Journal of Colloid and Interface Science 536 (2019) 536–547

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Journal of Colloid and Interface Science

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

Regular Article

Synthesis and characterization of poly(N-isopropylacrylamide-co-

acrylamide) mesoglobule core–silica shell nanoparticles
Ngoc-Hanh Cao-Luu a, Quoc-Thai Pham a, Zong-Han Yao c, Fu-Ming Wang b, Chorng-Shyan Chern a,⇑
a
Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 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 106, Taiwan

g r a p h i c a l a b s t r a c t

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

Article history: Hypothesis: How to encapsulate poly(N-isopropylacrylamide) (PNIPAM) mesoglobule cores by silica
Received 10 September 2018 shells greatly affects the resultant nanoparticle structures. Incorporation of acrylamide (AM) unit into
Revised 26 October 2018 PNIPAM in combination with 3-glycidyloxypropyltrimethoxysilane (GLYMO, as a coupling agent)
Accepted 27 October 2018
effectively induces nucleation and growth of silica on PNIPAM core surfaces, where the –NH2 of
Available online 29 October 2018
acrylamide reacts with the epoxide of GLYMO while GLYMO further participates in subsequent sol-gel
reaction of tetraethyl orthosilicate (TEOS), thereby leading to desirable particle morphology.
Keywords:
Experiments: PNIPAM-based core–silica shell nanoparticles were prepared by sol-gel reaction of TEOS
PNIPAM based mesoglobule
Silica
and GLYMO in the presence of polymeric core particles. The major parameters investigated in a system-
Coupling agents atic fashion include acrylamide concentration and weight ratio of polymer:GLYMO:TEOS. GPC, DLS, DSC,
Hybrid core–shell nanoparticles FE-SEM, TEM, FTIR and TGA were then used to characterize polymeric cores and hybrid nanoparticles.
Findings: The particle morphology was governed primarily by the acrylamide content and the weight
ratio of PNIPAM/AM:GLYMO:TEOS, and desirable hybrid nanoparticles with narrow particle size distribu-
tion were achieved. The LCST of PNIPAM-based mesoglobules increases with increasing acrylamide
content. Encapsulation of PNIPAM-based mesoglobules with silica also reduces their thermo-
sensitivity. This is the first report of developing a novel approach to prepare PNIPAM-based mesoglobule
core–silica shell nanoparticles with controllable particle morphologies.
Ó 2018 Published by Elsevier Inc.

1. Introduction

Amongst various thermo-sensitive polymers, N-

isopropylacrylamide (PNIPAM) is the most prominent candidate
⇑ Corresponding author. for biomedical applications because of its biocompatibility and
E-mail address: cschern@mail.ntust.edu.tw (C.-S. Chern).

https://doi.org/10.1016/j.jcis.2018.10.091
0021-9797/Ó 2018 Published by Elsevier Inc.
 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547
the lower critical solution temperature (LCST) around 32 °C that is
quite close to the physiological temperature of human body [1,2].
PNIPAM comprising both the hydrophilic amide group and
hydrophobic isopropyl group is well characterized [3–5]. Below
LCST, the amide group of PNIPAM interacts strongly with water
molecules via hydrogen bonding, thereby leading to a large
amount of water being contained in the expanded polymer coils
in water (as a homogeneous aqueous polymer solution) [6–11].
In contrast, PNIPAM chain becomes more compact due to the dis-
rupted hydrogen bonds between the amide group of PNIPAM and
water molecules when the temperature is greater than LCST
[12–16]. This will result in separation of liquid and solid phases
and then cause collapse of the swollen polymer coils (termed the
mesoglobules) [12–16].
Nun et al. [17] reported that PNIPAM is of relatively high soft-
ness in the hydrated state, which greatly limits its mechanical sta-
bility. To resolve this issue, interpenetrating networks comprising
PNIPAM and polymers with desirable mechanical properties or
the incorporation of inorganic nanoparticles into PNIPAM were
proposed [17]. Byun et al. [18] pointed out that inorganic silica
showing excellent physicochemical properties (e.g., mechanical
strength, chemical and thermal stability, biocompatibility, low tox-
icity and low permeability) and low cost. Furthermore, the synthe-
sis of silica can be directly carried out on the PNIPAM particle core
surfaces to form PNIPAM core–silica shell particles, which is a
highly desirable approach [17]. For example, PNIPAM particles
filled with multiple colloidal silica with the particle size close to
1 mm via in situ sol-gel process was achieved [18]. The thermo-
sensitive raspberry-like hybrid particles (particle size 500 nm in
diameter) consisting of PNIPAM microgel cores decorated with sil-
ica particles was reported by Dechezelles et al. [19]. Wang and
Asher [20] prepared the PNIPAM core surrounded by a shell com-
prising very small silica particles with a size of ca. 400 nm in diam-
eter. Poly(NIPAM-co-acrylic acid) (PNIPAM/AA) core–silica shell
particles (ca. 250 nm in diameter) were successfully synthesized
by Hu and co-workers [21]. Duan et al. [22] proposed an approach
to synthesize PNIPAM/silica composite microspheres by Pickering
emulsion polymerization. It is noteworthy that most of the PNI-
PAM/silica composite particles reported in the literature so far
are rather limited in drug delivery applications because of their
micron-sized characteristic, originating from the micron-sized
crosslinked PNIPAM core particles [17–23]. It is very difficult for
micron-sized particles (as a drug carrier) to penetrate tissues and
then enter the cells, thereby leading to inefficient delivery of drug
molecules to target sites of action [24–29]. Uptake of nanoparticles
is approximately 15–250 times higher than that of microparticles
in the particle size range 1–10 mm [25,30,31]. Therefore, it is crucial
for the dimension of PNIPAM/silica composite particles to be con-
trolled within the nano-sized range via minimizing the core parti-
cle size. In this regard, some representative methods involving
adjustment of the size of cross-linked PNIPAM core particles
include the addition of surfactants [32–34], electrolytes [35–38]
and highly charged co-monomers [35,39]. Nevertheless, the micro-
gel particle size was not optimally controlled in these studies, even
under well-managed experimental conditions [35].
In this work, we report a novel approach to control the size of
poly(NIPAM-co-acrylamide) (PNIPAM/AM) mesoglobule core–sil-
ica shell nanoparticles prepared at temperature above the LCST.
These mesoglobule cores in nanoscale form via separation of liquid
and solid phases and subsequent collapse of the swollen polymer
coils (in the absence of surfactant) above the LCST in the dilute
solution [40,41]. This is followed by using the mesoglobule cores
as the nucleating agent for silica encapsulation to form the perfect
core–shell nanostructure [42]. For efficient silica encapsulation, 3-
glycidyloxypropyltrimethoxysilane (GLYMO, a coupling agent)
containing one epoxide group and three methoxysilyl groups is
537
adopted to enhance the affinity between the organic and inorganic
part [43]. In this manner, the amide group of AM can react with the
epoxide group of GLYMO, while the four ethoxysilyl groups of TEOS
(silica precursor) and the three methoxysilyl groups of GLYMO can
simultaneously undergo the sol-gel reaction [43–45] to form tiny
silica nanoparticles right on the PNIPAM/AM mesoglobule core sur-
faces, thereby leading to the desirable particle morphology. The
results obtained from this work are useful in designing thermo-
responsive PNIPAM/AM mesoglobule core–silica shell nanoparti-
cles with controlled particle morphology and physicochemical
properties.
2. Experimental
2.1. Materials
The chemicals used in this work include N-isopropylacrylamide
(NIPAM, 99%, Acros), acrylamide (AM, 99%, Sigma-Aldrich), potas-
sium persulfate (KPS, 99%, Acros), 3-glycidyloxypropyltrimethoxy
silane (GLYMO, 98%, Evonik), tetraethyl orthosilicate (TEOS, 98%,
Acros), potassium bromide (KBr, 99+, Acros), tetrahydrofuran
(THF, 99.9%, Sigma-Aldrich) and ethanol (95%, Uni-Onward Corp).
Deionized water (Barnsted, Nanopure Ultrapure Water System,
specific conductance <0.057 mS cm 1) was used for all experiments.
All chemicals were reagent grade and used as received.
2.2. Synthesis of polymeric cores
The samples, PNIPAM, PNIPAM/5AM and PNIPAM/10AM, were
synthesized via free radical polymerization of 1 g of NIPAM in
the presence of 0, 0.05 and 0.1 g of AM, respectively, with 0.04 g
of KPS as the initiator in 10 g of water. The reaction was carried
out at 70 °C over a period of 24 h in nitrogen atmosphere. The
crude polymer solution was washed with hot water (50 °C) to
remove residual monomer(s) and initiator (if present). The resul-
tant polymer (PNIPAM, PNIPAM/5AM or PNIPAM/10AM) was then
dissolved in cold water and stored as the stock solution for further
experiments.
2.3. Synthesis of hybrid core–shell particles
The polymeric cores were encapsulated by silica shells via the
sol-gel reaction of GLYMO (a coupling agent) and tetraethyl
orthosilicate (TEOS, a silica precursor). First, the aqueous polymer
solution (0.5 wt%) was adjusted to pH 12 by sodium hydroxide
(0.5 M) and then heated up to 50 °C. Subsequently, GLYMO was
added into the polymer dispersion, immediately followed by addi-
tion of TEOS into the reaction mixture. The reaction was carried out
at 50 °C over a period of the prescribed time (e.g., 5 h). The final
product was first precipitated by centrifugation (25,000 rpm,
30 min) and washed with alcohol and then water three times.
Table 1 summarizes the recipes used to prepare the hybrid
organic–inorganic (core–shell) colloidal particles in this work.
2.4. Characterization
The relative weight average molecular weight (Mw) of polymer
was determined by gel permeation chromatography (GPC, Waters
Styragel HR2, HR4 and HR6). A series of polystyrene standards was
used to establish the calibration curve
THF was used as the eluent
solvent, and a flow rate of 1 mL min 1 used for GPC measurements
at 40 °C. The average hydrodynamic diameter of colloidal particles
(d) and the lower critical solution temperature (LCST) were
obtained from dynamic light scattering technique (DLS, Malvern
1000 HAS) in the temperature range 26–50 °C with 2 °C intervals
538 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547
Table 1
Recipes for encapsulation of PNIPAM-based core particles by silica.
Samples PNIPAM (g) PNIPAM/5AM (g)
a
PNIPAM-111 0.1 – –
PNIPAM/5AM-101a – 0.1
PNIPAM/5AM-111a – 0.1
PNIPAM/5AM-121 a – 0.1
PNIPAM/5AM-112 a – 0.1
PNIPAM/5AM-122 a – 0.1
PNIPAM/10AM-111 a – –
GLYMO/TEOS-11b – –
a
The last three digits represent the weight ratio of polymer:GLYMO:TEOS.
b
The last two digits represent the weight ratio of GLYMO:TEOS.
with a concentration range 0.1–1 wt%. The thermal behavior of
both polymer and core–shell particles with a total solids content
of 10% were investigated by Differential Scanning Calorimetry
(DSC, TA Instruments Q20) from 25 to 60 °C with a scanning rate
of 2 °C min 1. The dried particle size and morphology were charac-
terized by field emission scanning electron microscopy (FE-SEM,
JEOL JSM-6500F) and transmission electron microscopy (TEM, H-
7100 TEM, Hitachi). The sample was diluted in water to a total
solids content of ca. 0.5%, dropped on the carbon tapes (SEM) or
the polymer coated copper grids (TEM) and dried at room temper-
ature. The number average particle diameter (dn), weight average
particle diameter (dw) and polydispersity index (PDI = dw/dn) were
determined by SEM or TEM (at least 150 particles measured). Four-
ier transform infrared (FTIR) spectra were recorded on FTS-3500
instrument (Bio-Rad) in the wavenumber range 4000–400 cm 1
with a total of 32 scans and a resolution of 4 cm 1 under nitrogen
flow to remove the moisture (if present). Thermogravimetric anal-
ysis (TGA) measurement was carried out on a Perkin-Elmer Dia-
mond TG/DTA instrument with a heating rate of 10 °C min 1
under an air flow rate of 200 mL min 1 in the temperature range
100–800 °C.
3. Results and discussion
3.1. The approach used to synthesize PNIPAM based mesoglobule core–
silica shell nanoparticles
Formation of PNIPAM core–silica shell nanoparticles is
schematically shown in Scheme 1, in which mesoglobule cores
are encapsulated by silica nanoparticles with GLYMO as the cou-
pling agent. Note that GLYMO possessing the epoxy group that
can react with the amino group of the AM unit (as a comonomer,
if present) or it may react with the amide group of the NIPAM unit
by the ring-opening reactions. Note that the primary hydrogen of
Scheme 1. Schematic illustration of the formation of PNIPAM - silica (core - shell) nanoparticles.
PNIPAM/10AM (g) GLYMO (g) TEOS (g) H2O (g)
0.1 0.1 20
– – 0.1 20
– 0.1 0.1 20
– 0.2 0.1 20
– 0.1 0.2 20
– 0.2 0.2 20
0.1 0.1 0.1 20
– 0.1 0.1 20
the –NH2 group of the AM unit is much more reactive toward
GLYMO as compared to the secondary hydrogen of the >NH group
of the NIPAM unit in PNIPAM-based chain that is most likely due to
the satiric effect involved in N-isopropylacrylamide, as supported
by the literature dealing with competitive primary and secondary
amines in the ring-opening reaction of epoxy resins [45,46]. It is
crucial for the formation of silica nuclei to be induced on the sur-
face of polymeric cores during the early stage of the sol-gel process
in order to achieve desirable organic core–inorganic shell particle
morphology. This is followed by diffusion of hydrolyzed TEOS
[i.e., silicic acid (Si(OH)4)] and oligomeric silica from the bulk aque-
ous phase to the interfacial layer between the continuous aqueous
phase and the disperse phase, in which the subsequent sol-gel
reactions take place, thereby leading to the continuous growth of
the silica shell. Ultimately, the hybrid nanoparticles comprising
PNIPAM core and silica shell can be achieved.
3.2. Preparation and characterization of PNIPAM based mesoglobule
cores
PNIPAM based mesoglobule cores prepared by free radical poly-
merization of NIPAM in the presence of 0 wt% AM (PNIPAM), 5 wt%
AM (PNIPAM/5AM) and 10 wt% AM (PNIPAM/10AM) at 70 °C were
characterized by DLS and GPC, and the results summarized in
Table 2. Above LCST, the intra- and/or intermolecular hydrophobic
interactions of PNIPAM induce the precipitation of polymer chains
to form particle embryos in the continuous aqueous phase. This is
followed by the growth of these nuclei via molecular diffusion of
PNIPAM from the bulk aqueous phase to the particle surfaces
and subsequent deposition therein or aggregation of particles in
order to reduce the interfacial free energy. Table 2 shows that, at
constant AM concentration, the average hydrodynamic particle
diameter determined at 50 °C (d50) increases with increasing
concentration and the particle size distribution is quite broad
(PDI > 0.1). Yan et al. [10] indicated that the size of PNIPAM
 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547
Table 2
Particle size and particle size distribution and molecular weight and molecular weight distribution data for PNIPAM, PNIPAM/5AM and PNIPAM/10AM samples with different
concentrations.
Samples Concentration (wt%)
PNIPAM 0.1
0.5
1.0
PNIPAM/5AM 0.1
0.5
1.0
PNIPAM/10AM 0.1
0.5
1.0
a
d50 is the average hydrodynamic particle diameter and PDI is the polydispersity index determined by DLS at 50 °C. PDI < 0.1 indicates narrow particle size distribution,
whereas PDI > 0.1 then indicates broad particle size distribution. All experiments were conducted three times and DLS measurements are repeated ten times for each
experiment.
b
Mw is the weight-average molecular weight and PDI (=Mw/Mn) is the polydispersity index measured by GPC, where Mn is the number-average molecular weight.
particles was primarily dependent on the PNIPAM concentration
and molecular weight. In general, the lower the PNIPAM concen-
tration, the smaller the particles formed [12]. Particle embryos
generated in the continuous aqueous phase tend to associate into
multi-chain aggregates, which in many instances stop growing
once a certain dimension is achieved during the particle nucleation
process [12].
It is also interesting to note that, at constant a concentration
(e.g., 0.5 wt%), the relative weight-average molecular weight
(Mw) decreases with increasing AM concentration. In brief, free
radical polymerization taking place in the heterogeneous reaction
system (e.g., emulsion polymerization) generally results in higher
polymer molecular weight as compared to the solution polymer-
ization. For the copolymerization of NIPAM and AM using KPS as
the initiator at 70 °C, the solution polymerization of the water-
soluble AM with NIPAM becomes more important and, thus,
polymer chains with lower molecular weight form. By contrast,
the molecular weight distribution (PDI in the range 1.7–2.0, char-
acteristic of emulsion polymerization [47,48]) does not vary signif-
icantly as the AM concentration is increased. In this study, PNIPAM,
PNIPAM/5AM and PNIPAM/10AM with a concentration of 0.5 wt%
that balance the small enough particle size and high enough total
solids content were chosen for further silica encapsulation.
3.3. Encapsulation of PNIPAM based mesoglobule cores with silica
shells
3.3.1. Effects of reaction temperature and time
First, PNIPAM/5AM mesoglobules encapsulated by silica shells
via the sol-gel reaction of TEOS in the absence of coupling agent
above its LCST (34.7 °C determined by DSC) were investigated.
The variables chosen for study are the reaction temperature and
time. It should be noted that the initial reaction mixture is trans-
parent at room temperature (ca. 25 °C < TLCST) and it becomes
translucent or milky white (observed at room temperature) after
the reaction was carried out above LCST over a period of the pre-
scribed time (e.g., 1, 3, 5 and 7 h). At 40 °C, it took about 5 h for
the reaction mixture to become a stable milky dispersion
(observed at room temperature), indicating the successful forma-
tion of hybrid organic core–inorganic shell particles. The resulting
particles with dw = 132 nm and PDI = 1.09 obtained from silica
encapsulation over a period of 7 h show characteristic of spherical
shape and rough particle surface, as shown by SEM (Fig. S1A). As
expected, the appearance of the reaction mixture at 50 °C over a
period of 3 h was transformed into milky white (observed at room
temperature). The values of dw and PDI for the sample prepared at
50 °C for 5 h are 92 nm and 1.06, respectively (Fig. S1B). This is fol-
lowed by extensive agglomeration to form the network structure
539
d50a (nm) PDIa Mwb  104 (g mol 1
) PDIb
42 ± 1 0.08–0.10 6.33 1.71
65 ± 2 0.06–0.08
98 ± 5 0.06–0.14
56 ± 2 0.06–0.10 1.88 1.99
76 ± 4 0.05–0.09
119 ± 4 0.07–0.17
58 ± 2 0.07–0.11 1.07 1.70
79 ± 5 0.08–0.14
136 ± 6 0.09–0.19
over a period of 7 h (Fig. S1C). It is noteworthy that smaller hybrid
core–shell particles were produced in the run at 50 °C for 5 h in
comparison with that at 40 °C for 7 h. This is because the stronger
hydrophobic interactions of PNIPAM/5AM at higher temperature
allow these mesoglobules to favorably expel their water contents
and subsequently form the tightly collapsed particle structure
[49]. For the reaction conducted at the highest temperature
(60 °C) over a period of ca. 1 h, the reaction mixture rapidly turned
to a milky white dispersion (observed at room temperature), fol-
lowed by fast particle aggregation to form the network structure,
as shown in Fig. S1D.
3.3.2. Effects of GLYMO and TEOS concentrations
In this series of experiments, the reaction temperature and time
were kept constant at 50 °C and 5 h, respectively, and the weight
percentage of PNIPAM based mesoglobule cores was also kept con-
stant at 0.5 wt%. In this manner, the effects of the weight ratio of
GLYMO (as a coupling agent) to TEOS were investigated. The initial
compositions of PNIPAM, GLYMO and TEOS for the runs
PNIPAM/5AM-111, PNIPAM/5AM-121, PNIPAM/5AM-112 and
PNIPAM/5AM-122 can be found in Table 1. For example, the last
three digits in PNIPAM/5AM-111 represent the weight ratio of PNI-
PAM/5AM:GLYMO:TEOS = 1:1:1. For comparison, PNIPAM/5AM-
101 (in the absence of coupling agent) was also included in this
study.
For the run PNIPAM/5AM-101, the reaction system of TEOS in
the presence of PNIPAM/5AM mesoglobules remained translucent
at room temperature. It was then postulated that the nucleation
and growth of silica nuclei occurred primarily in the continuous
aqueous phase and encapsulation of PNIPAM/5AM mesoglobules
by silica (if present) did not contribute to the sol-gel reaction of
TEOS to an appreciable extent. This scenario might explain why
PNIPAM/5AM-101 appears translucent, which is a great contrast
to the opaque PNIPAM/5AM-111 (see Fig. S2). Nevertheless, inde-
pendent experiments are required to verify this speculation. This
is attributed to GLYMO possessing one reactive epoxide group
and three methoxysilyl groups. The epoxide group can react with
the amide group of AM under basic conditions via the ring-
opening reaction (Scheme 2). On the other hand, the methoxysilyl
groups can be hydrolyzed to form reactive silanol groups, which
can participate in the sol-gel reaction of TEOS [45]. This will then
promote the sol-gel reaction of TEOS taking place on the
PNIPAM/5AM-111 mesoglobule cores via the bridging effect of
GLYMO. Under the circumstances, these mesoglobule cores were
capable of growing effectively with the aid of GLYMO during the
sol-gelsol-gel reaction of TEOS and reached the ultimate dry
weight-average particle diameter of 92 nm determined by SEM
and TEM. Experiments with other compositions showed similar
540 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547
Scheme 2. Schematic illustration of possible reactions between the epoxide group
of GLYMO and the primary amine group of the AM unit and/or the secondary amine
group of the NIPAM unit.
silica encapsulation behavior, and some representative data shown
in Figs. 1 (SEM) and 2 (TEM) and Table 3 (particle size data mea-
sured by SEM and TEM).
First, the weight-average PNIPAM/5AM core–silica shell particle
diameter (dw) increases with increasing GLYMO or TEOS concen-
tration (Table 3). Taking the effect of GLYMO concentration as an
example, at constant TEOS concentration, comparing
PNIPAM/5AM-111 with PNIPAM/5AM-121 (or comparing
PNIPAM/5AM-112 with PNIPAM/5AM-122), dw is increased by a
factor of ca. 57% {=[(146 92)/92 + (143 92)/92]/2, in which
the first term in the numerator is based on the dw1 data, and the
second term based on the dw2 data in Table 3} (or 29%). This result
suggests that doubling the GLYMO concentration significantly
increases the probability of nucleation and growth of silica
embryos surrounding the PNIPAM/5AM mesogloblue cores,
thereby leading to thicker silica shells and higher surface rough-
ness (Fig. 2C and D). However, at higher TEOS concentration
Fig. 1. Representative SEM images of PNIPAM/5AM core–silica shell particles obtained from the runs: (A) PNIPAM/5AM-111, (B) PNIPAM/5AM-121, (C) PNIPAM/5AM-112
and (D) PNIPAM/5AM-122.
(PNIPAM/5AM-112 vs. PNIPAM/5AM-122), the effect of doubling
the GLYMO concentration on the resultant hybrid particle size
becomes less pronounced (an increase in dw by a factor of only
ca. 29%). This is simply because the runs with higher TEOS concen-
tration provide the reaction system with more silica precursors
available for encapsulation of PNIPAM/5AM mesoglobule cores,
which compensates the effect of doubling the GLYMO concentra-
tion to some extent. It is also interesting to note that Fig. 1 and
the insets in Fig. 2 clearly show the PNIPAM encapsulated by tiny
silica nanoparticles.
The significance of this result is that we have established an
effective approach for silica encapsulation of PNIPAM based
mesoglobule cores, which involves the incorporation of some
comonomer units (e.g., AM chosen for this study) into PNIPAM
cores in combination with an adequate coupling agent (e.g.,
GLYMO), which can simultaneously react to the amide group of
the AM unit in PNIPAM and the silica precursors originating from
TEOS. In this manner, desirable nucleation and growth of silica
embryos occurring primarily on the PNIPAM based mesoglobule
core surfaces to form hybrid nanoparticles can thus be achieved.
Furthermore, this approach allows one to fine tune the particle size
and the thickness and morphology of the shell (i.e., the permeabil-
ity of the shell) of PNIPAM based mesoglobule core–silica shell
particles.
3.3.3. Effect of AM content
The effects of AM content in PNIPAM based mesoglobule core–
silica shell particles on their physical properties are shown in
Table 3 and Figs. 1A, 2A, 3 and 4. First, PNIPAM/5AM-111 shows
the comparable particle size and particle size distribution deter-
mined by SEM to PNIPAM-111 in the absence of AM (Table 3).
 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547 541

Fig. 2. Representative TEM images of PNIPAM/5AM core–silica shell particles obtained from the runs: (A) PNIPAM/5AM-111, (B) PNIPAM/5AM-121, (C) PNIPAM/5AM-112
and (D) PNIPAM/5AM-122.

Table 3 ably due to the greatly enhanced nucleation and growth of silica on
Particle size and particle size distribution data for PNIPAM/5AM core–silica shell the PNIPAM-based mesoglobule surfaces containing very high con-
particles obtained from the runs with different weight ratios of PNIPAM/5AM:
centration of AM units. This will then greatly promote the sol-gel
GLYMO:TEOS.
reaction between the methoxysilyl groups of GLYMO and the
Samples dw1a (nm) PDI a
dw2 (nm) a
PDI a
ethoxysilyl groups of TEOS on the polymeric core surfaces, thereby
PNIPAM-111 90 1.13 – – increasing the probability of forming oblong nanoparticles. Never-
PNIPAM/5AM-111 92 1.06 92 1.07 theless, additional independent experiments are required to verify
PNIPAM/5AM-121 146 1.15 143 1.06
this speculation. Nevertheless, the abundant AM-rich chain
PNIPAM/5AM-112 143 1.11 153 1.10
PNIPAM/5AM-122 176 1.14 206 1.23 segments in PNIPAM/10AM mesoglobule cores might play an
important role in the evolution of such particle morphology with
a
dw1 and dw2 are the weight-average particle diameter and polydispersity index
the minimal interfacial free energy. Finally, the TEM images in
(PDI = dw/dn, where dn is the number-average particle diameter) determined by
SEM and TEM, respectively.
Figs. 2A and 4A show the contrast difference between the core
and shell phases, indicating the formation of PNIPAM based
mesoglobule core–silica shell particle morphology for PNIPAM-
These two products are characterized by relatively spherical shape 111 and PNIPAM/5AM-111. Unfortunately, the ambiguous
and raspberry morphology (Figs. 1A vs. 3A (SEM) and 2A vs. 4A boundary between the core and shell phases prevented one from
(TEM)). On the other hand, PNIPAM/10AM-111 is characterized estimating the shell thickness. Fig. 4B also illustrates the oblong
by mixed oblong (with the longitudinal length being about two and spherical particles with the core phase inside for
to three times of the latitudinal length) and spherical particle mor- PNIPAM/10AM-111.
phology with relatively smooth particle surface (Fig. 4B). It is also
interesting to note that the transition from the spherical particle
morphology to oblong shape with a higher aspect ratio for 3.4. Characterization of PNIPAM-based core–silica shell particles
PNIPAM/10AM-111 is quite similar to those surfactant systems
where the transition from spherical micelles to oblong ones were The hydrodynamic hybrid particle diameter (d) determined by
reported [50,51] though they may be attributed to different mech- DLS as a function of temperature (T) profiles is shown in Fig. 5A.
anisms. In this case, such a particle morphology transition is prob- By taking the first derivative of the d vs. T curve, the LCST was iden-
542 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547
Fig. 3. Representative SEM images of PNIPAM-based core–silica shell particles obtained from the runs: (A) PNIPAM-111 and (B) PNIPAM/10AM-111.
Fig. 4. Representative TEM images of PNIPAM-based core–silica shell particles obtained from the runs: (A) PNIPAM-111 and (B) PNIPAM/10AM-111.
tified as the temperature at which point the minimum occurs in
the d d/d T vs. T curve, as shown in Fig. 5B.
Fig. 5A demonstrates that, just like PNIPAM based mesoglobules,
the hybrid particles shrink significantly with increasing tempera-
ture primarily due to the permeability of the silica layer [52]. This
is attributed to the shell structure of silica clusters containing
numerous slots that allow water molecules in PNIPAM based
mesoglobule cores to be expelled through the silica shells to the con-
tinuous aqueous phase as the temperature is increased. Moreover,
these slots in the silica shell provide the hybrid particle with the
buffering space for tightening the silica clusters during the phase
transition from the swelling state to the shrinking state. This is the
reason why PNIPAM based mesoglobule core–silica shell particles
still can exhibit a distinct LCST phase transition behavior. The LCST
determined by DLS shifts slightly to higher temperature with
increasing AM concentration due to the higher degree of hydration
around the AM-rich chain segments, which can form much
stronger hydrogen bonding with water molecules. The LCST data
for PNIPAM-111, PNIPAM/5AM-111, PNIPAM/5AM-121, PNIPAM/
5AM-112, PNIPAM/5AM-122 and PNIPAM/10AM-111 obtained
from the DLS technique are summarized in Table 4. It is noteworthy
that, at constant T, the hydrodynamic hybrid particle size (d)
increases with increasing AM, GLYMO and TEOS concentration,
which is consistent with the results attained from both SEM and
TEM (Table 3).
DSC was also used to study the thermo-responsive property of
PNIPAM based mesoglobules (Fig. 6A) and PNIPAM based core–sil-
ica shell particles (Fig. 6B) in the temperature range 25–60 °C at a
heating rate of 2 °C min 1. The temperature corresponding to the
minimal endothermic peak in Fig. 6A and B was defined as the LCST
phase transition temperature [53], and the results listed in Table 4.
The LCST data determined by DSC show the same trend as those
measured by DLS (Table 4). Furthermore, both incorporation of
AM units into PNIPAM and the encapsulation of PNIPAM-based
mesoglobules with silica tend to reduce the thermo-sensitivity of
PNIPAM based core–silica shell particles. The total heat (DH) corre-
sponding to the DSC peak related to breaking of hydrogen bonds
between the polymeric repeating units and the surrounding water
molecules is also included in Table 4. As expected, the DH of PNI-
PAM based mesoglobules is significantly higher than that of the
counterpart of PNIPAM based core–silica shell particles (e.g., PNIPA-
M/5AM vs. PNIPAM/5AM-111). This can be attributed to the fact
that AM units in the mesoglobule cores are not thermo-sensitive
to an appreciable extent and the dilution effect of the inorganic silica
content. In addition, the DH data for both PNIPAM based mesoglob-
ules (e.g., PNIPAM/5AM vs. PNIPAM/10AM) and PNIPAM based
core–silica shell particles (e.g., PNIPAM/5AM-111 vs. PNIPAM/
10AM-111) show that DH decreases with increasing AM content.
PNIPAM based mesoglobule core–silica shell particles of
PNIPAM-111, PNIPAM/5AM-111, PNIPAM/5AM-121, PNIPAM/
5AM-112, PNIPAM/5AM-122 and PNIPAM/10AM-111 were further
characterized by FTIR. For comparison, the samples of GLYMO/
TEOS-11 (the weight ratio of GLYMO:TEOS = 1:1, Fig. 7(VII)) and
PNIPAM/10AM (Fig. 7(VIII)) were also included in this study.
First, all hybrid particles (Fig. 7(I)–(VI)) show similar character-
istic absorption peaks to PNIPAM/10AM in the wavenumber range
 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547 543

Fig. 5. (A) Hydrodynamic hybrid particle diameter (d) as a function of temperature (T) profiles and (B) d d/d T vs. T curves: ( ) PNIPAM-111, (r) PNIPAM/5AM-111, (.)
PNIPAM/10AM-111, ( ) PNIPAM/5AM-112, (d) PNIPAM/5AM-121, (j) PNIPAM/5AM-122.

Table 4 1351–4000 cm 1. The peaks at 1351 and 1458 cm 1 are attributed

Some LCST phase transition data for PNIPAM based mesoglobules and PNIPAM-based to vibration of isopropyl group, and those at 1602 and 3321 cm 1
mesoglobule core–silica shell particles determined by the DLS and DSC techniques.
due to the NAH stretching of the amide group in PNIPAM based
Samples LCSTa (°C) DHb (J g 1) chain [21]. The peak at 1730 cm 1 can be attributed to the intrinsic
DLS DSC vibrational band of carbonyl group of NIPAM and AM units [21]. As
to the triplet peaks at 2876, 2935 and 2972 cm 1, they are assigned
PNIPAM – 32.1 ± 0.1 42.9 ± 0.7
PNIPAM-111 32.0 ± 0.4 32.0 ± 0.1 18.6 ± 0.4 to CAH bands [54]. The shoulder appearing at 3082 cm 1 is
PNIPAM/5AM – 34.7 ± 0.1 34.2 ± 0.9 ascribed to the NAH stretching vibration of the AM unit [55]. On
PNIPAM/5AM-111 35.0 ± 0.3 33.4 ± 0.2 16.9 ± 1.2 the other hand, the peaks with the wavenumber smaller than
PNIPAM/5AM-121 35.3 ± 0.4 33.7 ± 0.3 16.4 ± 1.3
1351 cm 1, the characteristic bands from 1056 to 1250 cm 1 in
PNIPAM/5AM-112 35.2 ± 0.3 34.9 ± 0.3 12.1 ± 0.8
PNIPAM/5AM-122 35.0 ± 0.5 34.8 ± 0.2 10.6 ± 0.9
the GLYMO/TEOS-11 spectrum representing the SiAOASi network
PNIPAM/10AM – 37.2 ± 0.1 27.6 ± 0.5 structure are also observed in PNIPAM-111, PNIPAM/5AM-111,
PNIPAM/10AM-111 37.0 ± 0.5 35.6 ± 0.3 10.2 ± 0.4 PNIPAM/5AM-112, PNIPAM/5AM-121, PNIPAM/5AM-122 and
a
The LCST was identified by taking the first derivative of the average hydrody-
PNIPAM/10AM-111, in which the ring-opening reaction of the
namic diameter vs. T (DLS) or the minimum of the endothermic peak (DSC). The epoxide group of GLYMO by the amide group of AM unit in PNIPAM
standard error was calculated based on three runs for each sample. based chain and hydrolysis and condensation between the
b
The total heat (DH) for the phase transition was determined from the integral methoxysilyl group of GLYMO and the ethoxysilyl group of TEOS
area under the endothermic peak of the DSC curve.
to form the Si-O-Si network structure between the organic core

Fig. 6. Non-isothermal DSC profiles at a heating rate of 2 °C min 1 (a) PNIPAM, (b) PNIPAM/5AM, (c) PNIPAM/10AM (d) PNIPAM-111, (e) PNIPAM/5AM-111, (f) PNIPAM/5AM-
121, (g) PNIPAM/5AM-112, (h) PNIPAM/5AM-122, and (i) PNIPAM/10AM-111.
544 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547
Fig. 7. FTIR spectra for (I) PNIPAM-111, (II) PNIPAM/5AM-111, (III) PNIPAM/5AM-
112, (IV) PNIPAM/5AM-121, (V) PNIPAM/5AM-122, (VI) PNIPAM/10AM-111, (VII)
GLYMO/TEOS-11, and (VIII) PNIPAM/10AM.
and inorganic shell phases. In addition, there are weak peaks at
about 451, 692 and 787 cm 1, which correspond to the SiAOAC
bond mostly present in the interfacial region between the organic
core and the inorganic shell phases [56].
The effect of AM, GLYMO and TEOS content in PNIPAM based
mesoglobule core–silica shell on their thermal properties mea-
sured by TGA is shown in Fig. 8. The residue at 800 °C increases
gradually from 37% to 45% with the AM content being increased
from 0 to 10 wt%. This result provides supporting evidence for
the primary amide group of AM is much more reactive to
GLYMO than the secondary amide group of NIPAM. Moreover,
the residue of hybrid samples also increases from 41% to 49%
with the weight ratio of GLYMO (or TEOS) to PNIPAM/5AM being
increased from 1 to 2. This is most likely due to the increased
probability of silica particle nucleation and growth on PNIPAM
based mesoglobule cores when the AM concentration is
increased.
Finally, the morphology of PNIPAM-based mesoglobule core–
silica shell particles were confirmed by the SEM images
(Fig. 9). The samples were calcined in TGA cell with the gradu-
ally increased temperature from 500 to 800 °C over a period of
30 min, followed by remaining at 800 °C for 30 min in air. For
both PNIPAM-111 (Fig. 9A) and PNIPAM/5AM-111 (Fig. 9B), the
inorganic silica shells are not significantly affected by calcina-
tion, as evidenced by the hollow particle structure, in which
the organic PNIPAM based mesoglobule cores can be effectively
decomposed and eventually removed. It is noteworthy that both
samples with hollow particle structure show comparable particle
sizes to those of the original hybrid core–shell particles. How-
ever, PNIPAM/5AM-111 exhibits distinct hollow silica particles,
while PNIPAM-111 particles seem to undergo aggregation to
form the silica clumps containing hollow hemispherical holes.
In contrast, PNIPAM/10AM-111 with the highest AM content in
organic mesoglobule cores does not maintain the core–shell
structure after calcination (Fig. 9C). In cases of samples with
increasing GLYMO or TEOS concentration (Fig. 9D–F), although
they do not show hollow spherical holes due to their thicker
shells, they have the equivalent particle size with original hybrid
core–shell particles as well as the significant weight reduction
during the calcination. It is implied that the hollow holes can
be contained inside the thick and rigid silica layers.
Fig. 8. TGA profiles for (I) PNIPAM-111, (II) PNIPAM/5AM-111, (III) PNIPAM/5AM-
112, (IV) PNIPAM/5AM-121, (V) PNIPAM/5AM-122, (VI) PNIPAM/10AM-111, and
(VII) GLYMO/TEOS-11.
4. Conclusion
The way to encapsulate PNIPAM mesoglobule cores by silica
shells significantly affects the resultant hybrid nanoparticle struc-
tures and their physicochemical properties. This work presented a
novel approach to prepare thermo-responsive PNIPAM-based
mesoglobule core–silica shell nanoparticles with narrow particle
size distribution. The key of this unique technique is to incorporate
some acrylamide (AM) units into PNIPAM chain in combination
with 3-glycidyloxypropyltrimethoxysilane (GLYMO, as a coupling
agent), in which the –NH2 group of the AM unit in mesoglobule
core can react with the epoxide group of GLYMO and the four
ethoxysilyl groups of TEOS (silica precursor) and the three
methoxysilyl groups of GLYMO can simultaneously undergo sol-
gel reaction to form silica. Thus, the probability of silica particle
nucleation and growth on PNIPAM-based mesoglobule core sur-
faces is greatly increased, thereby leading to highly desirable
hybrid organic core–inorganic shell particle morphology.
The particle morphology including the shape, core size, shell
thickness and surface roughness can be controlled primarily by
the AM content and the weight ratio of PNIPAM/AM:GLYMO:TEOS.
For example, the PNIPAM/5AM core (i.e., containing 5 wt% AM)–sil-
ica shell particle size increases with increasing GLYMO (or TEOS)
concentration in the silica encapsulation process. For the series of
experiments with the weight ratio of PNIPAM/nAM:GLYMO:
TEOS = 1:1:1 and n = 0, 5 and 10 wt%, PNIPAM/5AM-111 shows
comparable particle size (dw = 92 nm) and particle size distribution
(PDI = 1.13) to PNIPAM-111 in the absence of AM. Furthermore,
these two products are characterized by relatively spherical shape
and raspberry morphology. On the other hand, PNIPAM/10AM-111
shows mixed oblong (with the longitudinal length being about two
to three times of the latitudinal length) and spherical particle mor-
phology with relatively smooth particle surface. The LCST of
PNIPAM-based mesoglobules increases with increasing AM con-
tent. This is due to the fact that the more hydrophilic AM unit in
PNIPAM-based chain makes it less sensitive to changes in temper-
ature. In addition, encapsulation of PNIPAM-based mesoglobules
with silica reduces the thermo-sensitivity of PNIPAM-based core–
silica shell nanoparticles.
It was reported that PNIPAM core–silica shell particles were
prepared by encapsulation of silica (or precursor of silica) onto
 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547 545

Fig. 9. Representative SEM images of PNIPAM-based core–silica shell particles obtained from the runs: (A) PNIPAM-111, (B) PNIPAM/5AM-111, (C) PNIPAM/10AM-111, (D)
PNIPAM/5AM-121, (E) PNIPAM/5AM-112, and (F) PNIPAM/5AM-122 after calcination.

crosslinked PNIPAM microgel particles in the presence of surfac- loidal and interfacial phenomena are of great challenge to the future
tant [19–21]. The resultant hybrid particle sizes are about 2.5–5 work.
times larger than those of PNIPAM-based mesoglobule core–silica
shell nanoparticles prepared in this work. Such a characteristic
Acknowledgements
dimension of crosslinked PNIPAM microgel core–silica shell parti-
cles greatly limits their use in drug carrier application although
Financial support from Ministry of Science and Technology,
surfactant was used in an attempt to improve the colloidal stability
Taiwan is gratefully acknowledged.
and reduce the particle size.
How to fine tune the LCST of PNIPAM-based core–silica shell
nanoparticles without detriment to their thermo-sensitivity and Appendix A. Supplementary material
form well defined pore structure of the silica shell is an important
issue in biomedical applications. These subjects dealing with the Supplementary data to this article can be found online at
integration of organic and inorganic materials and the related col- https://doi.org/10.1016/j.jcis.2018.10.091.
546 N.-H. Cao-Luu et al. / Journal of Colloid and Interface Science 536 (2019) 536–547

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