Pseudo-graft polymer based on adamantyl-terminated poly(oligo(ethylene glycol) methacrylate) and homopolymer with cyclodextrin as pendant: Its thermoresponsivity through polymeric self-assembly and host-guest inclusion complexation

Article abstract of DOI:10.1039/c3ra47861k

A series of well-defined adamantyl-terminated thermally responsive copolymers (Ad-POEGMAs) were synthesized by atom transfer radical polymerization (ATRP), in which 2-(2-methoxyethoxy) ethyl methacrylate (MEO₂MA) and oligo(ethylene glycol) methacrylate (OEGMA) served as the thermosensitive building blocks. Moreover, cyclodextrins (CDs) as bulky pendant grafted polymers (PGCD) were synthesized by homopolymerization of aminoethyl methacrylate β-cyclodextrin (GCD). The thermal-responsive behaviors were investigated by a combination of ¹H NMR, UV-vis spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM). In comparison to other thermal-responsive copolymers based on POEGMAs, Ad-POEGMAs exhibited unusual thermally induced aggregation processes. The Ad group assembled and POEGMA chains associated to produce stable water-soluble nano-aggregates, followed by a rearrangement process at the second thermal transition. Moreover, it was found that a noncovalently connected supramolecular pseudo-graft polymer was formed via inclusion complexation in aqueous solution. This pseudo-graft polymer underwent a reversible temperature-induced transition from solution to micelle under suitable conditions. The cyclodextrin (CD) moiety attached to the main chain played two roles. As supramolecular host moieties, CDs formed inclusion complexes with guest-ended polymers, leading to graft-like polymers. As bulky hydrophilic moieties, CDs stabilized the micelles induced by the coil-to-globule transition of POEGMA segments. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra47861k

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PAPER
Pseudo-graft polymer based on adamantyl-
terminated poly(oligo(ethylene glycol)
methacrylate) and homopolymer with cyclodextrin
as pendant: its thermoresponsivity through
polymeric self-assembly and host–guest inclusion
complexation
Cite this: RSC Adv., 2014, 4, 17768
ab
ab
ab
ab
ab
Yinwen Li, Huilong Guo, Yunfei Zhang, Jian Zheng, Jianqun Gan,
Xiaoxiao Guan and Mangeng Lu*a
ab
A series of well-defined adamantyl-terminated thermally responsive copolymers (Ad-POEGMAs) were
synthesized by atom transfer radical polymerization (ATRP), in which 2-(2-methoxyethoxy) ethyl
2
methacrylate (MEO MA) and oligo(ethylene glycol) methacrylate (OEGMA) served as the thermosensitive
building blocks. Moreover, cyclodextrins (CDs) as bulky pendant grafted polymers (PGCD) were
synthesized by homopolymerization of aminoethyl methacrylate b-cyclodextrin (GCD). The thermal-
1
responsive behaviors were investigated by a combination of H NMR, UV-vis spectroscopy, dynamic light
scattering (DLS), and transmission electron microscopy (TEM). In comparison to other thermal-
responsive copolymers based on POEGMAs, Ad-POEGMAs exhibited unusual thermally induced
aggregation processes. The Ad group assembled and POEGMA chains associated to produce stable
water-soluble nano-aggregates, followed by a rearrangement process at the second thermal transition.
Moreover, it was found that a noncovalently connected supramolecular pseudo-graft polymer was
formed via inclusion complexation in aqueous solution. This pseudo-graft polymer underwent a
reversible temperature-induced transition from solution to micelle under suitable conditions. The
cyclodextrin (CD) moiety attached to the main chain played two roles. As supramolecular host moieties,
CDs formed inclusion complexes with guest-ended polymers, leading to graft-like polymers. As bulky
hydrophilic moieties, CDs stabilized the micelles induced by the coil-to-globule transition of POEGMA
segments.
Received 21st December 2013
Accepted 14th March 2014
DOI: 10.1039/c3ra47861k
www.rsc.org/advances
phase transition behavior in aqueous solutions and a lower
Introduction
8–11
critical solution temperature (LCST).
Progress in the design
Polymers that respond with a property alteration towards and application of PNIPAM-based thermoresponsive polymers
environmental changes are oen referred to as “smart” poly- during the past decades has been covered in a range of review
12,13
meric systems because they exhibit reversible property changes articles.
Recently, a series of methacrylate-based poly-
in response to changes in external conditions such as pH, ethylene glycol(PEG) polymers (POEGMAs) substituted with
temperature, ionic strength, light irradiation, mechanical force, oligo(ethylene glycol) (OEG) units as side chains were reported
electric and magnetic elds, and analytes of interest (e.g., ions to possess a thermosensitivity similar to or even superior than
1–7
and bioactive molecules) or an integration of these factors.
For cases in which the external trigger is temperature, polymers attention.
PNIPAMs, and these POEGMAs have attracted a great deal of
14–20
POEGMAs have good phase transition reversibil-
are believed to exhibit thermoresponsive properties. Poly(N- ities and tunable lower critical solution temperatures (LCSTs) in
isopropylacrylamide) (PNIPAM), one of the most popular ther- aqueous media and have excellent biocompatibility. Moreover,
mally responsive polymers, possesses dramatic and reversible by the copolymerization of various OEGMA monomers with
different side chain lengths and by varying the feed molar ratio
a
of the comonomers, the LCSTs of POEGMAs can be conve-
Key Laboratory of Cellulose and Lignocellulosics Chemistry, Chinese Academy of
Sciences, Key Laboratory of Polymer Materials for Electronics, Guangzhou institute niently adjusted. To date, substantial attention has been given
of Chemistry, Chinese Academy of Sciences, Guangzhou 510650, PR China. E-mail: for the design of POEGMA-based polymers, which have
mglu@gic.ac.cn; liyinwen06@126.com
been widely incorporated into dendrimers, microgels, block or
b
University of Chinese Academy of Sciences, Beijing 100039, PR China
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comb-like copolymers, polymeric brushes and gold surfaces soluble PGCD was prepared by homopolymerization, and its
which provide these materials with fascinating properties. SEC polydispersity index (M /M ) was low at 1.19.
w
n
Furthermore, although studies have indicated that the thermal-
responsive mechanism of POEGMAs can also be regarded as a
consequence of the competition between hydrophilic polymer–
water interactions and hydrophobic polymer–polymer interac-
Synthesis and structure analysis of AdBB and Ad-terminated
P(MEO MA-co-OEGMA) copolymers (Ad-POEGMAs)
2
tions, the role of POEGMAs in a thermally induced self- The AdBB initiator was synthesized by 2-bromopropiomyl
assembly process has not been sufficiently studied, especially bromide and 1-adamantanamine with high purity and yield.
when POEGMAs serve as thermosensitive components for Using AdBB as the initiator and MEO
2
MA and OEGMA as
21–23
composite systems that include various components.
comonomers, Ad-POEGMAs were synthesized by atom transfer
Compared with traditional chemistry based on covalent radical polymerization (ATRP). As reported by Lutz et al.,
bonds, supramolecular chemistry based on non-covalent bonds increasing the feed molar ratio of MEO MA to OEGMA leads to a
2
has become a powerful method of constructing supramolecular decrease in the LCST of POEGMAs. Therefore, three Ad-POEG-
systems in a facile and dynamic manner. A variety of subtle non- MAs named A , A , and A with molar ratios of MEO MA to
1 2 3 2
covalent interactions such as hydrogen bonding, metal–ligand OEGMA of 95 : 5, 90 : 10, and 85 : 15, respectively, were used in
coordination interaction, electrostatic attraction, and host– this study. The polymerization conditions and results are
1
guest inclusion complexation have been widely used as driving summarized in Table 1. Fig. 2 shows the H NMR spectra of
24–34
forces for constructing supramolecular systems.
Therefore, AdBB and A . In addition to the resonance peaks of the POEG-
1
on the basis of these results, well-dened Ad-POEGMAs are MAs segment in the range of d ¼ 0.8–4.1 ppm, the characteristic
synthesized in this study for the rst time and are used to ne- signals of the Ad segment, were also observed at d ¼ 1.6–
tune the LCSTs of PEG-based thermoresponsive polymers. 2.1 ppm, indicating that Ad-POEGMAs were successfully
Moreover, this work focuses on the self-assembly behavior of a synthesized, although the signals of Ad moiety were partly
composite system between Ad-POEGMAs as guests consisting of overlapped by the relative signals of the main-chain methylene
POEGMAs as thermal blocks and PGCD as multi-host with protons of the main chains at d ¼ 1.3–2.4 ppm.
1
pendant CD cavities via inclusion complexation. The design of
Fig. 3 presents the 2D H NOESY spectrum of the mixture of
this special composite system is based on the following facts Ad-POEGMA (A ) guest and PGCD host in DMSO-d , which
1
6
and considerations: the main parts of Ad-POEGMAs are provides direct evidence for the formation of the pseudo-gra
thermal-sensitive POEGMA segments; thus, thermally induced PGCD–Ad-POEGMA polymer. The NOESY cross-peaks between
self-assembly is possible. Moreover, the CD species is a bulky the signals at 3.0–4.0 ppm ascribed to the inner protons C(3)H
group that provides the PGCD with some characteristics of a and C(5)H of b-CD segments and the signals at 1.6–2.1 ppm
comb-like polymer. Further, the hydrophobic interior cavity of assigned to the methine protons (Hb) and the methylene
b-CD can accommodate a variety of guest molecules. Among protons (Ha and Hc) of adamantyl moieties were clearly
them, the b-CD–Ad pair is well-known due to its high associa- observed, which indicates that Ad moieties were included in the
tion constant; thus, PGCD may show some peculiar character- cavity of b-CD. Therefore, the Ad-POEGMAs were successfully
istics in assembly. Finally, the CD cavities as hosts are available synthesized by atom transfer radical polymerization.
for post-polymerization modications by POEGMA with Ad
guest ends via inclusion complexation to construct a complex
supramolecular system. In the current work, this supramolec-
ular system is formed with mixtures of Ad-POEGMAs and PGCD
Thermoresponsive behavior of the Ad-POEGMAs and host–
guest inclusion complexation system
due to the inclusion complexation between terminal CD and Ad Polyethylene glycol (PEG) and its derivatives are well known for
moieties. Because it possesses thermoresponsive POEGMAs, the their highly hydrophilic, or water-soluble, nature and exhibit
14–19
obtained supramolecular pseudo-gra polymer is expected to LCSTs in aqueous solutions.
They are water-soluble below
exhibit intriguing aggregation properties in aqueous solutions. their LCSTs and water-insoluble above. The mechanism
proposed for explaining the thermoresponsiveness of POEG-
MAs is summarized as follows: the conformationally favored
formation of H-bonds between the ether oxygens of PEG and
Results and discussion
Synthesis and structure analysis of b-CD based monomers
water hydrogens is one of the key factors responsible for the
21,22
unusual water solubility of PEG-type polymers.
POEGMAs are expected to self-assemble into nano-sized
Thus, Ad-
and PGCD homopolymer
Herein, we systematically report an efficient and preparatively aggregates or micelles in their aqueous solutions by altering
simple approach for the generation of b-CD-based monomers their temperatures. Moreover, the interesting thermoresponsive
with high purity and excellent yield, which all were conrmed behavior of the host–guest system comprising a polymeric host
1
13
by element analysis and IR, H NMR, C NMR, and MALDI-TOF PGCD with CD as pendant and a polymeric guest Ad segment
measurements. The detailed synthesis processes of b-CD based with POEGMAs in an aqueous solution was investigated. In this
35
monomers are shown in our previous reports. The synthetic study, the thermally induced self-assembly behaviors were
1
route of TCD, ECD, and GCD are shown in Scheme 1, and the H investigated in detail by a combination of UV-vis, DLS, TEM,
1
36
NMR spectra of TCD, ECD, and GCD are shown in Fig. 1. Water- and H NMR in D
2
O.
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Scheme 1 Synthetic routes employed for the preparation of CD based monomers and PGCD, and ATRP initiator AdBB and Ad-POEGMAs.
(
a) Determination of the LCSTs of Ad-POEGMAs. UV-vis guest polymers used in this study were all soluble at room
was rst used to determine the LCSTs of the Ad-POEGMAs. The temperature. Fig. 5 shows information on the thermoresponsive
results are shown in Fig. 4. A gradual decline in solution behaviors of a series of mixtures of PGCD and Ad-POEGMAs
transmittance could be observed with elevated temperature, with varied host–guest ratios. The individual aqueous pure
indicating that the three Ad-POEGMAs were all thermally guest exhibited a thermoresponsive prole, although the host
ꢀ
ꢀ
responsive. The LCSTs for A
1
, A
2
, and A
3
were 37.94 C, 42.07 C, polymer exhibited no thermoresponsive prole. When the two
ꢀ
and 46.71 C, respectively, and they increased with an increase components were mixed, the LCSTs of the host–guest supra-
in OEGMA content. Previous studies have indicated that the molecular systems decreased, and when the added amount of
LCSTs of the copolymers of 2-(2-methoxyethoxy) ethyl methac- polymeric host PGCD increased to some extent, the LCST
rylate (MEO MA) and u-methoxy (oligoethyleneoxy) ethyl became almost saturated when the composite system exhibited
2
methacrylate (OEGMA) also increased signicantly with an a 1 : 1 complexation between adamantyl moiety and b-CD core.
increase in OEGMA content. In this study, in contrast to that in The detailed experimental results for the aqueous mixtures of
previous reports, the Ad group was rstly introduced to the
POEGMA system, although similar results were further
conrmed for different POEGMA copolymers with hydrophobic
A
1
and PGCD are given below as a typical example.
Fig. 5 shows that the LCST of the pure guest (A
C, which is somewhat higher than body temperature and
) was 37.94
1
ꢀ
Ad groups. However, the difference for Ad-POEGMAs is that the promising for biomedical application, and shied to a lower
LCSTs are higher than those in the POEGMA copolymers temperature upon the addition of the host (PGCD). The LCST
without Ad groups.
b) Determination of the LCSTs of the supramolecular to pure guest) of 1.45 C, 1.74 C, 3.13 C, and 3.65 C with the
signicantly changed with LCST decreases (DLCST, referenced
ꢀ
ꢀ
ꢀ
ꢀ
(
system of Ad-POEGMAs and PGCD. In this study, the interesting host–guest ratio of 0.25, 0.5, 1.0, and 1.5, respectively. Finally,
thermoresponsive behavior was further investigated for the the LCST change with further addition of host became imper-
host–guest system comprising polymeric guest Ad-POEGMAs ceptible, indicating that the composite system involved
and host PGCD in an aqueous solution. Both the host and the complexation equilibrium between the adamantyl moiety (Ad)
and b-CD core. The Ad-terminated POEGMAs could be
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1
Fig. 1 H NMR spectra of b-CD based monomers (TCD and ECD) and GCD.
Table 1 Summary of structural parameters of PGCD and Ad-termi- contributed to an increase in water solubility of the supramo-
nated POEGMA copolymers (A
1
, A
2
3
and A )
lecular polymeric system. However, when the added amount of
PGCD exceeded the requirement of the complexation equilib-
rium, the excess PGCD reduced the thermal sensitivity of this
supramolecular system.
c
d
d
d
Samples
Initiator
n
MEO MA : nOEGMA
M
n,SEC
M
w,SEC
PDI
2
a
PGCD
—
—
11 950
23 163
29 610
34 667
14 220
30 427
39 604
46 535
1.19
1.32
1.35
1.34
b
A
1
A
2
A
3
AdBB
AdBB
AdBB
95 : 5
90 : 10
85 : 15
b
b
Size and morphology of the Ad-POEGMAs and host–guest
a
inclusion complexation system
Synthesized via the homopolymerization of aminoethyl methacrylate
b
b-cyclodextrin. Synthesized by the ATRP of MEO
2
MA and OEGMA
MA and OEGMA in
feed. Molecular weights and molecular distributions (M /M , PDI)
(a) Size and morphology of the assemblies formed by Ad-
c
using AdBB as initiator. Mole ratio (%) of MEO
2
d
POEGMAs. Although researchers have demonstrated that comb-
were determined by SEC using THF as the eluent relative to like polymers with multiple PEG side chains generally adopt a
w
n
polystyrene standards.
compact coil conformation in water, the existence of intermo-
lecular associations resulting in the formation of larger aggre-
37,38
gates such as polymer vesicles has also been suggested.
incorporated to the b-CD core via inclusion complexation to Moreover, previous reports have indicated the existence of a
form a pseudo-gra supramolecular polymer. Through forma- hydrophilic propionate-terminated poly(MEO MA–OEGMA)
2
tion of this polymer, such networks stabilized not only by single solution that had a coexistence of small particles with a
21
CD–Ad complexes but also by pairs of CD–Ad complexes, and hydrodynamic radius (R
h
) less than 10 nm. Thus, in the
the hydrophilic POEGMA arms on the guest polymer present case, it is important to study the exact conformation of
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1
Fig. 2 H NMR spectra of AdBB and a Ad-terminated P(MEO
2 1
MA-co-OEGMA) copolymer (A ) containing 5 mol% of OEGMA per chain recorded
3
in CDCl .
Ad-POEGMAs in aqueous solutions above and below the LCSTs. chains-dehydrated chains-loosely aggregated micelles-densely
3
9,40
Fig. 6 shows the typical size distributions measured by dynamic aggregated micelles during the self-aggregation process.
ꢁ1
light scattering (DLS) for an aqueous solution (3 mg mL ) of Therefore, a reasonable explanation for Ad-POEGMAs can be
the Ad-POEGMAs (A ) containing 5 mol% of OEGMA. This summed as follows: as shown in Scheme 2, the special hydro-
1
solution was optically clear at room temperature; however, the phobic Ad groups connected to POEGMAs covered in PEG
DLS intensity distribution indicated the coexistence of small chains or those self-assembled partly resulted in different
particles with a hydrodynamic radius (R ) of approximately 10– aggregates sizes in their aqueous solutions. A plausible struc-
h
100 nm and larger aggregates with a radius of roughly 350 nm; ture of aggregates should be that with hydrophobic adamantyl
the latter were indeed a negligible minority, as evidenced by the (Ad) chains towards the interior, whereas hydrophilic POEGMA
number distribution shown. Hence, the size distributions of the chains were exposed and stretched in water by the hydrophilic–
Ad-POEGMAs in aqueous solutions presented a wide poly-dis- hydrophilic interactions and therefore behaved as water
persity with a large hydrodynamic radius below the LCSTs, soluble. As the temperature increased, the partial dehydration
indicating that Ad-POEGMAs not only exist as a random coil of PEG side chains collapsed rst to get close to the hydro-
conformation in aqueous solutions but also with pseudo phobic backbones or Ad group, then distorted to expose
aggregates. However, under lower temperature (<LCSTs), the hydrophilic ether oxygen groups to the outer shell of the
Ad-POEGMAs were still easily soluble.
According to previous reports, the self-assembly mechanism rose above the LCSTs, the Ad-POEGMAs self-assembled into
of random copolymers of P(MEO MA-co-OEGMA) includes nano-sized aggregates in their aqueous solutions. The uniform
four consecutive conformation changes of hydrated aggregates formed with values ranging from 150 nm to 250 nm
polymer chains as much as possible. When the temperature
2
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1
ꢀ
Fig. 3 2D H NOESY spectrum of the host–guest mixture of PGCD host and Ad-POEGMA guest in DMSO-d at 25 C.
6
Fig. 5 Turbidity variations of aqueous solutions of Ad-POEGMAs (A
1
)
Fig. 4 Plots of transmittance as a function of temperature measured
for aqueous solutions (3 mg mL ) of Ad-POEGMAs (A , A and A ).
1 2 3
ꢁ1
(guest) as a function of temperature upon the addition of PGCD (host).
ꢁ1
c
guest ¼ 3 mg mL (pure guest); nPGCD–Ad-POEGMA ¼ 0.25, 0.5, 1,
1
.5 separately.
with a Z-average diameter (D
Z
¼ 181 nm, PDI ¼ 0.116),
revealing the occurrence of thermally induced self-assembly of deuterated solvents. Fig. 7 compares the spectra measured
the Ad-POEGMAs. However, the sizes of this nano-sized for the Ad-POEGMAs (A
aggregates of Ad-POEGMAs were obvious larger than those in and 50 C. As shown in Fig. 2, in deuterated chloroform, all of
ꢀ
1
) in deuterated water (D
2
O) at 25 C
ꢀ
previous reports on P(MEO MA-co-OEGMA) copolymers the protons of A1 led to sharp and intense signals, which
2
resulting from the Ad group.
suggests that the macromolecule was uniformly molecularly
O. At
1
) were investigated by H NMR in various 25 C and 50 C, the peaks corresponding to the protons of
To further conrm the self-assembly mechanism, Ad- dissolved. Rather different results were observed in D
POEGMAs (A
2
1
ꢀ
ꢀ
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ꢁ1
ꢀ
Fig. 6 Size distributions of the aggregates formed by A
1
(A and C), and A
1
+ PGCD (B and D) in aqueous solution (3 mg mL ) at 25 and 50 C,
separately.
the oligo (ethylene glycol) side chains remained sharp; (A ) and 1 : 1 host–guest mixtures of Ad-POEGMAs (A ) and
1
1
ꢀ
ꢀ
however, the signals of the protons belonging to the Ad group PGCD at 25 C and 50 C, respectively. From the TEM micro-
ꢀ
and backbone or those located in close proximity to the graphs, At 25 C, the Ad-POEGMAs dissolved in water as
backbone d ¼ 1.6–2.1 ppm reduced considerably and broad- uneven and loose single- or multi-molecular spherical parti-
ꢀ
ened more than those observed in CDCl
3
. In D
2
O at 50 C, the cles with diameters ranging from 10 nm to 100 nm, whereas
signals of the protons belonging to the Ad group disappeared larger micelles 150–230 nm in diameter were observed for the
ꢀ
ꢀ
compared to those observed in D O at 25 C. On the basis of sample solution prepared and dried at 50 C, showing that the
2
the above analysis, it can be concluded that the nano- noncovalently connected micelles formed at higher tempera-
assemblies formed by the Ad-POEGMAs were stabilized by Ad ture were larger. In contrast, spherical uneven and loose nano-
ꢀ
segment aggregation and POEGMA chains dehydrated and assembled vesicles were observed at 25 C for host–guest
aggregated jointly through hydrophobic–hydrophobic mixtures of A
interactions. results measured by DLS at the same temperature. These
b) Size and morphology of the assemblies formed by host– results demonstrate that nano-sized aggregates indeed formed
1
and PGCD, which agreed quite well with the
(
guest inclusion complexation system. DLS has proven to be a via inclusion complexation of Ad-POEGMAs and PGCD. For
sensitive method for tracing the formation of noncovalently the host–guest composite system of A and PGCD, dense, dark
1
connected nano-assemblies according to the changes in particle spherical particles were observed, which was especially clear
4
1,42
ꢀ
size and scattered light intensity.
The changes in micelle size for the sample prepared and dried at 50 C. This result is due
ꢀ
ꢀ
with temperature (25 C and 50 C) for the 1 : 1 host–guest to the action of the staining agent, phosphotungstic acid,
system of Ad-POEGMAs (A
1
) and PGCD are shown in Fig. 6. The which stains the hydrophobic segments to a greater extent.
R
h
of the nano-assemblies were approximately 10–300 nm, and However, it was found that the diameters of the micelles from
they were kept unevenly under low temperature (<LCST). the TEM micrographs were clearly smaller than those from
However, the values increased dramatically to 200–350 nm with DLS measurements. This result may be related to the fact that
a Z-average diameter (DZ ¼ 273 nm, PDI ¼ 0.121) when the DLS measures the hydrodynamic diameters of the micelles in
temperature was increased above LCST. This increase can be an aqueous environment, whereas the TEM micrographs show
1
7
attributed to changes in the refractive index of the guest dehydrated solid states of the micelles.
molecule because its POEGMA arms underwent a phase tran-
Furthermore, obvious differences in morphology were
15,43,44
sition from random coil to condensed globule.
This observed by comparing the TEM images of the nano-assem-
change clearly shows that the micelles began to form near the blies. Those constructed from Ad-POEGMAs showed relatively
LCST; this result from DLS study was consistent with that light aggregates below the LCST and dark, condensed globules
following TEM investigation.
above, presenting typical micellar characteristics of POEGMA-
39,45
The self-assembly mechanism of the host–guest composite based polymers.
For those that formed from host–guest
system was further conrmed by comparing the TEM images mixtures of A and PGCD, a strong contrast between the light
1
ꢀ
of the polymeric solutions, which were prepared at 25 C and center and the dark, thin periphery was observed below the
ꢀ
46,47
5
0
C. Fig. 8 shows the representative TEM micrographs of LCST, which is characteristic of vesicular nano-structures.
noncovalently connected micelles formed from Ad-POEGMAs When the temperature rose above the LCST, dense aggregates
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Scheme 2 Schematic illustration of the dynamic self-aggregation and self-disaggregation mechanism of Ad-POEGMAs in water during heating
and cooling.
formed. Hence, from the results of DLS and TEM, it was found These polymers were able to self-assemble into noncovalently
that nano-assemblies with different morphologies can be con- connected micelles with the Ad segments as the cores and
structed from Ad-POEGMAs and the supramolecular system of hydrophilic POEGMAs as the coronas. Moreover, a composite
Ad-POEGMAs and PGCD by simply elevating the temperature. system was designed using Ad-terminated POEGMAs and
In such cases, Ad-POEGMAs formed micelle-like nano-struc- PGCD, which was able to form thermoresponsive pseudo-gra
tures, and the supramolecular system of Ad-POEGMAs and polymers in aqueous solutions via host–guest complexation
PGCD organized into vesicle-like nano-aggregates. The proce- between the b-CD core of the host polymer and the adamantyl
dures for inclusion complexation, thermally induced dehydra- moiety of the guest polymer. This polymer stabilized by single
tion, and subsequent self-assembly of the pseudo-gra CD–Ad complexes and by pairs of CD–Ad complexes. The
polymer based on Ad-POEGMAs and PGCD are illustrated in pseudo-gra polymer was shown to self-assemble to form
Scheme 3.
nano-sized aggregations above and below the LCST in
aqueous solutions. As a result of the tunability of its ther-
moresponsive behavior, noncovalent connected micelle-
forming ability, and potential biocompatibility, the pseudo-
Conclusions
Thermally responsive Ad-POEGMAs were synthesized and gra polymer shows potential interest for applications in
shown to have tunable LCST behavior in aqueous solutions. biomedical science.
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1
ꢀ
Fig. 7 H NMR spectra of a copolymer P(MEO
2
MA-co-OEGMA) containing 5 mol% of OEGMA per chain recorded in D
2
O at 25 and 50 C.
were obtained from Aldrich. 2-(2-Methoxyethoxy) ethyl meth-
ꢁ
1
acrylate (MEO
2
MA, M
n
¼ 188 g mol ) and oligo (ethylene
ꢁ1
glycol) methyl ether methacrylate (OEGMA, M ¼ 475 g mol
)
n
were acquired from Aladdin. Tetrahydrofuran (THF) was
initially dried over sodium wire and reuxed over potassium
for three days before use. Dichloromethane (CH
dimethylformamide (DMF) were reuxed over CaH
before use. Ethanol was also reuxed over CaH
2
Cl
2
) and N,N-
separately
2
2
before use. All
other reagents were used as received without further
purication.
Characterization
Fig. 8 Typical tem images obtained by aqueous solutions of A
1
(a and Fourier transform infrared (FT-IR) spectra were recorded on a
ꢁ1
ꢀ
b) and A
1
+ PGCD (c and d) (3 mg mL ) at 25 and 50 C.
Nicolet 5100 spectrometer by the KBr sample holder method in
ꢁ
1 1
the fundamental region of 400–4000 cm
. H NMR spectra
were obtained by a Bruker DMX-400 spectrometer. Deuterated
chloroform (CDCl ), deuterated water (D O), and deuterated
3
2
Materials and methods
Materials
dimethyl sulfoxide (DMSO-d ) were used as solvents. The
6
MALDI-TOF mass spectrum was recorded in the reector mode
b-Cyclodextrin was purchased from Sigma and was used aer on a Bruker Autoex III Smartbeam mass spectrometer using a
ꢀ
recrystallization from water and was dried at 100 C under nitrogen laser, and a-cyano-4-hydroxycinnamic acid (CCA) was
n
vacuum. Glycidyl methacrylate (GMA) was purchased from used as the matrix. The number-average molecular weight (M )
TCI, Japan. p-Toluenesulfonyl chloride (p-TsCl), ethanedi- and polydispersity index (M
w
/M
n
) of each polymer were deter-
ꢀ
amine, and azoisobutyronitrile (AIBN) were all purchased mined at 35 C using a Waters 1515 size exclusion chromato-
from Sigma, China. Copper(I) bromide was washed with glacial graph (SEC) equipped with a Waters 2414 refractive index (RI)
acetic acid in order to remove any soluble oxidized species, detector. DMF and THF were used as eluants, and the columns
then was ltered, washed with ethanol, and dried. 2-Bromo- used were the styragel HR3 and HR4 columns calibrated by
propiomyl bromide, 1-adamantanamine and 2,2-bipyridine narrow PS standards.
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Scheme 3 The procedures for inclusion complexation, the thermally induced dehydration and subsequent self-assembly of the pseudo-graft
polymer based on Ad-POEGMAs and PGCD.
The LCSTs of the polymers were determined by UV-vis was obtained as a white solid (5.14 g yield: 21.40%). IR (KBr,
ꢁ
1
1
spectroscopy (U-3010 Spectrophotometer). The transmittance of cm ): 3388 (s, OH), 2928 (w, CH
2
), 1597 (s, Ph). H NMR (400
ꢁ
1
the polymeric aqueous solution (3 mg mL ) was recorded at MHz, DMSO-d
6
): d 7.42 (2H), 7.74 (2H), 4.75 (7H), 3.49–3.64
ꢀ
ꢀ
13
temperatures ranging from 20 C to 65 C. The lower critical (28H), 3.28–3.36 (14H), 2.42 (3H). C NMR (DMSO): d 144.9 (s),
solution temperature (LCST) value of the aqueous polymer 132.7 (s), 129.9 (s), 127.6 (s), 102.3 (m), 81.5 (m), 71.9–73.1 (m),
solution at a specic concentration was determined as the 69.8, 69.0, 59.5 (t), 21.3 (s) ppm. MALDI-TOF on CCA matrix
+
+
temperature corresponding to a 10% decrease in optical trans- (TCD + Na ) m/z calcd for C H NaO S (TCD + Na ) 1311.37,
4
9
76
37
mittance. The hydrodynamic diameters (D ) of the capsules and measured 1311.13.
h
their polydispersity indices (PDI) were determined by dynamic
(b) Synthesis of mono (6-amino-6-deoxy)-b-CD (ECD). 5.0 g
light scattering (DLS) on a Malven Zetasizer Nano System (Nano- of TCD was reacted with an excess amount of EDA (30 mL) in
ꢀ
zs90). The solutions were passed through 0.45 mm lters before 20 mL DMF at 80 C for 6 h. Aer the reaction was completed,
DLS measurement. The measurements were conducted in a the mixture was allowed to cool to room temperature and was
3
.0 mL quartz cuvette using a 670 nm diode laser, and the then precipitated with acetone. The sample obtained was
ꢀ
ꢀ
dried at 40 C for 72 h in a vacuum oven, and ECD was
scattering angle used was 90 .
ꢁ1
The micromorphology was visualized by transmission elec- obtained as a white solid (3.96 g yield: 79.10%). IR (KBr, cm ):
1
tron microscopy (TEM). The samples were prepared by placing 3388 (s, OH, NH ), 2928 (w, CH ). H NMR (400 MHz, DMSO-
2
2
polymer aqueous solutions on copper grids in a biochemical
incubator thermostated at 25 C or 50 C and were stained with (4H). C NMR (DMSO): d 102.0 (s), 81.6 (s), 72.1–73.1 (m), 60.0
phosphotungstic acid before TEM observation with a JEM- (s), 40.1–39.5 (m) ppm. MALDI-TOF on CCA matrix (ECD + Na )
6
d ): d 4.85 (7H), 3.54–3.64 (28H), 3.27–3.41 (14H), 2.72–2.92
ꢀ
ꢀ
13
+
+
100CX II microscope operated at 80 kV.
m/z calcd for C44
199.20.
c) Synthesis of aminoethyl methacrylate b-cyclodextrin
GCD). 5.98 g ECD was dissolved in 30 mL DMF, and a small
H
76
N
2
NaO34 (ECD + Na ) 1199.42, measured
1
(
Sample synthesis
a) Synthesis of mono-6-OTs-CD (TCD). The synthesis of
TCD was conducted according to that in previous literature with
(
(
amount of inhibitor was added. Then 2.49 g GMA was added
dropwise. Aer the reaction was completed, the mixture was
allowed to cool to room temperature, then was precipitated with
acetone and nally dried at room temperature for 2 days under
33,34
a few modications.
b-CD (24 g) was suspended in 180 mL of
water. NaOH (2.623 g) in 20 mL of water was added dropwise
over a 30 min period and was reacted under vigorous agitation
ꢁ1
vacuum (4.90 g yield: 82.0%). IR (KBr, cm ): 3388 (s, OH), 2928
ꢀ
at 0 C for a period of 1 h. Then p-toluenesulfonyl chloride
1
(
(
2
(
5
w, CH
2
), 1720 (w, C]O). H NMR (400 MHz, DMSO-d
6
): d 6.05
(4.032 g) in 20 mL of acetonitrile was added dropwise for a
2H), 4.81 (7H), 4.48 (1H), 3.54–3.62 (28H), 3.29–3.43 (14H),
period of 1 h, which causing immediate formation of a white
13
.72–2.92 (6H), 1.87 (3H). C NMR: (DMSO) d 166.6 (s), 135.9
s), 125.8 (s), 102.0 (s), 81.6 (s), 72.0–73.1 (m), 66.9 (s), 59.9 (s),
6.1 (s), 40.1–39.5 (m), 20.6 (t), ppm. MALDI-TOF on CCA matrix
ꢀ
precipitate. Aer 3 h of stirring at 20 C, the unreacted tolue-
nesulfonyl chloride was ltered off. The solution was then
neutralized and refrigerated, and the precipitate was recovered
by suction ltration and recrystallization in water. The sample
+
+
(
GCD + Na ) m/z calcd for C51
86 2
H N NaO37 (GCD + Na ) 1341.48,
measured 1341.09.
ꢀ
obtained was dried at 60 C for 48 h in a vacuum oven, and TCD
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(
d) Homopolymerization of aminoethyl methacrylate b- of b-CD-based monomers and PGCD, in addition to the ada-
cyclodextrin (PGCD). Radical copolymerizations of GCD were mantane-based initiator and adamantyl-terminated POEGMAs,
initiated by AIBN. A typical experiment for the polymerization are shown in Scheme 1.
procedure is as follows: in a 50 mL three-neck round-bottom

ask, GCD (1.5 g) and AIBN (0.1 g) were mixed with 10 mL of
Acknowledgements
DMF. The solution was bubbled under argon for 30 min at room
temperature to remove free oxygen. The ask was then
The authors appreciate the Integration of Industry, Education
and Research of Guangdong Province project (project no.
ꢀ
immersed in an oil bath thermostated at 80 C, and the reaction
was maintained for 6 h under argon. Homopolymer was directly
precipitated by acetone, washed at least three times using a
2011A091000007), Guangdong-Hongkong Technology Cooper-
ation Funding (project no. 2009A091300012) and the National
Natural Science Foundation of China (project no. 20974121).
They also wish to thank Professor Yu Qijun (South China
University of Technology) for his support and collaboration in
the test involved in this study.
ꢀ
large amount of acetone, then dried at 50 C under vacuum to
yield a ne white powder.
(
e) Synthesis
of
1-adamantyl-2-bromopropionamide
(
AdBB). The ATRP initiator, AdBB, was prepared by the amida-
tion reaction of 1-adamantanamine with 2-bromopropiomyl
bromide. A 100 mL round-bottom ask was charged with 1-
adamantanamine (3.03 g), TEA (3.04 g), and dry CH
2
Cl
2
(30 mL).
References
ꢀ
The mixture was cooled to 0 C in an ice-water bath. 2-bromo-
propiomyl bromide (6.48 g) in THF (20 mL) was then added
dropwise over 2 h. Aer the addition was completed, the reac-
1 C. Weber, R. Hoogenboom and U. S. Schubert, Prog. Polym.
Sci., 2012, 3, 686.
ꢀ
tion mixture was stirred at 0 C for an additional 2 h and then at
2 M. Y. Guo and M. Jiang, So Matter, 2009, 5, 495.
3 G. S. Chen and M. Jiang, Chem. Soc. Rev., 2011, 40, 2254.
4 Y. Y. Mai and A. Eisenberg, Chem. Soc. Rev., 2012, 41, 5969.
5 M. A. Ward and T. K. Georgiou, Polymers, 2011, 3, 1215.
6 F. Liu and M. W. Urban, Prog. Polym. Sci., 2010, 35, 3.
7 C. Tsitsilianis, G. Gotzamanis and Z. Iatridi, Eur. Polym. J.,
2011, 47, 497.
8 J. Zou, B. Guan, X. J. Liao, M. Jiang and F. G. Tao,
Macromolecules, 2009, 42, 7465.
9 Z. X. Zhang, X. Liu, F. J. Xu, X. J. Loh, E. T. Kang, K. G. Neoh
and J. Li, Macromolecules, 2008, 41, 5967.
ꢀ
30
C for 24 h. The mixture was allowed to cool to room
temperature, and the insoluble salts were removed by suction
ltration. The organic solution was washed with an aqueous
sodium bicarbonate solution (2 ꢂ 100 mL) and distilled water

(
2 ꢂ 100 mL) and was then dried with anhydrous magnesium
sulfate and concentrated by a rotary evaporator. The concen-
trated syrup was puried by silica gel column chromatography
using ethyl acetate–petroleum ether (1 : 3 v/v) as the eluent. The
solvents were then removed by a rotary evaporator and dried in
vacuum oven at 50 C for 2 days. AdBB was obtained as a white
solid (1.24 g, yield: 82%). H NMR (CDCl ): d (ppm) 5.99 (1H, 10 F. Sakai, G. S. Chen and M. Jiang, Polym. Chem., 2012, 3, 954.
ꢀ
1
3
NHCO), 4.25–4.30 (1H, BrCHCH
CH ), 1.81 (3H, CH –Br), 1.63 (6H, CH
ppm) 168.1 (C]O), 52.3(C–O), 46.1 (BrCH), 41.1 (CH
CH ), 29.3 (CH ), 23.1 (CH).
f) Synthesis of adamantyl-terminated P(MEO
OEGMA) (Ad-POEGMAs). Ad-POEGMAs were synthesized by the
ATRP of MEO MA and OEGMA monomer using AdBB as the 14 S. Han, M. Hagiwara and T. Ishizone, Macromolecules, 2003,
3
), 2.07 (3H, –CH), 1.98 (6H, 11 Z. S. Ge and S. Y. Liu, Macromol. Rapid Commun., 2009, 30,
1
3
–
2
3
2
). C NMR (CDCl
3
): d
1523.
(
(
2
), 36.2 12 A. K. Bajpai, S. K. Shukla, S. Bhanu and S. Kankane, Prog.
Polym. Sci., 2009, 33, 1088.
2
3
(
2
MA-co- 13 D. Roy, J. N. Cambre and B. S. Sumerlin, Prog. Polym. Sci.,
2010, 35, 278.
2
initiator. A typical procedure is described as follows: a Schlenk
tube was purged with dry argon for 30 minutes, and a degassed 15 J. F. Lutz, O. Akdemir and H. Ann, J. Am. Chem. Soc., 2006,
mixture of 2-(2-methoxyethoxy) ethyl methacrylate (95 eq.), oligo
128, 13046.
ethylene glycol) methyl ether methacrylate (5 eq.), ethanol 16 Z. X. Zhang, K. L. Liu and J. Li, Macromolecules, 2011, 44,
monomers–ethanol ꢃ1 : 1.5 v/v), AdBB (1 eq.) initiator and
1182.
36, 8312.
(
(
copper bromide (1 eq.) was added to the Schlenk tube. The 17 C. G. Mu, X. D. Fan, W. Tian, Y. Bai and X. Zhou, Polym.
mixture was degassed via three freeze–thaw–pump cycles and
Chem., 2012, 3, 1137.
was back-lled with argon. Then 2,2-bipyridyl (2 eq.) was added. 18 C. R. Becer, S. Hahn, M. W. M. Fijten, H. M. L. Thijs,
ꢀ
The mixture was heated at 60 C in an oil bath for 6 h. The
R. Hoogenboom and U. S. Schubert, J. Polym. Sci., Part A:
Polym. Chem., 2008, 46, 7138.
experiment was stopped by opening the ask and exposing the
catalyst to air. The nal mixture was diluted in ethanol and was 19 O. G. Schramm, G. M. Pavlov, H. P. Erp, M. A. R. Meier,
passed through a short neutral alumina column (200 mesh) in
order to remove the copper catalyst. Then, the ltered solution
R. Hoogenboom and U. S. Schubert, Macromolecules, 2009,
42, 1808.
was diluted with ethanol and was subsequently puried by 20 E. W. Edwards, M. Chanana, D. Y. Wang and H. M ¨o hwald,
dialysis in water (molecular weight cut-off: 3500). Finally, aer
Angew. Chem., Int. Ed., 2008, 47, 320.
freeze-drying in a vacuum, Ad-POEGMAs were obtained as a 21 J. F. Lutz, K. Weichenhan, O. Akdemir and A. Hoth,
viscous solid. The synthetic routes employed for the preparation
Macromolecules, 2007, 40, 2503.
22 J. F. Lutz, J. Polym. Sci., Part A: Polym. Chem., 2008, 46, 3459.
17778 | RSC Adv., 2014, 4, 17768–17779
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
2
3 H. Kitano, T. Hirabayashi, M. Gemmei-Ide and M. Kyogoku, 36 Y. L. Liu, Z. Q. Wang and X. Zhang, Chem. Soc. Rev., 2012, 41,
Macromol. Chem. Phys., 2004, 205, 1651. 5922.
4 M. Miyauchi and A. Harada, J. Am. Chem. Soc., 2004, 126, 37 T. Ishizone, A. Seki, M. Hagiwara, S. Han, H. Yokoyama,
2
1
1418.
A. Oyane, A. Deffieux and S. Carlotti, Macromolecules, 2008,
41, 2963.
2
2
5 J. Wang and M. Jiang, J. Am. Chem. Soc., 2006, 128, 3703.
6 L. Z. Wang, Y. M. Yang, M. R. Zhu, G. J. Qiu, G. L. Wu and 38 Y. Maeda, T. Kubota and H. Yamauchi, Langmuir, 2007, 23,
H. Gao, RSC Adv., 2014, 4, 6478. 11259.
7 L. Janus, B. Carbonnier, A. Deratani, M. Bacquet, G. Crini, 39 B. L. Peng, N. Grishkewich, Z. L. Yao, X. Han, H. L. Liu and
J. Laureynsd and M. Morcellet, New J. Chem., 2003, 27, 307. K. C. Tam, ACS Macro Lett., 2012, 1, 632.
8 R. Mach ´ı n, J. R. Isasi and I. V ´e laz, Carbohydr. Polym., 2012, 40 S. T. Sun and P. Y. Wu, Macromolecules, 2013, 46, 236.
2
2
2
3
3
3
3
3
3
87, 2024.
41 H. Liu, Y. F. Zhang, J. M. Hu, C. H. Li and S. Y. Liu, Macromol.
Chem. Phys., 2009, 210, 2125.
9 Y. Ping, C. Liu, Z. Zhang, K. L. Liu, J. Chen and J. Li,
Biomaterials, 2011, 32, 8328.
0 Z. S. Ge, H. Liu, Y. F. Zhang and S. Y. Liu, Macromol. Rapid
Commun., 2011, 32, 68.
42 L. Li, X. H. Guo, J. Wang, P. Liu, R. K. Prud'homme, B. L. May
and S. F. Lincoln, Macromolecules, 2008, 41, 8677.
43 J. G. Zeng, K. Y. Shi, Y. Y. Zhang, X. H. Sun and B. L. Zhang,
Chem. Commun., 2008, 3753.
44 L. H. He, J. Huang, Y. M. Chen and L. P. Liu, Macromolecules,
2005, 38, 3351.
1 W. Tian, A. L. Lv, Y. C. Xie, X. Y. Wei, B. W. Liu and X. Y. Lv,
RSC Adv., 2012, 2, 11976.
2 J. Wu, P. H. Ni, M. Z. Zhang and X. L. Zhu, So Matter, 2010,
6
, 3751.
45 X. Y. Huan, D. L. Wang, R. J. Dong, C. L. Tu, B. S. Zhu,
D. Y. Yan and X. Y. Zhu, Macromolecules, 2012, 45,
5941.
3 R. C. Petter, J. S. Salek, C. T. Sikorski, G. Kumaravel and
F. T. Lin, J. Am. Chem. Soc., 1990, 112, 3860.
4 Y. Y. Liu, X. D. Fan and L. Gao, Macromol. Biosci., 2003, 3, 46 Y. Chen, X. H. Pang and C. M. Dong, Adv. Funct. Mater., 2010,
15. 20, 579.
5 Y. W. Li, H. L. Guo, Y. F. Zhang, J. Zheng, Z. X. Li, C. H. Yang 47 O. Kretschmann, C. Steffens and H. Ritter, Angew. Chem., Int.
and M. G. Lu, Carbohydr. Polym., 2014, 102, 278. Ed., 2007, 46, 2708.
7
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RSC Adv., 2014, 4, 17768–17779 | 17779