A responsive hyperbranched polymer not only can self-immolate but also can self-cross-link

Article abstract of DOI:10.1021/ma5009012

Though many responsive polymers have been prepared, none of them can both self-immolate and self-cross-link via responding to the changes of the environment. Here, we introduce a new responsive hyperbranched polymer, which not only can self-immolate but also can self-cross-link via responding to the external stimuli. Moreover, the obtained polymer can form a bioreducible nanogel in its aqueous solution simply via heating, and the formed nanogel can self-immolate via UV irradiation.

Full text of DOI:10.1021/ma5009012

Article
pubs.acs.org/Macromolecules
A Responsive Hyperbranched Polymer Not Only Can Self-Immolate
but Also Can Self-Cross-Link
Zhi-Qiang Yu,†,‡ Xiao-Man Xu,† Chun-Yan Hong,*,† De-Cheng Wu,§ and Ye-Zi You†
†CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and
Technology of China, Hefei 230026, Anhui, P. R. China
‡Chemical Engineering and Pharmaceutics School, Henan University of Science and Technology of China, Luoyang 471032, Henan,
P. R. China
§Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics & Chemistry, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: Though many responsive polymers have been
prepared, none of them can both self-immolate and self-cross-
link via responding to the changes of the environment. Here,
we introduce a new responsive hyperbranched polymer, which
not only can self-immolate but also can self-cross-link via
responding to the external stimuli. Moreover, the obtained
polymer can form a bioreducible nanogel in its aqueous
solution simply via heating, and the formed nanogel can self-
immolate via UV irradiation.
nitrobenzyl)thio)ethanol terminals. The N,N′-dimethylamine
unit is pH- and temperature-responsive, and hence the N,N′-
dimethylamine side unit can be used as responsive units to
trigger its assembly. Disulfide bonds in the backbone can
undergo disulfide exchange via heating the aqueous solution of
polymers, which can reversibly cross-link the macromole-
cules.25−28 2-((2-Nitrobenzyl)thio)ethanol terminals can in situ
release thiols via UV irradiation,29,30 which can further break
the disulfide bonds in the backbone. Therefore, this kind of
macromolecules not only can self-cross-link but also can self-
immolate via responding to the stimuli-changes of the
environment, which will have potential applications in nano-
medicine.
INTRODUCTION
■
Nature can synthesize tailored macromolecules or biomacro-
molecules that can both assemble and disassemble via
responding to the stimulus changes of the environment to
sustain life and maintain biological function.1 The synthetic
macromolecules with responsibility are often prepared for a
broad range of applications,2−7 and now these macromolecules
are playing a very important role in drug delivery,8,9
diagnostics,10−12 biosensors,10,13 microelectromechanical sys-
tems,14 coatings,15 and textiles.1 Though many responsive
polymers have been synthesized, most of them cannot self-
degrade. In order to meet the demands in the field of
biomaterials, the polymers that can self-degrade have been
papered recent years,16 which have self-immolative linkers in
the backbone.17,18 This new class of linker, which becomes
labile via activation, leading to the rapid degradation of the
parent polymer, has gained popularity in recent years in
controlled release.18−21 This ability has prompted numerous
studies on the design and development of new self-immolative
linkers and the kinetics surrounding their disassembly.
However, most of the prepared polymers have poor solubility
in water, and their preparation procedure is very complex.17 On
the other hand, disulfide-containing hyperbranched polymers
have attracted great interest of polymer chemists for
constructing bioreducible polymers used in nanomedicine.22−24
Based on previous findings, these polymers cannot self-
immolate under external stimuli. In the current study, we
introduce a novel macromolecule that can self-immolate and
self-cross-link via responding to the changes of the environ-
ment. This macromolecule bears disulfide bonds in the
backbone, N,N′-dimethylamine side units and 2-((2-
EXPERIMENTAL SECTION
■
The synthesis of N-(2-aminoethyl)-4-(((2-hydroxyethyl)thio)methyl)-
3-nitrobenzamide is shown in Scheme 1.
Synthesis of 4-(Bromomethyl)benzoic Acid (1). p-Toluic acid
(10.88 g, 80 mmol), N-bromosuccinimide (NBS, 17.10 g, 96 mmol),
and benzoyl peroxide (BPO, 200 mg, 0.8 mmol) were added to 100
mL of CHCl3. The reaction was refluxed for 14 h under vigorous
stirring. After cooling to room temperature, the precipitate was
collected via filtration. The desired 4-(bromomethyl)benzoic acid (1)
(12.5 g, yield is 72.5%) was then obtained by washing with hot water
(3 × 100 mL), drying in vacuum, and recrystallizing from hot
1
methanol. H NMR (300 MHz, d6-DMSO): δ (ppm), 7.92 (d, 2H),
7.56 (d, 2H), 4.75 (s, 2H).
Received: April 30, 2014
Revised: June 10, 2014
Published: June 23, 2014
© 2014 American Chemical Society
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Scheme 1. Synthesis of N-(2-Aminoethyl)-4-(((2-hydroxyethyl)thio)methyl)-3-nitrobenzamide
Synthesis of 4-Bromomethyl-3-nitrobenzoic Acid (2). 4-
(Bromomethyl)benzoic acid (1) (5.0 g, 23.2 mmol) was slowly
added to fuming HNO3 (50 mL) at −10 °C using a NaCl−ice bath.
After 2.5 h, the reaction mixture was poured onto crushed ice; the
product (4.5 g, 17.3 mmol, yield is 74.6%) was obtained by filtering,
washing with cold water, and recrystallizing from dichloromethane−
hexane (1/1, v/v). 1H NMR (300 MHz, d6-DMSO): δ (ppm), 8.48 (s,
1H), 8.24 (d, 1H), 7.90 (d, 1H), 4.99 (s, 2H).
Synthesis of N,N′-Cystaminebis(acrylamide) (CBA). After the
mixture of cysteamine hydrochloride (11.6 g, 50 mmol) in water (50
mL) was cooled to 0 °C, acryloyl chloride (9.30 g, 100 mmol) in
CH2Cl2 (10.0 mL) and aqueous NaOH solution (1.0 M, 100 mL)
were added simultaneously via separated dropping funnels in 1 h at 0
°C. The reaction mixture was stirred for more 2 h at room
temperature. Then, the reaction mixture was washed three times
with deionized water, and the white powders were collected by
filtration, recrystallized twice from ethyl acetate. Yield is 51%. 1H
NMR (300 MHz, d6-DMSO): δ (ppm), 8.32 (s, 2H), 6.21 (q, 2H),
6.09 (d, 2H), 5.59 (d, 2H), 3.41 (t, 4H), 2.80 (t, 4H).
Synthesis of Hyperbranched Poly(amidoamine)s with 2-((2-
Nitrobenzyl)thio)ethanol Terminals.31 N,N′-Cystaminebis-
(acrylamide) (CBA, 260 mg, 1.0 mmol) and N,N′-dimethyldipropy-
lenetriamine (DMDPTA, 79.6 mg, 0.5 mmol) were added into a vial
containing 5.0 mL of methanol/water mixture (7/3, v/v). Sub-
sequently, the polymerization was carried out at 50 °C in the vial
under an argon atmosphere. After the polymerization has been carried
out for 5 days, N-(2-aminoethyl)-4-(((2-hydroxyethyl)thio)methyl)-3-
nitrobenzamide (AHTMN, 600 mg) was added into the polymer-
ization mixture to change the vinyl terminals into 2-((2-nitrobenzyl)-
thio)ethanol terminals. Mn is 8.7 kDa and PDI is 2.09.
Synthesis of 4-(((2-Hydroxyethyl)thio)methyl)-3-nitroben-
zoic Acid (3). 2-Mercaptoethanol (0.94 g, 12 mmol, 1.2 equiv) and
triethylamine (TEA, 2.02 g, 20.0 mmol, 2 equiv) were added to a
solution of 4-bromomethyl-3-nitrobenzoic acid (2.60 g, 10 mmol, 1
equiv) in 40 mL of methanol under stirring at room temperature;
subsequently, the reaction was performed at 50 °C for 5 h. Then, the
reaction solution was concentrated and poured into 100 mL of HCl
solution (2 M). The product (2.2 g, 8.5 mmol, yield is 85%) was
1
obtained by filtering, washing with water, and drying in a vacuum. H
NMR (300 MHz, d6-DMSO): δ (ppm), 8.41 (s, 1H), 8.16 (d, 1H),
7.72 (d, 1H), 4.11 (s, 2H), 3.45 (t, 2H), 2.48 (t, 2H).
Synthesis of tert-Butyl (2-(4-(((2-Hydroxyethyl)thio)methyl)-
3-nitrobenzamido)ethyl)carbamate (4). 4-(((2-Hydroxyethyl)-
thio)methyl)-3-nitrobenzoic acid (2.1 g, 8.2 mmol, 1 equiv) and
triethylamine (TEA, 1.7 g, 16.4 mmol, 2 equiv) were dissolved in 50
mL of dichloromethane; subsequently, tert-butyl (2-aminoethyl)-
carbamate (1.44 g, 9.0 mmol, 1.1 equiv) and 1-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride (EDC, 2.34 g,
12.3 mmol, 1.5 equiv) were added into the mixture. After stirring at
room temperature for 24 h, the reaction solution was concentrated and
poured into 100 mL of 5% acetic acid solution. The product (1.15 g,
2.87 mmol, yield is 35%) was obtained by filtering, washing with water,
and drying in a vacuum. 1H NMR (300 MHz, CDCl3): δ (ppm), 8.45
(s, 1H), 8.05 (d, 1H), 7.78 (s, broad, 2H), 7.56 (d, 1H), 5.04 (s, broad,
1H), 4.13 (s, 2H), 3.73 (t, 2H), 3.57 (t, 2H), 3.43 (t, 2H), 2.66 (t,
2H), 1.45 (s, 9H).
Synthesis of N-(2-Aminoethyl)-4-(((2-hydroxyethyl)thio)-
methyl)-3-nitrobenzamide (5). tert-Butyl (2-(4-(((2-hydroxyethyl)-
thio)methyl)-3-nitrobenzamido)ethyl)carbamate (1.14 g) was dis-
solved in 40 mL of dichloromethane; subsequently, trifluoroacefic
acid (TFA, 10 mL) was added under stirring at room temperature.
After 12 h, the product (0.68 g, yield is 80%) was obtained by
concentrating the reaction solution, washing with diethyl ether twice,
and drying in a vacuum. 1H NMR (300 MHz, D2O): δ (ppm), 8.41 (s,
1H), 8.98 (d, 1H), 7.61 (d, 1H), 4.11 (s, 2H), 3.68 (t, 2H), 2.60 (t,
2H), 3.22 (t, 2H), 2.61 (t, 2H).
Preparation of Bioreducible Nanogels. The prepared hyper-
branched polymer was dissolved in NaH2PO4 aqueous solution; the
concentration was 5.0 mg/mL. pH value of the solution was tuned to
9.0 via adding NaOH solution; subsequently, the solution was heated
and remained at 50 °C for 30 min, and bioreducible nanogels formed.
RESULTS AND DISCUSSION
■
2-Mercaptoethanol has good solubility in water, affording it
with wide applications in biosystems. 2-Mercaptoethanol can
act as a reducing agent to reduce the disulfide bond, like
GSH.32,33 When the disulfide-containing poly(amidoamine) is
treated with 2-mercaptoethanol, the disulfide bonds will be
broken (Figure 1A); for example, poly(amidoamine) with
molecular weight of 7.8 kDa and PDI of 1.9 (see Supporting
Information) can be reduced into small molecules with
molecular weight of ∼300 Da after being treated with 2-
mercaptoethanol for 30 min (Figure 1B). On the other hand, 2-
((2-nitrobenzyl)thio)ethanol is protected unit for thiol, which
is able to in situ release 2-mercaptoethanol via UV
irradiation.29,30 Therefore, we can envisage that if we prepare
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(DMDPTA) at the molar ratio of 2:1 produces hyperbranched
poly(amidoamine) with vinyl terminals (HPAA-vinyl)31 as
shown in Scheme 2. Subsequently, N-(2-aminoethyl)-4-(((2-
hydroxyethyl)thio)methyl)-3-nitrobenzamide was added into
the polymerization mixture; the hyperbranched polymer with 2-
((2-nitrobenzyl)thio)ethanol terminals was obtained with Mn
of 8.7 kDa and PDI of 2.09. In its 1H NMR spectrum, it is clear
that the peaks corresponding to vinyl units are absent while the
peaks corresponding to 2-((2-nitrobenzyl)thio)ethanol appear
(Figure S7), indicating that 2-((2-nitrobenzyl)thio)ethanol
terminals have been linked onto the hyperbranched polymer.
It has been found that disulfide bonds can undergo
intermolecular exchange via heating.25,26,28,34−36 Thereby, the
prepared poly(amidoamine) with 2-((2-nitrobenzyl)thio)-
ethanol terminals and disulfide bonds in the backbone can
self-cross-link via intermolecular disulfide exchange via heating
(Figure 2A,B). The storage modulus G′ and loss modulus G″
curves as a function of time or frequency (ω) are a good
experimental estimate of the gel transition (cross-linking). The
values for G′ and G″ of the prepared hyperbranched polymer
slightly increase with time at 25 °C, and the G′ and G″ curves
do not intersect, indicating that the prepared hyperbranched
polymer will not cross-link at 25 °C (Figure 2B). However, at
60 °C the values for G′ and G″ of the prepared hyperbranched
polymer also increase with time and the G′ and G″ do intersect,
indicating that the prepared hyperbranched poly(amidoamine)
can self-cross-link upon heating (Figure 2B).25,26,37
Recently, it has been reported that 2-((2-nitrobenzyl)thio)-
ethanol can in situ release thiol via UV activation.29,30
Hyperbranched polymer with 2-((2-nitrobenzyl)thio)ethanol
terminals can also release 2-mercaptoethanol under UV
irradiation. In order to trace the release of 2-mercaptoethanol,
we record the absorption spectra of disulfide-containing
poly(amidoamine) via UV irradiation in the presence of
Ellman’s agent (5,5′-dithiobis(2-nitrobenzoic acid)) as shown
in Figure 2C. It is clear that the absorption increases with the
increase of irradiation time, indicating that 2-mercaptoethanol
has been released via UV irradiation and the amount of the
released 2-mercaptoethanol increases with the increase of
irradiation time. Based on the absorption value, the
Figure 1. (A) Scheme of 2-mercaptoethanol reducing the disulfide-
containing poly(amidoamine). (B) GPC traces of disulfide-containing
poly(amidoamine) before and after being treated with 2-mercaptoe-
thanol.
a hyperbranched polymer with both disulfide bonds and 2-((2-
nitrobenzyl)thio)ethanol units, 2-((2-nitrobenzyl)thio)ethanol
will release 2-mercaptoethanol via UV irradiation, and the
released 2-mercaptoethanol can break the disulfide bonds in the
polymer backbone, leading to the self-immolation of the
hyperbranched polymer.
Michael addition polymerization of N,N′-cystaminebis-
(acrylamide) (CBA) and N,N′-dimethyldipropylenetriamine
Scheme 2. Outline for the Synthesis of Self-Immolative and Self-Cross-Linking Hyperbranched Poly(amidoamine)
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Figure 2. (A) Scheme for that the hyperbranched polymer can self-cross-link via heating and self-immolate via UV irradiation. (B) Changes of G′
and G″ at 25 and 60 °C with time. (C) Absorption for disulfide-containing poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol terminals via UV
irradiation in the presence of Ellman’s agent at different time. (D) Fluorescent spectra for disulfide-containing poly(amidoamine) with 2-((2-
nitrobenzyl)thio)ethanol terminals via UV irradiation at different time (inset: the fluorescent images of this polymer via UV irradiation at different
times).
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1
Figure 3. (A) H NMR spectra of the disulfide-containing poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol terminals under UV irradiation.
(B) GPC traces of disulfide-containing poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol terminals before and after UV irradiation.
concentration of the released 2-mercaptoethanol is 1.2 mM
after 3 h irradiation when the polymer concentration is 10.0
mg/mL. For the hyperbranched poly(amidoamine) without 2-
((2-nitrobenzyl)thio)ethanol terminal, there is almost no
absorption in the presence of Ellman’s agent as shown in
Figure S9. Moreover, after the release of thiol, the system
becomes fluorescent (may be due to the produce of 2-
nitrobenzaldehyde units). Thereby, we record the fluorescence
changes during the self-immolation of poly(amidoamine) with
2-((2-nitrobenzyl)thio)ethanol terminals. The fluorescence
changes are shown in Figure 2D. Similar to absorption, the
fluorescence intensity increases with the increase of UV
irradiation time while there is almost no fluorescence for the
similar hyperbranched poly(amidoamine) without 2-((2-
nitrobenzyl)thio)ethanol terminal under UV irradiation (Figure
S10). Moreover, based on the self-immolative mechanism
(Figure 2A), CH2 unit between S atom and benzene unit will
be absent from the macromolecule after UV irradiation. We
All these results show that UV can activate the release of 2-
mercaptoethanol, which can act a reduction agent to reduce the
disulfide bonds. Here, it should be noted that the polymer
prepared has no primary amine in the backbone, most of the
amine units are tertiary amine, and there are few secondary
amines. The reactivity of formed benzaldehyde with the
secondary amine in the backbone is very slow; NMR result
shows that ∼90% of the formed benzaldehyde remained
unreacted based on integral value of CHO and benzene
protons. We also check the molecular weight change of
poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol termi-
nals under UV irradiation for 30 min via GPC; it is clear that
molecular weight decreases to 300 Da from 8.7 kDa (Figure
3B). Based on the above result, the prepared hyperbranched
poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol termi-
nals can self-immolate via UV irradiation.
Furthermore, this hyperbranched polymer is temperature and
pH-responsive (Figure S11).26 Therefore, this polymer can self-
construct a bioreducible nanogel in its solution simply by
increasing pH and temperature of the solution; moreover, the
formed bioreducible nanogel can self-immolate via UV
irradiation as shown in Figure 4A. The hyperbranched polymer
can shrink and collapse into nanoparticles via tuning pH of the
solution to 9.0, and the size of the nanoparticles is ∼380 nm
1
record H NMR spectra of hyperbranched poly(amidoamine)
before and after UV irradiation; it is clear that the signal at
about 4.1 ppm for the CH2 unit between S atom and benzene
unit becomes very weak after 4 h UV irradiation (the remaining
CH2 is only ∼10%) while there is a new peak at 10.2 ppm for
the produced aldehyde unit after UV irradiation (Figure 3A).
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Figure 4. (A) Scheme of the in situ formation of bioreducible nanogel and its self-immolation under the stimulus changes of the environment. (B)
Pictures for the changes of poly(amidoamine) (1) solution under pH, temperature, and UV irradiation. (C) Images the formed nanogel under UV
irradiation at different times. (D) DSL results for disulfide-containing poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol terminals; the nanogel
before and after UV irradiation. (E) AFM images for disulfide-containing poly(amidoamine) with 2-((2-nitrobenzyl)thio)ethanol terminals (a); the
formed nanogel before (b) and after UV activation (c).
(DLS) at polymer concentration of 5.0 mg/mL. Without
heating the solution, the formed nanoparticles are stabilized by
weak intermolecular associations (i.e., van der Waals inter-
actions), and the particles can readily redissolve by decreasing
pH to 7.0 (Figure 4B). However, after heating the solution to
50 °C for 30 min, the particles cannot redissolve (Figure 4B);
the reason is that the nanoparticles undergo intermolecular
disulfide exchange via heating to 50 °C, thereby self-cross-
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linking the nanoparticles into nanogels as shown in Figure 4A.
The formed nanogels have many 2-((2-nitrobenzyl)thio)-
ethanol units, via UV irradiation, 2-((2-nitrobenzyl)thio)-
ethanol can in situ release 2-mercaptoethanol, and the released
2-mercaptoethanol can break the disulfide bonds in the
nanogel; therefore, the nanogel self-immolates via UV
irradiation as shown Figure 4. In Figure 4C, it is clear that
the solution becomes clear from opaque via UV irradiation for
3 h. However, the nanogel without 2-((2-nitrobenzyl)thio)-
ethanol formed from disulfide-containing poly(amidoamine)
cannot self-immolate via UV irradiation; the solution keeps
opaque via UV irradiation for 3 h (Figure S12). Furthermore,
DLS results show that the nanogel with the size of 380 nm self-
immolates into small fragments with size of several nanometers
via UV irradiation. AFM images also indicate that the nanogel
with 2-((2-nitrobenzyl)thio)ethanol can self-immolate via UV
activation (Figure 4E).
Polyplexes consisting of gWiz-Luc plasmid DNA and the
prepared hyperbranched polymer were prepared in PBS (10
mM) at pH 7.4 with N/P ratios of 20 and 40. The polymer
solution was rapidly added to the DNA and mixed by vortex,
followed by 20 min incubation at room temperature prior to
use. Transfection efficiency was tested in Hela cell lines. After 4
h of incubation, the transfection mixture was removed and the
cells were cultured in fresh full DMEM media and under UV
irradiation for 0, 10, and 20 min. The result shows that the
transfection efficiency increases with the increase of UV
irradiation time, indicating that UV irradiation can help the
release of DNA in cell (Figure S13).
(WK2060200012), and the Program for New Century
Excellent Talents in Universities (NCET-11-0882) is gratefully
acknowledged.
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CONCLUSIONS
■
A novel multiresponsive macromolecule with disulfide bonds in
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
*Fax 86 551 63601592; Tel 86 551 63606081; e-mail hongcy@
ustc.edu.cn (C.-Y.H.).
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (51033005, 51273187, 21374107, and 21090354), the
Fundamental Research Funds for the Central Universities
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