Fructose-sensitive thermal transition behaviour of boronic ester-bearing telechelic poly(2-isopropyl-2-oxazoline)

Article abstract of DOI:10.1039/c8cc09835b

Boronic ester-bearing telechelic poly(2-isopropyl-2-oxazoline) (B-PiPrOx-B) exhibited a hydrophilic-hydrophobic phase transition near human-body temperature in aqueous media. The thermal transition temperature of B-PiPrOx-B changed notably upon addition o

Full text of DOI:10.1039/c8cc09835b

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Fructose-sensitive thermal transition behaviour of boronic ester-
bearing telechelic poly(2-isopropyl-2-oxazoline)
Jiyoung Lee, a Jong Min Parka and Woo-Dong Jang*, a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Boronic ester-bearing telechelic poly(2-isopropyl-2-oxazoline) (B- polymers.26, 27, 28 For example, hybrid systems of PiPrOx and
PiPrOx-B) exhibited a hydrophilic-hydrophobic phase transition azobenzene have been designed to obtain thermo- and
near human-body temperature in aqueous media. The thermal photoresponsive functional materials.29 Recently, we prepared
transition temperature of B-PiPrOx-B changed notably upon the uracil-bearing telechelic PiPrOx as a chemoresponsive PiPrOx,
addition of fructose.
which exhibited a drastic change in thermal transition
temperature in response to mercury ions.30 In this study, we
prepared a telechelic pinacol boronate-bearing PiPrOx (B-
PiPrOx-B) as a new type of chemoresponsive polymer. Boronic
esters are capable of undergoing exchange reactions with
chemicals having diol groups31, 32, 33, 34 and show particularly
high reactivity to cis-diols. Therefore, the thermal transition
temperature of B-PiPrOx-B can be varied by the addition of
various saccharides through the boronic ester exchange
reaction. Notably, fructose has the greatest effect on the
thermal transition temperature increment. Because the
continuous ingestion of the fructose is directly and indirectly
related to the pathogenesis of obesity, type 2 diabetes and
cardiovascular disease, fructose responsive polymers may
provide potential applications.35, 36, 37
Stimuli-responsive polymers that change their physicochemical
properties in response to external stimuli have been widely
utilised in various fields.1, 2, 3, 4, 5 In particular, thermoresponsive
polymers are highly useful in bio-related applications such as
sensors, bio-scaffolds, and smart biointerfaces because living
systems are homeostatic to temperature.6,
Especially,
7, 8,
9
isothermally responsive polymers that shows hydrophilic-
hydrophobic phase transition at specific temperature would be
very useful and desirable for the bio-related applications.10 Such
isothermally responsive polymers can be obtained by
combination of stimuli-responsive functional groups and
thermoresponsive polymers. Poly(2-isopropyl-2-oxazoline)
(PiPrOx) is a representative thermoresponsive polymer that
exhibits hydrophilic-hydrophobic phase transition via a lower
critical solution temperature (LCST).11 PiPrOx has excellent
biocompatibility and shows LCST behaviour near human-body
temperature.12, 13, 14 Therefore, the applications of PiPrOx in the
biomedical field are being actively studied.15, 16, 17 PiPrOx is
synthesized by the cationic ring-opening polymerization (CROP)
of an oxazoline monomer.18, 19 Because the polymerization of
PiPrOx proceeds via a living mechanism, the molecular weight
and distribution of the polymer can be easily controlled.20, 21, 22
More importantly, various functional groups can be introduced
to the initiation and termination ends of PiPrOx.23, 24, 25 By
exploiting the merits of living polymerization, additional stimuli-
responsive functional groups have been introduced to PiPrOx
for the preparation of multi-modal stimuli-responsive
X
NH
O
O
O
O
HO
OH
OH
i
iii
B
B
B
2: X = OH
3: X = Br
4
ii
1
O
N
O
O
O
B
N
n
4
N
B
O
3
O
MeCN
n = ~32
B-PiPrOx-B
Scheme 1. Synthesis of B-PiPrOx-B. Reagents and conditions: i) pinacol, Na2SO4, THF, 25
°C; ii) CBr4, PPh3, THF, 0 °C; iii) methylamine, dimethoxymethane.
The synthesis B-PiPrOx-B is illustrated in Scheme 1. First,
pinacol
was
allowed
to
react
with
4-
(hydroxymethyl)phenylboronic acid (1) to obtain 2. The
hydroxyl group of 2 was converted to bromide using CBr4 and
PPh3 to yield 3, which was used as the functional initiator for
CROP. Methylamine was allowed to react with 3 to obtain 4,
which was used as the functional terminator in the CROP. For
aDepartment of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul
03722, Korea. E-mail: wdjang@yonsei.ac.kr (Prof. W.-D. Jang)
Electronic Supplementary Information (ESI) available: [Experimental details and
additional data]. See DOI: 10.1039/x0xx00000xa
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the CROP, the ratio of 3 and the monomer (2-isopropyl-2-
oxazoline) was adjusted to 1:32, so that the theoretical number-
average molecular weight (Mn) became approximately 4.0 kDa.
When the monomer was fully consumed, an excess amount of
4 was added to the reaction mixture to obtain telechelic B-
PiPrOx-B. Then, the remaining terminator and low-molecular-
weight impurities were removed by recycling preparative size-
exclusion chromatography (SEC). The products of each reaction
were characterised by 1H NMR, SEC, and MALDI-TOF-MS
measurements. The 1H NMR spectra of B-PiPrOx-B showed
multiple peaks from 8.13 to 6.86 ppm, indicating the successful
introduction of the phenyl groups into both the initiation and
termination ends of the polymer (Fig. S4). The single peak at
1.31 ppm indicated the existence of pinacol moieties. The Mn
and dispersity index (Đ) of B-PiPrOx-B were estimated from the
results of SEC and MALDI-TOF-MS analyses. The result of
analytical SEC revealed a single sharp peak at the retention time
of 20.44 min. From the results of analytical SEC, the Mn and Đ of
B-PiPrOx-B were estimated to be 3.99 kDa and 1.12,
respectively, using polystyrene standards. A similar molecular
weight was deduced from MALDI-TOF-MS analysis. The MALDI-
TOF-MS profile of B-PiPrOx-B exhibited sets of peaks at 113.08
Da intervals, corresponding to the molar mass of the
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DOI: 10.1039/C8CC09835B
monomeric 2-isopropyl-2-oxazoline (Fig. S5). The maximum Figure 1. Thermoresponsiveness of B-PiPrOx-B in pH 7.4 PBS solution. a) Temperature-
dependent transmittance changes of B-PiPrOx-B at several concentrations; b)
concentration-dependent TCP of B-PiPrOx-B; c) temperature-dependent transmittance
changes of B-PiPrOx-B (4.0 g/L) with various saccharides (50 mM); d) TCP changes of B-
PiPrOx-B (4.0 g/L) by addition of various saccharides (50 mM); e) temperature-
peak appeared at 4.08 kDa, which coincided well with the
results of SEC as well as the theoretically expected Mn value
from the monomer to initiator ratio (Fig. S6). In addition to the
molecular ion peaks, two sets of satellite peaks were observed,
which were attributable to the fragment series formed by the
removal of pinacol moieties under the MALDI-TOF-MS
conditions.
dependent transmittance changes of B-PiPrOx-B (4.0 g/L) with various concentrations of
fructose (0, 1, 2, 5, 10, 20, 40, 50, 60, 80, 100, 150, and 200 mM); f) TCP of B-PiPrOx-B
(4.0 g/L) with various concentrations of fructose (0–200 mM).
Because boronic esters are capable of exchange reactions with
chemicals having diol groups,38 we investigated the changes in
the thermal transition temperature of B-PiPrOx-B in the
presence various saccharides such as maltose, lactose, glucose,
sucrose, mannose, galactose, and fructose (Fig. 1c-d). To a
solution of B-PiPrOx-B in 10 mM PBS (150 mM NaCl, pH 7.4),
various saccharides were added, and the final concentration of
B-PiPrOx-B and each saccharide was adjusted to 4.0 g/L and 50
mM, respectively. If the hydrophilic saccharides bond to the end
of B-PiPrOx-B by an exchange reaction, the thermal transition
temperature of the polymer might change because of the
increasing hydrophilicity. As expected, TCP of B-PiPrOx-B
increased with the addition of various saccharides. However,
the degree of TCP change greatly depended on the nature of the
saccharide (Fig. 1c,d, Table 1). For example, B-PiPrOx-B showed
only a 0.3 °C increase in TCP even after 24 h of maltose addition.
In the case of galactose addition to B-PiPrOx-B, TCP increased
only by 1.8 °C after 5 h of galactose addition. Unlike case of the
other saccharides, the addition of fructose greatly influenced
the TCP value of B-PiPrOx-B: TCP increased by 5.7 °C with the
addition of fructose. It is noteworthy that the TCP change of B-
PiPrOx-B was immediately saturated by the addition of
fructose, indicating a high rate of reaction between B-PiPrOx-B
and fructose. The fast response and large TCP change of B-
PiPrOx-B by fructose addition can be explained by the structural
aspect of the diol moiety and the high stability of the
Table 1. Time-dependent TCP changes (°C) of B-PiPrOx-B (4.0 g/L in 10 mM PBS, pH 7.4)
by addition of various saccharides (50 mM).
Time(h)
Maltose
Lactose
Glucose
Sucrose
Mannose
Galactose
Fructose
0*
1
0±0.11
0±0.10
0.1±0.08
0.1±0.09
0.3±0.10
0.4±0.07
0.4±0.09
0.5±0.11
0.6±0.12
0.6±0.10
0.8±0.11
0.8±0.09
0.1±0.07
0.3±0.11
0.4±0.09
0.8±0.07
1±0.11
1.3±0.10
1.6±0.14
1.7±0.13
1.7±0.12
1.7±0.10
1.7±0.10
1.7±0.09
1.7±0.11
1.8±0.11
1.8±0.10
5.7±0.11
5.7±0.10
5.7±0.08
5.7±0.11
5.7±0.11
3
0±0.09
5
0.2±0.07
0.3±0.10
24
*Immediately after addition.
The thermal transition temperatures of B-PiPrOx-B were
determined by temperature-dependent transmittance
measurements at 800 nm. For this experiment, B-PiPrOx-B was
dissolved in physiological saline-containing 10 mM phosphate-
buffered solution (PBS, 150 mM NaCl, pH 7.4), and the cloud
point temperature (TCP) was measured upon increasing the
temperature a rate of 2 °C/min, where TCP is defined as the
temperature corresponding to a 50% decrease in the optical
transmittance. Fig. 1a,b shows the temperature-dependent
transmittance changes of B-PiPrOx-B. TCP gradually decreased
with increasing concentration of B-PiPrOx-B from 0.5 to 8.0 g/L,
where the difference in TCP was approximately 13 °C between
8.0 g/L and 0.5 g/L. These trends are similar to those observed
for other types of thermoresponsive polymers.
2 | Chem. Commun., 2019, 00, 1-3
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saccharide-conjugated boronic ester structure, respectively.39, original TCP of B-PiPrOx-B without fructose. At very low
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40, 41 First, fructose has two syn-periplanar cis-diols, which would concentrations of fructose (1 and 2 mM), TCP continuously
DOI: 10.1039/C8CC09835B
be suitable functional groups for the fast boronic ester varied for 19 h, indicating that a long reaction time is needed to
exchange reaction.42 Moreover, furanose would be more reach equilibrium state. In contrast, TCP immediately reached to
reactive than pyranose because of the large angle between the equilibrium state when the concentration of fructose was
diol moieties, possibly reducing the angle strain in the five- higher than 5 mM. Notably, the B-PiPrOx-B solution containing
membered pentagonal ring structure of the saccharide- only 5 mM fructose showed a TCP increment of 2.1 °C. Therefore,
conjugated boronic ester.43 To confirm the influence of fructose we can conclude that B-PiPrOx-B has significantly higher
on the thermal transition behaviour of PiPrOx segment, the sensitivity to fructose than to other saccharide molecules.
temperature dependent transmittance changes of a propargyl- Because B-PiPrOx-B showed remarkably higher sensitivity to
bearing telechelic PiPrOx (Prop-PiPrOx-Prop; Figure S7) with fructose than to other saccharide molecules, we examined
and without fructose were measured.30 As a result, the thermal fructose-induced TCP changes in the presence of glucose. For
transition behaviour of Prop-PiPrOx-Prop was not changed this experiment, a solution containing B-PiPrOx-B (4.0 g/L, pH
after the addition of fructose. The TCP of B-PiPrOx-B was not 7.4 PBS buffer) with 50 mM of glucose was prepared and stirred
changed upon incubation for 24 h in 10 mM PBS (150 mM NaCl, for 24 h to allow the system to reach equilibrium. Then, we
pH 7.4) at 25 °C, indicating the sufficient stability of pinacol confirmed the TCP value of the initial glucose-containing B-
boronic ester (Fig. S8).
PiPrOx-B at 36.5 °C. To the glucose-containing B-PiPrOx-B
solution, fructose was added to a final concentration 50 mM. As
a result, TCP of B-PiPrOx-B gradually increased and finally
reached 41.4 °C, which is the same that of B-PiPrOx-B with 50
mM fructose but without glucose (Fig. 2a). Because the TCP of B-
PiPrOx-B with 50 mM fructose has the same value, regardless
of the presence or absence of glucose, we can conclude that the
interaction between boronic acid and fructose is quite strong,
and that all of the glucose molecules conjugated to B-PiPrOx-B
are replaced with fructose under these conditions. Because the
normal blood sugar level of human is about 5mM, the
competition experiment between fructose and glucose was
performed under that condition (Fig. S9).44 When 5 mM of
fructose was added to B-PiPrOx-B solution having TCP at 36.1 °C
with 5 mM of glucose, the TCP was changed to 37.9 °C, implying
that the sensitivity of B-PiPrOx-B to the fructose is sufficient in
the range of the normal blood sugar level, which is
comparatively low sugar concentration.
As mentioned previously, the boronic ester exchange from
pinacol to fructose was quite fast under the 50 mM fructose
conditions. In contrast, the exchange from glucose to fructose
is slower than that from pinacol to fructose. To confirm the rate
of boronic ester exchange from glucose to fructose, we
monitored the hydrophilic-hydrophobic transition of B-PiPrOx-
B at a specific temperature (38.0 °C). The solution containing B-
PiPrOx-B with 50 mM glucose is opaque at 38.0 °C because TCP
corresponds to 36.5 °C. After the addition of fructose, the
solution gradually becomes transparent because TCP of B-
PiPrOx-B with 50 mM fructose is 41.4 °C (Fig. 2b). In the time-
course measurements, the transmittance of the B-PiPrOx-B
solution at 38.0 °C reaches approximately 90% within 100 s,
where the rate of the exchange reaction depends on the
fructose concentration (Fig. 2c). Throughout the competition
experiment, we again confirm the high binding affinity of
fructose to B-PiPrOx-B. Moreover, we can control the solubility
of B-PiPrOx-B by the addition of saccharides near human-body
temperature.
Figure 2. Thermoresponsiveness of B-PiPrOx-B in pH 7.4 PBS solutions containing 50 mM
glucose: a) Temperature-dependent transmittance changes of B-PiPrOx-B solutions
before and after fructose addition (50 mM), b) time- course transmittance measurement
at 38 °C of B-PiPrOx-B solutions after addition of various concentrations of fructose, c)
photographs of B-PiPrOx-B solutions before and after fructose addition (50 mM).
Because fructose is the most reactive substrate for B-PiPrOx-B,
TCP of B-PiPrOx-B (4.0 g/L) in 10 mM PBS (150 mM NaCl, pH 7.4)
solution containing various concentrations of fructose (1–200
mM) was again measured (Fig. 1e,f). As the concentration of
fructose was increased, TCP gradually increased, with saturation
behaviour. At a fructose concentration of 200 mM, TCP of B-
PiPrOx-B became 42.0 °C, which is 6.3 °C higher than the
In summary, boronic ester-bearing telechelic poly(2-isopropyl-
2-oxazoline) was prepared as
a dual stimuli-responsive
functional polymer, which showed high sensitivity and
selectivity to fructose. At a certain temperature, B-PiPrOx-B
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exhibited hydrophobic-to-hydrophilic phase transition
Chemical Communications
19.
20.
21.
T. Lorson, S. Jaksch, M. M. Lübtow, T. JüngstV, iJe.wrA. rGticrloelOl,nTlin.e
a
Lühmann and R. Luxenhofer, Biomacromolecules, 2017,
DOI: 10.1039/C8CC09835B
through boronic ester exchange from glucose to fructose. Using
the transmittance change of the B-PiPrOx-B solution, the
binding affinities of two different saccharides to boronic acid
can be directly compared. In addition, the rate of the exchange
reaction can be evaluated on the basis of time-course
transmittance changes. Because the solubility of B-PiPrOx-B can
be controlled by adjusting the fructose concentration, the
design of a fructose-mediated delivery system is feasible.
This work was supported by the Mid-Career Researcher
Program (2017R1A2A1A17069537) funded by the National
Research Foundation (NRF) of Korea.
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Conflicts of interest
There are no conflicts to declare.
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