (dh) were measured at 25 °C affinity between the organic core (PNIPAM/MBA/AM) and inorganic
and 50 °C by the dynamic light scattering technique (DLS, Malvern shell (silica). Note that the amide groups of AM MBA and NIPAM units
Nano-S90), which provides users with a standard temperature range of can react with the epoxide group of GLYMO (Scheme 2), while the four
2 to 90 °C controlled through a Peltier. The temperature precision of ethoxysilyl groups of TEOS (silica precursor) and the three methoxysilyl
such instrument is 0.1 °C with an accuracy of 0.2 °C. This is equivalent groups of GLYMO can simultaneously undergo the sol-gel reaction to
to an error of 0.4% in the particle size for aqueous samples. Each form tiny silica nanoparticles right on the PNIPAM/AM microgel core
sample was diluted to appropriate concentration (ca. 0.05%) with water surfaces, thereby leading to the desirable ideal core – shell particle

3
N.-H. Cao-Luu, et al.
Scheme 1. Schematic illustration of the formation of P(NIPAM/AM/HS10) microgel core-silica shell particles in the presence of HS10.
morphology.
Before silica encapsulation, the average hydrodynamic diameter
(dc) and the size distribution of microgel core particles prepared by
recipes with different levels of HS10 (0–2 wt% based on the initial
weight of NIPAM monomer) and AM (2 and 5 wt% based on the initial
weight of NIPAM monomer) as a function of temperature (T) de-
termined by DLS are shown in Fig. 1. Representative particle size data
measured at 25 °C (dc25) and 50 °C (dc50) are summarized in Table 2.
As expected, at constant T, dc decreases with increasing HS10
concentration for microgel core particles prepared by recipes with
different levels of AM (Fig. 1a and b). This is because the number of
primary particles formed in the nucleation process increases with in-
creasing HS10 concentration according to the particle nucleation me-
chanisms involved in emulsion polymerization [39]. In addition, the
polydispersity index (PDI) of all microgel cores is smaller than 0.1 (data
not shown here), indicating narrow particle size distribution. This result
is consistent with the work of Mirja Andersson et al. [41]. It is note-
worthy that the swelling ratio (SR) of microgel particles increases with
increasing HS10 content, which is primarily attributed to the higher
osmotic pressure established by the presence of higher HS10 con-
centration in microgel cores.
For P(NIPAM/AM) microgel cores in the absence of HS10 (2AM/
0HS10 and 5AM/0HS10), they possess very large particle size and quite
low absolute value of zeta potential (∣ζ∣), as shown in Table 2. This is
because these two colloidal dispersions are stabilized only by the
terminal -SO4− groups of polymer chains anchored on particle surfaces
originating from the persulfate initiator, which imparts electrostatic
stabilization to the colloidal system [29]. As a result, particle nuclei can
grow via the limited flocculation process to greatly reduce the total
interfacial area (i.e., the interfacial free energy) [39] due to the in-
sufficient stabilizer (-SO4- in this case), as reflected in the very large
particle and the very low ∣ζ∣. In comparison with 2AM/0HS10 and
Scheme 2. Schematic representation of possible reactions between the epoxide group of GLYMO with the primary amide group of AM unit and/or the secondary
amide groups of NIPAM and MBA units during the silica encapsulation process.
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European Polymer Journal 120 (2019) 109263
5AM/0HS10, ∣ζ∣ increases significantly to 27.6 and 21.8 mV, respec-
tively, for 2AM/0.1HS10 and 5AM/0.1HS10 in the presence of a very
small amount of HS10 (0.1 wt%). It is noteworthy that ∣ζ∣ decreases
with increasing HS10 concentration for microgel cores containing HS10
(Table 2). This is probably due to the decreased surface charge density
with HS10 concentration, as reflected in the parameter CHS10/(1/D),
where CHS10 represents the HS10 concentration on the particle surface
and D the particle diameter (i.e., dc in this case). Note that, for constant
weight of colloidal particles, the total particle surface area (A) is pro-
portional to the reciprocal of D. This issue will be further discussed
later.
3.2. Synthesis and characterization of microgel core – silica shell particles
In this series of experiments, the effects of AM (2 or 5 wt%) and
HS10 (0, 0.1, 0.5, 1 or 2 wt%) on the morphology, particle size and zeta
potential of the hybrid microgel core – silica shell particles were in-
vestigated. The silica encapsulation temperature and time were kept
constant at 50 °C and 10 h, respectively, throughout this work. In ad-
dition, the weight ratio of microgel cores to GLYMO and TEOS was also
kept constant at 1:1:1.
Fig. 2 shows SEM images for microgel core – silica shell particles
and, at constant AM concentration, the weight average particle dia-
meter (dw1) decreases with increasing HS10 concentration (Table 3). It
is noteworthy that, at constant HS10 concentration, the hybrid particles
prepared by formula with 5 wt% AM show larger particle size than
those with 2 wt% AM. This is most likely due to the greatly enhanced
nucleation and growth of silica nuclei on microgel core surfaces with
higher AM concentration in combination with GLYMO [28,29]. It
should be noted that, at constant HS10 concentration, the relatively
hydrophobic microgel cores prepared by recipes with 2 wt% AM show
comparable dc50 data (DLS) to those with 5 wt% AM at 50 °C (Table 2).
N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Fig. 1. Hydrodynamic microgel particle diameter (dc) as a function of temperature (T) profiles of (a) 2% AM-containing samples: ( ) 2AM/0HS10, ( ) 2AM/
0.1HS10, ( ) 2AM/0.5HS10, ( ) 2AM/1HS10, ( ) 2AM/2HS10 and (b) 5% AM-containing samples: ( ) 5AM/0HS10, ( ) 5AM/0HS10, ( ) 5AM/0HS10, ( )
5AM/0HS10, ( ) 5AM/0HS10 and the corresponding d dc/d T vs. T curves of (c) 2%AM-containing samples and (d) 5%AM-containing samples. Note that the
dashed lines in (a) and (b) represent the least-squares best-fitted curves for the corresponding discrete data points by using “sigmoidal fit” in OriginPro 8.5 software,
and (c) and (d) obtained from the first derivative of the fitted curves in (a) and (b).

Table 2 Furthermore, all samples show well defined spherical shape with
Hydrodynamic particle size and zeta potential (ζ) data for microgel cores with monodisperse particle size distribution (PDI = dw1/dn1 very close to
different AM and/or HS10 concentrations. unity) except those samples containing 2 wt% HS10 (PDI = 1.27 and
Microgel cores dc25 (nm)a dc50 (nm)a SRa ζ (mV)b pHb 1.22 for 2AM/2HS10-111 and 5AM/2HS10-111, respectively). The re-
latively broader particle size distribution observed for 2AM/2HS10-111
2AM/0HS10 739 ± 21 373 ± 6 7.8 −5.9 ± 2.2 5.5 and 5AM/2HS10-111 can be attributed to the highest HS10 con-
2AM/0.1HS10 411 ± 8 195 ± 3 9.4 −27.6 ± 1.1 6.1
centration (2 wt%) that prolongs the particle nucleation process during
2AM/0.5HS10 378 ± 3 178 ± 3 9.6 −17.7 ± 1.0 5.9
2AM/1HS10 236 ± 9 110 ± 1 9.9 −9.2 ± 0.8 6.0
emulsion copolymerization of NIPAM, MBA, AM and HS10. Based on
2AM/2HS10 192 ± 2 87 ± 1 10.7 −4.2 ± 4.9 5.4 the Smith-Ewart theory [39], particle nuclei generated earlier in the
5AM/0HS10 848 ± 18 395 ± 15 9.9 −2.9 ± 4.9 5.5
nucleation stage are capable of growing longer via absorption of
5AM/0.1HS10 425 ± 1 197 ± 4 10.0 −21.8 ± 2.4 6.1 monomers and free radicals and aggregation (if present) to become
5AM/0.5HS10 395 ± 3 180 ± 8 10.6 −20.7 ± 0.9 5.7 larger particles. By contrast, particle embryos born latter in the nu-
5AM/1HS10 266 ± 10 119 ± 6 11.2 −12.5 ± 1.1 5.6 cleation stage only have rather limited time to grow and, therefore, the
5AM/2HS10 219 ± 6 93 ± 2 13.1 −8.9 ± 3.9 4.5
resultant particles are tiny. This will then lead to higher PDI values for
a
dc25 and dc50 are the average hydrodynamic particle diameters of poly- 2AM/2HS10-111 and 5AM/2HS10-111.
meric cores determined by DLS at 25 °C and 50 °C, respectively and the poly- The distinct core – shell structure of hybrid particles prepared by
dispersity index (PDI < 0.1) for all samples indicates the narrow particle size recipes with different AM and HS10 concentrations were confirmed by
distribution. SR defined as (dc25/dc50)3 is the swelling ratio of colloidal parti- TEM images, in which the microgel core is fully covered with a large
cles. number of tiny silica nanoparticles (Fig. 3). At constant AM con-
b
Zeta potential (ζ) was measured at 25 °C and at pH of original sample after centration, a decrease in the particle size with HS10 was also observed
purification. The standard error was calculated based on 10 runs for each (see dw2 data in Table 3), which is in agreement with SEM (see dw1 data
sample. in Table 3) and DLS (see dh50 data in Table 3) results. Interestingly
enough, the HS10-containing microgel core is covered by a porous silica

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N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Fig. 2. Representative SEM images of PNIPAM-based core – silica shell particles with different AM and HS10 concentrations: (a) 2AM/0HS10-111, (b) 2AM/0.1HS10-
111, (c) 2AM/0.5HS10-111, (d) 2AM/1HS10-111, (e) 2AM/2HS10-111, (f) 5AM/0HS10-111, (g) 5AM/0.1HS10-111, (h) 5AM/0.5HS10-111, (i) 5AM/1HS10-111
and (j) 5AM/2HS10-111.

shell instead of the continuous silica layer achieved by the HS10-free
samples (Fig. 3a and f). It is then postulated that the existence of an-
ionic HS10 species on the microgel core surface may exhibit much
stronger electrostatic repulsion force for the approaching negatively
charged silica nuclei. As a result, deposition of silica nuclei and sub-
sequent growth of these nuclei on the microgel core surface is limited to
the bare regions only. It is noteworthy that the drying process has a
significant effect on the morphologies of the hybrid core-shell particles
examined by SEM and TEM because the sample containing HS10 is too
soft. As a result, the samples with higher levels of HS10 (1 and 2 wt%)
show aggregation among the hybrid core-shell particles during drying.
In an attempt to further examine the silica shell morphology, the
sample of P(NIPAAm/AM/MBA) core-silica shell nanoparticles (5AM/
1HS10-111) subjected to the calcination process was examined by using
the FE-SEM technique, as shown in Fig. S1. The size of the calcined
silica particles is estimated to be ca. 20 nm (Fig. S1). This result may
serve as a supporting evidence for the nucleation and growth of silica
embryos to form tiny secondary nanoparticles on the PNIPAM-based
microgel core. In addition, TGA results in Fig. 4 and Table 3 show that
the average silica content (21.6%) for the hybrid particles prepared by
formula with 5 wt% AM and different HS10 concentrations is higher
than that (20.4%) for the hybrid particles prepared by formula with
2 wt% AM and different HS10 concentrations. These results provide
further supporting evidence for successful incorporation of silica on
microgel core surfaces and, furthermore, AM units located on microgel
core surfaces tend to promote the nucleation and growth of silica nuclei
therein.
The hydrodynamic diameters of hybrid microgel core – silica shell
particles (dh) were determined by DLS in the temperature range
25–50 °C (Fig. 5). As expected, dh decreases with increasing HS10
concentration, which is consistent with the results attained from both
SEM and TEM measurements (see dw1 and dw2 data in Table 3). In the
collapsed state (at 50 °C), dh50 data are also comparable to those ob-
tained from SEM or TEM measurements. In addition, the colloidal sta-
bility of hybrid particles was evaluated via zeta potential measure-
ments, and the results summarized in Table 3. The ∣ζ∣ for hybrid
particles are much higher than those for the microgel template
(Table 2), especially for the hybrid particles prepared by formula with
0.1 wt% and 0.5 wt% HS10. It is noteworthy that ∣ζ∣ decreases with
increasing HS10 concentration for both hybrid particles prepared by
recipes with 2 wt% and 5 wt% AM. This observation can be explained
by the ζ vs. CHS10/(1/D) profile, where D is the particle diameter of
hybrid particles in this case. Thus, the parameter CHS10/(1/D) more or
less represents the surface charge density and the higher the CHS10/(1/
D) (i.e., the more negatively charged HS10 species available for stabi-
lizing the colloidal dispersion), the smaller the particle size achieved.
As illustrated in Fig. S2, the experimental data confirm this rather
empirical relationship. This implies that incorporation of HS10 into
microgel core particles not only promotes formation of a large popu-
lation of template particles exhibiting a very large total particle surface
area but also effectively stabilizes microgel core particles and hybrid
particles from aggregation.

Table 3
Particle size and size distribution and zeta potential data for microgel core – silica shell particles with different AM and HS10 concentrations.
Hybrid particles dw1a (nm) PDIa dw2a (nm) PDIa dh25b(nm) dh50b (nm) SRb dh50/dc50 ζc (mV) pHc Silica content (%)d

2AM/0HS10-111 366 ± 19 1.01 380 ± 32 1.03 526 ± 11 383 ± 6 2.6 1.1 −8.0 ± 4.5 5.9 21
2AM/0.1HS10-111 205 ± 14 1.02 253 ± 19 1.02 323 ± 12 214 ± 2 3.4 1.1 −55.2 ± 0.9 6.8 21
2AM/0.5HS10-111 184 ± 11 1.02 215 ± 21 1.03 311 ± 3 185 ± 1 4.7 1.2 −43.5 ± 1.4 6.4 24
2AM/1HS10-111 148 ± 12 1.03 174 ± 14 1.03 254 ± 6 150 ± 2 4.9 1.3 −14.1 ± 2.8 6.3 20
2AM/2HS10-111 117 ± 22 1.27 106 ± 17 1.13 234 ± 2 131 ± 1 5.7 1.5 −12.8 ± 5.7 6.0 16

5AM/0HS10-111 437 ± 35 1.02 429 ± 39 1.04 539 ± 1 429 ± 2 2.0 1.2 −5.0 ± 7.3 5.5 19
5AM/0.1HS10-111 285 ± 14 1.01 300 ± 27 1.03 394 ± 15 309 ± 2 2.1 1.6 −46.0 ± 1.4 6.4 23
5AM/0.5HS10-111 251 ± 14 1.05 267 ± 27 1.04 343 ± 13 253 ± 3 2.5 1.4 −41.0 ± 1.6 6.4 26
5AM/1HS10-111 204 ± 22 1.02 201 ± 15 1.02 314 ± 3 196 ± 1 4.1 1.6 −16.5 ± 1.5 6.1 22
5AM/2HS10-111 142 ± 26 1.22 132 ± 22 1.14 260 ± 9 152 ± 2 4.9 1.5 −10.2 ± 5.9 6.0 18

a
dw1 and dw2 are the weight-average particle diameters and PDI = dw/dn the polydispersity index, where dn is the number-average particle diameter, determined
by SEM and TEM, respectively.
b
dh25 and dh50 are the average hydrodynamic particle diameters for hybrid particles determined by DLS at 25 °C and 50 °C, respectively, and (PDI < 0.1 for all
samples indicates narrow particle size distribution except 2AM/2HS10-111 and 5AM/2HS10-111, which show broad particle size distribution (PDI > 0.1). SR
defined as (dh25/dh50)3 is the swelling ratio of colloidal particles.
c
Zeta potential (ζ) was measured at 25 °C and at pH of the original sample after purification. The standard error was calculated based on 10 runs for each sample.
d
Silica content was determined by TGA measurements at 700 °C.

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N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Fig. 3. Representative TEM images of PNIPAM-based core – silica shell particles with different AM and HS10 concentrations: (a) 2AM/0HS10-111, (b) 2AM/
0.1HS10-111, (c) 2AM/0.5HS10-111, (d) 2AM/1HS10-111, (e) 2AM/2HS10-111, (f) 5AM/0HS10-111, (g) 5AM/0.1HS10-111, (h) 5AM/0.5HS10-111, (i) 5AM/
1HS10-111 and (j) 5AM/2HS10-111.

Fig. 4. TGA profiles of (A) samples with 2% AM: (a) 2AM/0HS10-111, (b) 2AM/0.1HS10-111, (c) 2AM/0.5HS10-111, (d) 2AM/1HS10-111, (e) 2AM/2HS10-111 and
(B) samples with 5% AM: (f) 5AM/0HS10-111, (g) 5AM/0.1HS10-111, (h) 5AM/0.5HS10-111, (i) 5AM/1HS10-111 and (j) 5AM/2HS10-111.

3.3. Thermo-responsive behavior
Figs. 1 and 5 show that the particle size of both microgel cores and
hybrid microgel core – silica shell particles decreases significantly upon
heating from 25 to 50 °C, which implies the volume phase transition
(LCST). The LCST was identified by taking the first derivative of the dc
(or dh) vs. T curve at which point the minimum occurs in the d dc/d T
(or d dh/d T) vs. T curve, as shown in Figs. 1c, d and 5c, d. The LCST
data for both microgel cores and hybrid particles prepared by recipes
with different AM and HS10 concentrations obtained from the DLS
technique are summarized in Table 4. The hybrid core – shell structure
still exhibits the thermo-sensitive properties in the temperature range
25–50 °C due to the permeability of the silica layer [28,42]. Moreover,
it can be predicted that the shell layers may be formed from many tiny
silica clusters (Scheme 1), which exhibit the relatively discrete dis-
tribution on the surface of the microgel core due to the reaction be-
tween the amino groups (from AM or NIPAM units) and epoxy groups
(from GLYMO). This is presumably due to the shell structure of silica
clusters containing numerous slots or channels that allow water mole-
cules through the silica shells, leading to PNIPAM-based microgel cores
can shrink or swell as the temperature is changed. Therefore, the stress
from shrinking or swelling of the thermo-responsive PNIPAM core
would lead to the displacement of the silica cluster. Further research
work is required to verify this speculation. This is the reason why
PNIPAM-based microgel core – silica shell particles still can exhibit a
distinct LCST phase transition behavior. It is shown that LCST values of
both microgel particles and hybrid particles increase significantly with
increasing AM concentration, especially for hybrid particles. By con-
trast, LCST is shifted slightly to higher temperature as the HS10 con-
centration is increased.
The LCST behavior was further investigated by the non-isothermal
DSC technique at a heating rate of 2 °C min−1, as shown by the en-
dothermic peaks in Fig. 6. The results are summarized in Table 4, which
are consistent with those data obtained from DLS measurements. The
total heat (ΔH) data corresponding to the DSC peak closely related to
breaking of hydrogen bonds between the repeating units of microgel
cores and the surrounding water molecules is also included in Table 4.
As expected, the ΔH value of microgel cores is significantly higher than
that of the counterpart of microgel core – silica shell particles. This is
simply due to the dilution effect caused by the silica shell that does not
contribute to the temperature sensitive properties. In summary, the ΔH
value is slightly reduced and LCST is shifted to higher temperature

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N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Fig. 5. Hydrodynamic hybrid particle diameter (dh) as a function of temperature (T) profiles of (a) 2% AM-containing samples: ( ) 2AM/0HS10-111, ( ) 2AM/
0.1HS10-111, ( ) 2AM/0.5HS10-111, ( ) 2AM/1HS10-111 and ( ) 2AM/2HS10-111 and (b) 5% AM-containing samples: ( ) 5AM/0HS10-111, ( ) 5AM/
0.1HS10-111, ( ) 5AM/0.5HS10-111, ( ) 5AM/1HS10-111 and ( ) 5AM/2HS10-111 and the corresponding d dh/d T vs. T curves of (c) 2% AM-containing
samples and (d) 5% AM-containing samples. Note that the dashed lines in (a) and (b) represent the least-squares best-fitted curves for the corresponding discrete data
points by using “sigmoidal fit” in OriginPro 8.5 software, and (c) and (d) obtained from the first derivative of the fitted curves in (a) and (b).

(even up to human body temperature) as the concentration of AM or
HS10 is increased.
3.4. Spectroscopic characterization
The representative samples of microgel cores (2AM/0HS10 and
2AM/1HS10) and hybrid microgel core – silica shell particle (2AM/
1HS10-111) were further characterized by FTIR (Fig. 7). For microgel
cores, there is almost no difference between the spectra of 2AM/0HS10
(Fig. 7a) and 2AM/1HS10 (Fig. 7b). This is most likely due to the very
low concentration of HS10 in 2AM/1HS10, which cannot be detected
by FTIR. For the hybrid core – shell particles, the spectrum of 2AM/
1HS10-111 (Fig. 7c) shows similar characteristic absorption peaks to
the corresponding 2AM/1HS10 spectrum (Fig. 7b) in the wavenumber
range 4000–1320 cm−1. The peaks at 1389 and 1462 cm−1 are attrib-
uted to vibration of isopropyl group, and those at 1537 and 3320 cm−1
attributed to the N-H stretching of amide group in PNIPAM-based chain
[18,43]. The peak at 1680 cm−1 can be attributed to the intrinsic vi-
brational band of carbonyl group of NIPAM and AM units [18,43]. As to
the triplet peaks from 2972 to 2876 cm−1, they are assigned to C-H
bands [43,44]. The shoulder appearing at 3082 cm−1 is ascribed to N-H
stretching vibration of the AM and MBA units [45–46]. Interestingly
enough, a newly peak in the hybrid spectra from 1320 to 950 cm−1
with wide and strong absorption are attributed to the Si-O-Si network
structure, which can be also observed in the GLYMO/TEOS-11 (=1/1
(w/w)) spectrum (Fig. 7d) [47]. This link is formed between the organic
core and inorganic shell phases, in which the ring-opening reaction of
the epoxide group of GLYMO with the amide group of AM unit in
PNIPAM-based chain and hydrolysis and condensation between the
methoxysilyl group of GLYMO and the ethoxysilyl group of TEOS. In
addition, there are rather weak peaks at 787, 690 and 450 cm−1, which
correspond to the SieOeC bond mostly present in the interfacial region
between the organic core and the inorganic shell phases [48].
The chemical incorporation of reactive surfactant HS10 into P
(NIPAM/AM) chains was confirmed by 1H NMR spectroscopy for the
sample prepared by the copolymerization of NIPAM/AM/HS10 [10/
0.2/1 (w/w/w)] in water, as shown in Fig. 8a. The 1H NMR spectra of P
(NIPAM/AM) [10/0.2 (w/w)] (Fig. 8b) and HS10 (Fig. 8c) were used as
references. All the proton signals assigned according to the polymer
structure were shown in the inset of the spectra. In comparison with P
(NIPAM/AM) spectrum, a newly formed characteristic peak at chemical
shift (δ) = 3.5 ppm obtained from P(NIPAM/AM/HS10) spectrum can
be assigned to protons (u′) of ethylene oxide units corresponding to
protons (u) on HS10 spectrum. This result is in agreement with the

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N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Table 4
LCST phase transition data for polymeric core and hybrid core – shell particles
with different AM and HS10 concentrations determined by DLS and DSC
techniques.
Samples LCST (oC)a ΔH (J g−1)b

DLS DSC

2AM/0HS10 34.2 34.3 44.7 ± 1.1

2AM/0.1HS10 34.2 34.8 32.2 ± 0.7
2AM/0.5HS10 34.2 34.9 28.1 ± 1.3
2AM/1HS10 34.2 35.0 28.0 ± 0.7
2AM/2HS10 34.8 35.1 24.5 ± 0.5

5AM/0HS10 34.5 35.3 32.8 ± 0.7

5AM/0.1HS10 34.5 36.7 35.6 ± 0.5
5AM/0.5HS10 34.5 36.5 22.6 ± 0.1
5AM/1HS10 34.8 36.8 22.5 ± 0.6
5AM/2HS10 35.1 37.0 22.1 ± 0.7

2AM/0HS10-111 34.2 34.2 13.9 ± 0.1

2AM/0.1HS10-111 34.3 34.8 13.8 ± 0.3
2AM/0.5HS10-111 34.2 35.3 12.3 ± 0.2
2AM/1HS10-111 34.5 35.2 10.5 ± 0.2
Fig. 7. FTIR spectra for (a) 2AM/0HS10, (b) 2AM/1HS10, (c) 2AM/1HS10-111
2AM/2HS10-111 36.0 36.4 9.7 ± 0.3
and (d) GLYMO/TEOS-11.
5AM/0HS10-111 35.2 35.0 13.8 ± 0.3
5AM/0.1HS10-111 35.6 36.8 12.6 ± 0.4
5AM/0.5HS10-111 36.3 36.9 10.2 ± 0.3 3.5. Surface area and pore size distribution
5AM/1HS10-111 36.3 36.8 8.6 ± 0.1
5AM/2HS10-111 37.5 37.4 8.3 ± 0.1 Finally, the specific surface areas of microgel cores and hybrid
particles in the absence of HS10 (2AM/0HS10 and 2AM/0HS10-111)
a
The LCST was identified by taking the first derivative of the average hy-
drodynamic diameter vs. T (DLS) or the endothermic peak (DSC). and the presence of HS10 (2AM/1HS10, 2AM/1HS10-111) were further
b
The total heat (ΔH) for the phase transition was determined from the in- investigated by nitrogen adsorption-desorption measurements, and the
tegral area under the endothermic peak of the DSC curve. Note that the total pore size distribution calculated by the Barrett-Joyner-Halenda (BJH)
heat was calculated based on the dry mass of the polymeric core or the hybrid method (Fig. 9). It is shown that the specific surface area of microgel
core – shell particles. The standard error was calculated based on three runs for cores containing HS10 (2AM/1HS10, ca. 4.5 m2 g−1) is larger than that
each sample. of surfmer-free sample (2AM/0HS10, ca. 2.2 m2 g−1), while the mean
pore diameter is 7.9 nm for 2AM/1HS10 and 8.5 nm for 2AM/0HS10.
studies of Chiu [49] and Mahajan [50]. It is also interesting to note that After silica encapsulation, the specific surface area of hybrid particles is
the chemical shift at 6.3 ppm observed in spectrum (c) can be attributed 0.4 m2 g−1 for 2AM/0HS10-111 and 1 m2 g−1 for 2AM/1HS10-111,
to the proton (q) of carbon-carbon double bonds, which disappeared via while the mean pore diameter is 13.2 nm for 2AM/0HS10-111 and
copolymerization reaction. In brief, with some new signals appeared in 9.7 nm for 2AM/1HS10-111. This result then indicates that incorpora-
the P(NIPAM/AM/HS10) spectrum corresponding to protons of HS10 tion of HS10 into microgel cores can effectively enhance the specific
spectrum, chemical incorporation of reactive surfactant HS10 into the P surface area for both P(NIPAM/AM) cores and P(NIPAM/AM) core –
(NIPAM/AM) chain was confirmed herein. silica shell particles.

Fig. 6. Non-isothermal DSC profiles at a heating rate of 2 °C min−1 for (A) the polymeric cores: (a) 2AM/0HS10, (b) 2AM/0.1HS10, (c) 2AM/0.5HS10, (d) 2AM/
1HS10, (e) 2AM/2HS10, (f) 5AM/0HS10, (g) 5AM/0.1HS10, (h) 5AM/0.5HS10, (i) 5AM/1HS10, (j) 5AM/2HS10 and (B) the hybrid core – shell particles: (a’) 2AM/
0HS10-111, (b’) 2AM/0.1HS10-111, (c’) 2AM/0.5HS10-111, (d’) 2AM/1HS10-111, (e’) 2AM/2HS10-111, (f’) 5AM/0HS10-111, (g’) 5AM/0.1HS10-111, (h’) 5AM/
0.5HS10-111, (i’) 5AM/1HS10-111 and (j’) 5AM/2HS10-111.

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N.-H. Cao-Luu, et al. European Polymer Journal 120 (2019) 109263

Fig. 8. 1H NMR spectra of (a) P(NIPAM/AM/HS10), (b) P(NIPAM/AM) and (c) HS10 in DMSO‑d6.

Fig. 9. (A) Nitrogen adsorption-desorption isotherms and (B) BJH pore size distribution curves of the polymeric cores and the hybrid core – shell particles in the
absence or presence of HS10.

10
N.-H. Cao-Luu, et al.
4. Conclusions
A novel approach involving chemical incorporation of the surfmer
(polyoxyethylene alkylphenyl ether ammonium sulfate (HS10)) into P
(NIPAM/MBA/AM) chains not only effectively controls the microgel
core size and the subsequently formed microgel core – silica shell
structure but also enhances their specific surface areas. Moreover, using
a relatively low level of anionic HS10 in emulsion polymerization sig-
nificantly alleviates its negative effect on the thermo-sensitivity of final
products. The microgel core – silica shell particles decrease gradually
from ca. 400 to 100 nm when HS10 concentration is increased from 0 to
2%. The hybrid organic – inorganic particles showed well defined
spherical morphology and monodisperse particle size distribution for
the samples containing 0–1 wt% HS10. TEM images confirmed that the
HS10-containing microgel core is covered by a porous silica shell. For
the HS10-free sample, a more or less continuous silica shell surrounding
the microgel particle was observed instead. The LCST of microgel cores
and hybrid core – silica shell particles slightly increases with increasing
HS10 content. By contrast, hybrid nanoparticles showed comparable
LCST to the template (microgel cores).
It was reported that crosslinked PNIPAM core – silica shell particles
were prepared by encapsulation of silica onto crosslinked PNIPAM
microgel particles in the presence of conventional surfactant [16–18].
However, the resultant hybrid particle sizes are about 2–3 times larger
than those of PNIPAM-based microgel core – silica shell nanoparticles
prepared in the presence of HS10 in this work. Such an advancement
may facilitate development of crosslinked PNIPAM-based microgel core
– silica shell nanoparticles as drug carriers in our future work.
Acknowledgement
Financial support from Ministry of Science and Technology, Taiwan
is gratefully acknowledged.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.eurpolymj.2019.109263.
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