Novel redox-responsive nanogels based on poly(ionic liquid)s for the triggered loading and release of cargos

Article abstract of DOI:10.1039/c5ra21820a

The unique disulfide chemistry has been widely explored for novel and versatile delivery systems addressing both intracellular and extracellular barriers. In this study, novel redox-responsive nanogels were fabricated by radical copolymerization of ionic liquid (IL)-based monomers, 1,n-butanediyl-3,3′-bis-1-vinylimidazolium dibromide ([C_nVIm]Br, n = 4, 6), and disulphide dimethacrylate (DSDMA) in selective solvents. The as-synthesized nanogels were characterized using scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analyses (TG), dynamic laser scattering (DLS) and zeta (ζ)-potential measurements. The results demonstrated that the sizes of poly(ionic liquid) (PIL)-based nanogels can be tuned by the feed ratio of the monomers and DSDMA. Moreover, the redox-response performances of these nanogels were evaluated through the size variation in the presence of dithiothreitol (DTT) and benzoyl peroxide (BPO). The capability of PIL-based nanogels for controlled release was also investigated by using rhodamine B (RhB) as prototype model drug. It was found that DTT-triggered release of RhB could be achieved. Therefore, a redox-triggered loading and release matrix can be conveniently fabricated via PIL-based nanogels. And it can also be potentially used as a controlled carrier in biological medicine.

Full text of DOI:10.1039/c5ra21820a

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Novel redox-responsive nanogels based on
poly(ionic liquid)s for the triggered loading and
Cite this: RSC Adv., 2016, 6, 3013
release of cargos†
a
a
a
a
ab
*
Congcong Miao, Feng Li, Yong Zuo, Rongmin Wang and Yubing Xiong
The unique disulfide chemistry has been widely explored for novel and versatile delivery systems addressing
both intracellular and extracellular barriers. In this study, novel redox-responsive nanogels were fabricated
by radical copolymerization of ionic liquid (IL)-based monomers, 1,n-butanediyl-3,30-bis-1-
vinylimidazolium dibromide ([CnVIm]Br, n ¼ 4, 6), and disulphide dimethacrylate (DSDMA) in selective
solvents. The as-synthesized nanogels were characterized using scanning electron microscopy (SEM),
Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analyses (TG), dynamic laser scattering
(DLS) and zeta (z)-potential measurements. The results demonstrated that the sizes of poly(ionic liquid)
(PIL)-based nanogels can be tuned by the feed ratio of the monomers and DSDMA. Moreover, the
redox-response performances of these nanogels were evaluated through the size variation in the
presence of dithiothreitol (DTT) and benzoyl peroxide (BPO). The capability of PIL-based nanogels for
controlled release was also investigated by using rhodamine B (RhB) as prototype model drug. It was
found that DTT-triggered release of RhB could be achieved. Therefore, a redox-triggered loading and
release matrix can be conveniently fabricated via PIL-based nanogels. And it can also be potentially used
as a controlled carrier in biological medicine.
Received 19th October 2015
Accepted 20th December 2015
DOI: 10.1039/c5ra21820a
www.rsc.org/advances
glutathione (GSH).18 Till now, many studies have been focusing
on the utilization of disulde-functionalized linkages to build
Introduction
redox-responsive matrixes for controlling the biodegradability
and drug release.19–25 Recently, polymeric nanomaterials, espe-
cially nanogels, have been widely developed as the matrix with
all kinds of stimuli-response.26,27 Although the recent reports
have demonstrated a great potential of redox-responsive nano-
gels as drug and catalyst carriers or nanoreactors, multiple
functional nanogels for practical applications remain an active
research eld because of the difficulties in facile clean prepa-
ration, uniformity in shape and network, and well surface
modication that arises from the complicated polymerization
and post-treatment procedures.28,29
Ionic liquids (ILs), composed entirely of ions in the liquid
state below 100 ꢀC, have garnered extensive attention in
a variety of elds. The current interests in ILs are motivated by
their unique properties, including negligible vapor pressure,
thermal stability, high polarity, solvating characteristics, non-
ammability, high ionic conductivity, and a wide electro-
chemical stability window.30–35 Recently, it has been found to be
a signicant topic on the design of poly(ionic liquid) (PIL)
bearing thermoresponsive phase behavior in water and other
solvents.36–38 In the previous studies, our group has demon-
strated a facile one-step synthesis strategy to prepare PIL-based
nanogels via the conventional radical copolymerization of
IL-based monomers and the cross-linkers ethylene glycol
dimethacrylate (EGDMA) and divinylbenzene (DVB) in selective
Smart nanomaterials, which can respond quickly to environ-
mental stimuli, such as temperature, light, electricity, ultra-
sound, magnetic eld, enzymes, pH, electrolytes and redox
potential etc., have generated tremendous interest in the past
several decades due to their potential fundamental and indus-
trial applications.1–7 In these various stimuli-responses, redox-
responsive materials have drawn increasing attention because
they contain redox-responsive polymers with a high redox
potential difference (100–1000 fold) between the reducing
intracellular space and the oxidizing extracellular space.8–12
These interesting features enable them to be promising candi-
dates for controlled drug delivery systems with optimized drug
loading and release, prolonged circulation time, and accurate
targeting.13–17
Moreover, it is well-known that the signicant difference of
redox potential between the extracelluar and intracellular
compartments is due to the existence of high concentration
aKey Laboratory of Eco-Environment-Related Polymer Materials, Ministry of
Education, College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou 730070, China. E-mail: xiongyb@mpip-mainz.mpg.de
bMax Planck Institute for Polymer Research, Ackermannweg 10, Mainz 55128,
Germany
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra21820a
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solvents.39,40 In addition, thermo-responsive nanogels could in a round-bottom ask tted with a condenser and N2 bubbler.
also be prepared for the rst time via the copolymerization of Subsequently, the mixture was stirred at 70 ꢀC for 48 h under
the geminal dicationic, 1,n-butanediyl-3,30-bis-1-vinyl imidazo- nitrogen atmosphere. Aer then, the reaction solution was
lium halides (n ¼ 4, 6, 8, 12), and the cross-linkers described precipitated from diethyl ether (150 mL), and the solid was dis-
above under the same conditions.41,42 To endow PIL-based solved in methanol and precipitated from diethyl ether two times.
nanogels with more performances, herein, disulde- The obtained product was dried under vacuum for 24 h at R.T.
functionalized
cross-linker,
disulphide
dimethacrylate [C4VIm]Br was obtained as white solid (yield: 5.3 g, 65.6%). Mp:
(DSDMA), was synthesized and copolymerized with biimidazo- 150–151 ꢀC. 1H NMR (D2O, 400 MHz, ppm): 7.59(1H, d), 7.39(1H,
lium ionic liquid (BImIL)-based monomers, [CnVIm]Br (n ¼ 4, d), 6.94(1H, m), 5.59(1H, m), 5.24(1H, m), 4.12(2H, s), 1.78(2H, s).
6), in selective solvent. Therefore, novel redox-responsive 13C NMR (D2O, 100 MHz, ppm): 134.61, 128.49, 123.10, 119.91,
nanogels can be obtained, and the sizes of these PIL-based 109.62, 49.34, 26.31. ESI-MS (m/z): calcd for C14H20N4Br2: 404.15;
nanogels can be tuned by reductant and oxidant. Additionally, found: 404.1. EA (%): calcd for: C, 41.61, H, 4.99, N, 13.86, Br,
model drug rhodamine B (RhB) can be loaded and released 39.54; found: C, 40.53, H, 5.34, N, 13.55, Br, 40.58.
controllably by the redox-responsive nanogels.
Synthesis of 1,6-hexanediyl-3,30-bis-1-vinylimidazolium dibro-
mide ([C6VIm]Br). 1,6-Butanediyl-3,30-bis-1-vinylimidazolium
dibromide ([C6VIm]Br) was prepared according to the similar
method. [C6VIm]Br was obtained as white solid (yield: 6.2 g,
64.8%). Mp: 219 ꢀC. 1H NMR (D2O, 400 MHz, ppm): 7.57(1H, s),
Experimental
Materials and methods
All the reagents were purchased from commercial supplier. 7.37(1H, s), 6.93(1H, m), 5.60(1H, d), 5.22(1H, d), 4.04(2H, t),
Vinyl imidazole (VIm, 99%) was distilled on vacuum to remove 1.70(2H, s), 1.17(2H, s). 1H NMR (DMSO, 400 MHz, ppm):
the inhibitor before use. Azobisisobutyronitrile (AIBN) was 9.66(1H, s), 8.24(1H, t), 7.99(1H, t), 7.33(1H, m), 5.99(1H, m),
recrystallized from methanol before use. All other chemicals 5.43(1H, m), 4.22(2H, t), 1.83(2H, d), 1.31(2H, s). 13C NMR
were used without further treatment.
(DMSO, 100 MHz, ppm): 135.36, 128.88, 123.31, 119.23, 109.04,
Fourier transform infrared (FT-IR) spectra were recorded on 49.02, 28.80, 24.77. ESI-MS (m/z): calcd for C16H24N4Br2: 432.2;
1
a DIGIL FTS3000 spectrophotometer using KBr tablets. H and found 432.2. EA (%): calcd C, 44.46; H, 5.60; N, 12.96; Br, 36.98.
13C NMR spectra were recorded on a Brucker AM 400 MHz Found: C, 42.94; H, 5.36; N, 12.50; Br, 39.20.
ꢀ
spectrometer at 25 C. Thermogravimetric analyses (TGA) were
Synthesis of disulphide dimethacrylate (DSDMA). Disul-
measured on a Perkin Elmer TG/TGA 6300 at a heating rate of 10 phide dimethacrylate (DSDMA), was synthesized according to the
ꢀC minꢁ1. Differential scanning calorimetry (DSC) measure- literature.46 In a typical reaction, bis-(2-hydroxyethyl) disulphide
ments were recorded on a DSC 822e thermal analysis system (BHEDS, 10.00 g, 64.84 mmol) and triethylamine (54 mL, 38
(Mettler Toledꢁo1Instruments Inc. Switzerland) at a heating rate mmol) were dissolved in anhydrous dichloromethane (150 mL)
of ꢂ1 ꢀC min with nitrogen protected (80 mL minꢁ1). The in a round-bottom ask equipped with a stirrer, a thermometer,
morphology of nanogels was observed by scanning electron and drippꢀing funnel. Then, the ask was immersed in an ice
microscopy (SEM, JSM 6700F, Japan). Dynamic laser scattering bath (0–5 C), and methacryloyl chloride (MAC, 20.08 g, 192.09
(DLS) measurements were carried out on a commercial laser mmol) was added dropwise. The reaction continued for 30 min
ꢀ
light scattering instrument (Malvern Autosizer 4700, Malvern at 0 C, and another 24 h at room temperature. Aer then, the
ꢀ
Instruments) at 25 C and 90ꢀ scattering angle. The measured reaction was stopped and triethylamine hydrochloride was
time correlation function was analyzed by the automatic removed by ltration. The solvent in the ltrate was eliminated
program equipped with the correlator. The z-average hydrody- through rotary evaporation. Yellow liquid was obtained and
namic diameter (Dh) and polydispersity index (PDI, m2/G2) were washed with sodium carbonate aqueous solution and water three
obtained by CONTIN mode analysis.43,44 Zeta (z)-potential times, respectively. The organic phase was dried with anhydrous
measurements were performed on a ZetaSizer Nano ZS90 magnesium sulfate, and the crude product was puried by silica
(Malvern Instruments). Electrophoresis mobility was measured gel column chromatography (eluant : dichloromethane : petro-
and z-potential was calculated by the Dispersion Technology leum ether ¼ 2 : 1, v/v). Finally, DSDMA was obtained as a lightly
Soware provided by Malvern according to Henry equation: UE yellow transparent liquid (yield: 76%) and was stored in a fridge
1
¼ (23z/3m)f(ka), where 3, m, f(ka) are the dielectric permittivity of in the absence of light prior to use. H NMR (CDCl3, 400 MHz,
the solvent, viscosity of the solution, and Henry's function, ppm): 6.14(2H, s), 5.59(2H, d), 4.41(4H, t), 2.98(4H, t), 1.95(6H, s).
respectively.45 The elemental analyses (EA) are measured 13C NMR (CDCl3, 100 MHz, ppm): 166.90, 135.90, 125.79, 62.36,
directly without any additives using a Vario EL Cube (Elementar 37.21, 18.11. All the NMR spectra were provided in the ESI
Analysensysteme, Germany), and Mass Spectroscopy (MS) were (Fig. S1–S7†).
performed using water as the solvent without additives on
a micrOTOF-QII mass spectrometer (Bruker Company, USA).
Preparation of redox-responsive polymeric nanogels. Redox-
responsive polymeric nanogels were synthesized via cross-
Synthesis of 1,4-butanediyl-3,30-bis-1-vinylimidazolium dibro- linking copolymerization of imidazolium ionic liquid-based
mide ([C4VIm]Br). 1,4-Butanediyl-3,30-bis-1-vinylimidazolium monomers [CnVIm]Br (n ¼ 4, 6) and the cross-linkers DSDMA
dibromide ([C4VIm]Br) was synthesized according to litera- using AIBN as initiator in selective solvents.41 The following
ture.41,42 Vinyl imidazole (Vim, 4.00 g, 42.5 mmol) and 1,4-dibro- protocol is representative of all nanogel syntheses. [C4VIm]Br
mobutane (4.75 g, 20 mmol) were dissolved in methanol (50 mL) (0.57 g, 1.40 mmol), DSDMA (0.043 g, 0.14 mmol), and AIBN (8.3
3014 | RSC Adv., 2016, 6, 3013–3019
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mg, 0.051 mmol) were dissolved in methanol (30 mL), and the (molecular weight cut off 14 000), containing RhB-loaded
ꢀ
solution was stirred at 70 C for 12 h. Aer the polymerization nanogels (0.10 g) dispersed in PBS solution (5 mL), dialyzed
ꢀ
was quenched by immersing into ice/water mixture, the reac- against 20 mL PBS solution at 37 C in a 30 mL serum bottle
tion solution was precipitated from diethyl ether (150 mL), and with gently shaken (200 rpm). The drug release was assumed to
the solid product was washed using THF, and diethyl ether, start as soon as the dialysis bags were placed into the reservoir.
respectively. The products were dried under vacuum for 24 h at At predetermined periods, 4 mL of the solution was obtained
50 ꢀC (yield: 67%). [C6VIm]Br-based nanogels were prepared periodically from the reservoir, and 4 mL fresh phosphate
according to the similar process.
buffer solution (pH 7.4) was added into the reservoir. Four
Redox-triggered decross-linking and recross-linking of hours later, 5 mmol DDT was added, and the samples were
BImIL-based nanogels. The hydrodynamic diameter (Dh) varie- taken out as previous manipulations. The absorption at 552 nm
ties of BImIL-based nanogels in response to reductant dithio- of the release buffer was measured to calculate the RhB
threitol (DTT) and oxidant benzoyl peroxide (BPO) was concentration as described above. All RhB release data were
monitored by dynamic light scattering (DLS) measurement. averaged over three measurements.
Briey, 5 mg nanogels were dispersed into 10 mL phosphate
buffer (10 mM, pH 7.4) solution under sonication, and then 5
mg DTT was added. The solution was stirred at room temper-
ature under nitrogen atmosphere. At predetermined intervals,
samples were collected and their Dh were determined using
Results and discussion
As demonstrated in our previous studies,39–42 one-step cross-
linking copolymerization of IL-based monomers is an efficient
tactics to prepare functional nanogels, as well as thermo-
responsive nanogels by introducing hydrogen (H)-bonding
interactions. To explore more possibility of stimuli-responsive
nanogel via one-step synthesis, disulde-functionalized cross-
linker, disulphide dimethacrylate (DSDMA), was used to copo-
lymerize with biimidazolium-based monomers. As illustrated in
Scheme 1, both of the monomers contain two polymerizable
vinyl double bonds. Normally, the as-prepared polymers either
precipitate or gelate in the absence of stabilizer. However, when
these two monomers were copolymerized in methanol, stable
nanogel solution could be obtained (as the photo showed in
Scheme 1). Therefore, it is believed that the polymerization
process is regulated by a similar mechanism in the previous
reports.39,42 That is, poly(BImIL) segments in the copolymer can
stabilize the nanogels due to their high affinity to the solvent,
and the polymerization process follows the mechanism of
disperse polymerization.
Dynamic laser scattering (DLS) was used to investigate the
hydrodynamic diameter (Dh) of the as-prepared nanogels. The
results are summarized in Table 1. As it shows, Dh of these
nanogels are in the range of 25 nm to 310 nm with the various
feed ratio of BImIL and DSDMA. And the diameter of nanogels
increases with increasing BImIL in feed. Too less BImIL in the
feed (less than 5 : 1) will result in the precipitation of particles
from the solvent, because the particles cannot be stabilized by
DLS. Aer 24 h, the oxidant BPO (10 mg) was added, and the
solution was stirred under air for another 24 h. Finally, samples
were collected and their Dh were measured using DLS.
Drug encapsulation and redox-triggered drug release.
Rhodamine B (RhB) was selected as the model drug to investi-
gate the redox-triggered drug loading and release behavior of
BImIL-based nanogels. Typically, dried nanogel (0.50 g) was
dispersed in 30 mL of phosphate buffer solution (pH 7.4) by low-
power bath sonication (50 W) for 30 min at room temperature.
Then, DTT (100 mg) and RhB (50 mg) were added, and the
solution was stirred gently under nitrogen atmosphere for 24 h.
Aer that, BPO (150 mg) was added and the solution was stirred
for another 24 h. The free RhB in the solution was separated
from the nanogels by a highow ultraltration membrane
(cutoff molecular weight 10 kDa; MicroconYM-10, Millipore)
and was collected in the ultraltrate. The adsorption of RhB on
the ultraltration membrane was calibrated by a standard free
RhB solution at the same condition. The absorption at 552 nm
of the ultraltrate was measured on a TU-1901 spectropho-
tometer (Purkinje General Instrument Co., Ltd, Beijing, China)
to calculate the free RhB concentration. The working curve was
obtained by standard RhB solutions with different concentra-
tions. The loading efficiency and loading amount were calcu-
lated using the following equations:
DLCð%Þ ¼
initial weight of RhB ꢁ weight of RhB in supernatant
weight of RhB loaded nanogel
ꢃ 100%
weight of RhB in nanogel
DLE ð%Þ ¼
ꢃ 100%
initial weight of RhB
Free RhB in the solution was separated by dialyzation, and
RhB-loaded nanogels were obtained by lyophilization. The
release of RhB is conducted in a phosphate buffered saline
(PBS) solution (pH 7.4). In each sample, a membrane tubing
Scheme 1 Schematic illustration of one-step synthesis of BImIL-
based nanogels (n ¼ 4, 6, the inset photo shows the as-prepared
nanogel solution).
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Table 1 Influence of various feed ratio on sizes of BVIm-based
Infrared spectra (FTIR) of BImIL-based nanogels are shown
in Fig. 2. Some typical peaks attributed to BIm-based IL and
DSDMA copolymer can be clearly recognized, such as aromatic
benzene ring (1646, 1500 cmꢁ1, stretching vibration), aromatic
imidazolium ring (1454, 1180 cmꢁ1 stretching vibration),
carbonyl group (1728 cmꢁ1, stretching vibration), etc. Espe-
cially, a weak absorption at 650 cmꢁ1 ascribed to the absorption
peak of the disulde bonds can also be observed. At the same
time, the peak ascribed to the carbon–carbon double bond
(1582 cmꢁ1, stretching vibration) in the vinyl group of the
monomers disappeared. These results demonstrate the forma-
tion of BImIL and DSDMA copolymers. Furthermore, thermo-
stabilities of the as-prepared nanogels were determined using
thermogravimetric analysis (TGA). As illustrated in Fig. 3, these
BImIL-based copolymers are stable below 250 ꢀC, which may be
due to their highly cross-linked structure. However, the onset
decompositꢀion temperature (Tdec) of [C4VIm]Br-based nanogels
(about 280 C) are lower than those of [C6VIm]Br-based nano-
gels (about 290 ꢀC). Disulde bond contained compound are
extensively utilized to fabricate redox-responsive matrixes.
Therefore, the as-prepared nanogels are denitely redox-
responsive. Under the reduce condition, the disulde bonds
can be cleaved and the nanogel will get bigger because of the
less cross-linking points. On the contrary, the nanogel will
become smaller due to formation of disulde bonds in the
nanogelsa
Entry
Monomer
Feed ratiob
Dh (nm)
PDI
Zeta (mV)
NG1
NG2
NG3
NG4
NG5
NG6
NG7
NG8
NG9
[C4VIm]Br
[C4VIm]Br
[C4VIm]Br
[C4VIm]Br
[C6VIm]Br
[C6VIm]Br
[C6VIm]Br
[C6VIm]Br
[C6VIm]Br
5 : 1
25
65
214
304
40
0.632
0.592
0.273
0.645
0.190
0.120
0.396
0.422
0.296
6.8
7.3
14.4
14.2
7.2
10 : 1
15 : 1
20 : 1
5 : 1
10 : 1
15 : 1
20 : 1
30 : 1
93
8.5
105
217
263
11.8
11.9
11.3
a
Polymerization conditions: ([monomer] + [cross-linker])/[AIBN] ¼ 30,
b
in 30 mL methanol, 70 ꢀC, 12 h. Molar ratio of [CnVIm]Br to
DSDMA; Dh: hydrodynamic diameter, PDI: polydispersity index of
nanogels.
BImIL segments in the copolymers. When the feed ratio is
higher than 15 : 1, the diameter of nanogels with [C4VIm]Br
monomer is signicantly larger than [C6VIm]Br monomer.
It is probably because [C4VIm]Br is more affinitive to the
solvent, as a result, it can stabilize the particles more efficiently
which benets to the growth of nanogels in the polymerization
process. In addition, the higher PDI indicates that the BImIL-
based nanogels are in wide dispersion, which is consistent
with the previous studies. All the nanogels are very stable in the
solution because they are positively charged.
The morphologies of BImIL-based nanogels were also
examined using scanning electron microscope (SEM). As shown
in Fig. 1 and S8 in the ESI,† the nanogels with spherical
morphology are well-dispersed in the substrate. Moreover, their
sizes are in the range of 20 to 200 nm, which are smaller than
those measured by DLS. It is because DLS provides the results of
swollen nanogels in the solution, whereas SEM gives the results
of dried nanogels.
Fig. 2 FTIR spectra of DSDMA and BImIL-based nanogels ((a) DSDMA;
(b) NG4; (c) NG2; (d) NG9; (e) NG6).
Fig. 1 Typical SEM images of BImIL-based nanogels ((a) NG3; (b) NG5; Fig.
3
TGA curves of BImIL-based nanogels with different
(c) NG6; (d) NG9; all the scale bar are 1 mm).
composition.
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Scheme 2 Schematic illustration of redox-triggered drug loading and
release of BImIL-based nanogel.
presence of oxidant (as illustrated in Scheme 2). By utilizing the
redox-triggered transformation in size of BImIL-based nano-
gels, rhodamine B (RhB), due to its hydrophilicity and ionic
structure, was selected as the model drug to investigate the
loading and release performance in the presence of reducing
agent and oxidant, respectively. As a result, a novel redox-
triggered drug loading and release matrix could be achieved
conveniently through one-step synthesis of IL-based nanogels.
To testify the above possible redox-responsive performances
of BImIL-based nanogels, the size variation of these nanogels in
response to DTT and BPO in PBS (pH 7.4) solution was inves-
tigated using DLS measurement. As shown in Fig. 4, the size of
all these nanogels increases when incubated with 3.2 mM DTT
in PBS solution for 2 h. With the incubation time extended,
these nanogels become larger and larger. This variation in size
is denitely because of the cleavage of disulde bonds of
PDSDMA in the reductive environment, which results in the
swollen of BImIL-based nanogels by solvent. Especially, because
of the high hydrophilicity of BImIL, the size of NG7 can become
as large as 7 times of original particles. When these nanogels
with cleaved disulde bonds were incubated with BPO for
another 24 h, it can be found that the sizes increased signi-
cantly, and particles in the submicrometer are obtained.
However, BPO has been found to induce tumor and inam-
matory responses in vivo.47,48 A bio-friendly oxidant should be
employed in the future applications. The performance of BVIm-
based nanogels is different from that illustrated in Scheme 2. It
is probably because of the formation of disulde bonds between
inter-nanogels instead of intra-nanogels.
Fig. 4 Size varieties of BImIL-based nanogels under redox conditions
(pH ¼ 7.4 buffer solution). ((A and A0) NG4; (B and B0) NG7; (C and C0)
NG9).
based nanogels, only very few RhB (less than 10%) could be
loaded when it was incubated with the particles directly, which
are probably absorbed on the surface of nanogels. To improve
the drug loading efficiency, BVIm-based nanogels were rstly
treated by DTT before the drug loading. Then, the drug RhB was
added, and the solution was incubated for 24 h under nitrogen
atmosphere. The mixture solutions were further treated by BPO
to trap the cargos through the formation of disulde bonds, and
the free RhB were removed by dialysis from deionized water.
The results are summarized in Table 2, it can be seen that both
DLE and DLC increase obviously, which demonstrates that
cleavage and formation of disulde bond is a feasible technique
to encapsulate the cargos for BVIm-based nanogels. Moreover,
both DLC and DLE decrease with the increase of monomer
[CnVIm]Br (n ¼ 4, 6) in the feed ratio. It likely results from the
lower containing of disulde bond in the nanogels with the
increase of [CnVIm]Br in the feed. As a result, the nanogels will
be still hyper cross-linked aer the disulde cleavage, which is
unfavorable to RhB encapsulation. On the contrary, more
disulde bonds will be favorable to the swelling of nanogels
aer DTT treatment, and RhB will pervade easily into the
nanogels. The sizes of RhB-loaded nanogels were also checked
by DLS. As indicated in Table 2, the diameters of RhB-loaded
nanogels become much bigger than the nanogels without
drugs, which should be because of the formation of disulde
bonds between nanogels in the process of BPO treatment.
Moreover, there is no signicant change on the z-potential aer
RhB was loaded.
DLS results showed that BImIL-based nanogels can respond
to DTT obviously. Therefore, RhB was selected as the model
drug to investigate the controlled encapsulation and release
triggered by redox reaction. The drug loading efficiency (DLE)
was calculated according to a working curve determined by UV-
Vis spectrum. Due to the hyper cross-linked structure of BImIL-
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Table 2 DLE and DLC of RhB loaded in BImIL-based nanogels
has been successfully achieved by cross-linking copolymeriza-
tion of BImIL-based monomers and DSDMA in selective solvent.
Zetac
(mV)
DLC
wt%
DLE
wt%
b
Feed
Dh
Entry
[CnVIm]Br
ratioa
(mm)
Conclusions
NG1
NG2
NG3
NG4
NG5
NG6
NG7
NG8
NG9
[C4VIm]Br
[C4VIm]Br
[C4VIm]Br
[C4VIm]Br
[C6VIm]Br
[C6VIm]Br
[C6VIm]Br
[C6VIm]Br
[C6VIm]Br
5 : 1
0.67
1.26
1.74
1.81
0.75
1.16
1.38
1.50
1.72
7.1
8.2
14.1
13.8
7.8
10.2
12.2
12.6
11.9
10.3
9.5
8.6
60.5
58.4
58.1
57.3
64.3
62.1
59.3
58.9
58.7
10 : 1
15 : 1
20 : 1
5 : 1
10 : 1
15 : 1
20 : 1
30 : 1
In summary, novel redox responsive nanogels have been
developed readily by one-step cross-linking copolymerization of
[CnVIm]Br (n ¼ 4 and 6) and DSDMA in selective solvent. The
results illustrated that these novel BImIL-based nanogels can
response to the redox stimuli, which would result in the size
change of nanogels. By use of this virtue of BImIL-based
nanogels, model cargo RhB could be uploaded under the
reduction conditions. And the drug-loaded particles were
further oxidized to form the disulde bonds again, which could
prevent cargos from leakage. Only less than 50% RhB could be
released in the absence of DTT, while over 80% RhB could be
released with the addition of DTT. This high cargos release is
denitely attributed to the cleavage of disulde bonds
in reducing environments. Therefore, the novel redox-
responsive nanogels could selectively increase intracellular
drug release and potentially used as controlled carrier in bio-
logical medicine.
7.5
10.9
10.1
9.6
8.4
8.0
a
Molar ratio of [CnVIm]Br to DSDMA. b Dh of RhB loaded nanogel. c z-
Potential of RhB loaded nanogel.
Fig. 5 shows the accumulative release of RhB from nanogels
composed of different ratios of BImIL to DSDMA in PBS solu-
tion (pH ¼ 7.4). The results illustrate that only less than 50%
RhB can be released from the nanogels in the absence of DTT
aer 28 h incubation. The released RhB are possibly those
absorbed on the surface of nanogels. However, over 80% RhB
could be released in the same duration in the presence of DTT.
The result suggests that both RhB absorbed on the surface and
embedded in the interior of nanogels can be released in the
presence of DTT. A redox-triggered loading and release matrix
Acknowledgements
The authors are grateful for the nancial support given by the
National Natural Science Foundation of China (Project No.
21164008, 21474080) and Natural Science Foundation of Gansu
Province (Project No. 1208RJZA167). Program for Changjiang
Scholars and Innovative Research Team in University of
Ministry of Education of China (Project No. IRT1177), Scientic
and Technical Innovation Project of Northwest Normal
University (nwnu-kjcxgc-03-63).
Notes and references
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