Facile fabrication of dextran-based fluorescent nanogels as potential glucose sensors

Article abstract of DOI:10.1039/c3cc45668d

Glucose-responsive nanogels based on dextran and poly(3- acrylamidophenylboronic acid) (PAAPBA) were fabricated by a facile self-assembly assisted (SAA) strategy. Further introduction of the fluorescent agent 2-[4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy]

Full text of DOI:10.1039/c3cc45668d

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Facile fabrication of dextran-based fluorescent
nanogels as potential glucose sensors†
Cite this: Chem. Commun., 2013,
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9, 9473
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Shuyan Zhou, Xue Min, Hongjing Dou,* Kang Sun,* Chun-Yen Chen,
Received 25th July 2013,
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Chao-Tsen Chen,* Zhaofeng Zhang, Yuqing Jin and Zunli Shen
Accepted 15th August 2013
DOI: 10.1039/c3cc45668d
www.rsc.org/chemcomm
Glucose-responsive nanogels based on dextran and poly(3-acryl- molecular species and the negatively charged ionic species.
amidophenylboronic acid) (PAAPBA) were fabricated by a facile Both of these species are capable of binding with diols, but only
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self-assembly assisted (SAA) strategy. Further introduction of the the charged species can form a stable complex. In order to
fluorescent agent 2-[4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy]- maintain this chemical equilibrium at a given pH, the boronic
ethylacrylamide (3HF-AM) allowed visualization of this glucose acid ionization equilibrium shifts to increase the concentration
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sensitivity, thus ensuring their potential use as glucose sensors.
of the charged PBA species.
Among various PBA containing
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materials, 3-acrylamidophenylboronic acid (AAPBA) provides
In recent decades, stimuli-responsive systems that undergo an excellent building block for the preparation of nano-sized
physical or chemical changes upon exposure to one or multiple particles due to its pK of B8.2, which is near physiological
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environmental stimuli, such as pH, temperature, magnetic pH and because it possesses a double bond that can undergo
fields and certain molecules such as glucose, have attracted polymerization reactions.
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great interest in the scientific field. As one of the important
Herein we have successfully developed a facile self-assembly
precursors for fabricating stimuli-responsive systems, polymers assisted (SAA) synthetic method of fabricating glucose-responsive
that respond to glucose have received considerable attention dextran-PAAPBA nanogels (DABA NGs) with narrow size dispersity,
because of their potential use in glucose quantification and for by using ceric ammonium nitrate (CAN) as the initiator and
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self-regulated insulin delivery.
Glucose-responsive systems are typically based on one of in Fig. 1). This SAA method was developed by our group to
N,N -methylene bisacrylamide (MBA) as the crosslinker (as illustrated
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three different mechanisms,
which include the enzymatic fabricate nanogels based on various polysaccharides, which
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oxidation of glucose by glucose oxidase (GOD),
of glucose with lectin Concanavalin A (ConA)
the binding include dextran and acrylic acid, where the assembly was driven
or reversible by hydrogen bonding between the proton-accepting groups of the
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covalent bond formation between glucose and phenylboronic polysaccharide and the carboxyl groups of the poly(acrylic acid)
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acid (PBA) derivatives.
In the case of the systems utilizing
GOD, the glucose must be consumed by the enzyme in order to
generate a response. Meanwhile, ConA evokes cytotoxic effects
due to its heterogeneity. Consequently, neither the GOD-based
nor the ConA-based systems are suitable for use within the human
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body. PBA-bearing polymers exhibit glucose responsiveness
due to the fact that PBA exists in two forms that are in equilibrium
with each other in aqueous solution, including the uncharged
a
The State Key Laboratory of Metal Matrix Composites, School of Materials Science
and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
E-mail: hjdou@sjtu.edu.cn, ksun@sjtu.edu.cn
b
Department of Chemistry, National Taiwan University, No. 1, Sec. 4,
Roosevelt Road, Taipei, 10617 Taiwan, Republic of China.
E-mail: chenct@ntu.edu.tw
c
Department of Plastic and Reconstructive Surgery, Shanghai First People’s Hospital,
School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, P. R. China
†
Electronic supplementary information (ESI) available: Experimental details.
Fig. 1 Schematic illustrations showing the fabrication of DABA NGs and their
See DOI: 10.1039/c3cc45668d
glucose responsiveness (a) and the synthesis of DABA NGs (b).
This journal is c The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 9473--9475 9473

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building blocks.
The crucial difference between the current
system and previously reported systems is that the AAPBA
monomer is hydrophobic under acidic conditions, and as the
polymerization progresses the resultant PAAPBA chains become
insoluble in the acidic aqueous reaction medium. Therefore,
it was the hydrophobic effects, rather than hydrogen bonding
interactions, that induced the polymer chains to aggregate and
form micelle-like nanoaggregates. With the participation of
MBA, the structure of the aggregates was stabilized, so that
they could yield the final nanogels. The successful preparation
of DABA NGs expanded the scope of the SAA approach from
proton–donor containing hydrophilic monomers to hydrophobic
monomers, thus allowing the fabrication of a diverse range of
Fig. 3 TEM images of DABA NG3 in water (a), at pH = 10 (b), and at pH = 10 in the
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dextran-based nanogels. In addition, the resultant nanogels presence of 5 mg mL of glucose (c). Also shown are hD i (d) and zeta potentials
h
were anticipated to exhibit glucose-responsive behaviour.
(e) of DABA NG3 at various glucose concentrations and different pH.
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The DABA NGs were characterized via H NMR and FT-IR
spectroscopy (Fig. 2, the chemical structure of the AAPBA
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monomer was also confirmed using H NMR spectroscopy, as increase and zeta potential decrease upon glucose addition.
shown in Fig. S1 in the ESI†). DABA NG3 was chosen as a typical As the solution became more alkaline, e.g. pH = 10, glucose
sample to display the characterization results due to its appro- addition induced an obvious diameter increase and zeta potential
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priate size for biomedical applications and narrow size distri- decrease between the glucose concentrations of 1 and 2 mg mL
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bution. In comparison with that of dextran, the FT-IR spectrum and reached equilibrium at B2 mg mL (Fig. 3d and e). TEM
of DABA NG3 exhibited two new absorption peaks at 1657 images also revealed a similar glucose responsiveness which
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and 1540 cm . These signals corresponded to the primary was consistent with the DLS results. The DABA NG3 particles
and secondary amide bands in the PAAPBA grafts (the feed possessed a diameter of B25 nm and an electron-dense PAAPBA
ratios of the DABA NG3 and other DABA NGs are shown in core after they were removed from aqueous solution and dried
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Table S1, ESI†). The H NMR spectrum of DABA NG3 that was (Fig. 3a). At elevated pH values, the former core–shell structure
recorded at pH = 12 also exhibited signals at 6–8 ppm that disappeared and was replaced by a much larger homogeneous
corresponded to the phenyl group and signals appearing at dispersion (Fig. 3b). In addition, the DABA NG3 particles conti-
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–3 ppm that corresponded to the methylene and methine nued to swell as more glucose was added (Fig. 3c). Although
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groups. The FT-IR and H NMR measurements, in combination the swelling rate of the DABA NG3 was not as good as has been
with the thermal gravimetric analysis (TGA) curves (shown in described in other reports on PBA-containing nanoparticles,
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Fig. S2 of the ESI†), confirmed that the DABA NGs consisted the glucose responsiveness of the DABA NGs particles was still
mainly of dextran and PAAPBA. Additionally, transmission electron apparent, as confirmed using DLS and TEM characterization.
microscopy (TEM) observations (Fig. 3a–c) and dynamic light
The glucose sensitivity of the PAAPBA-containing nanogels
scattering (DLS) measurements (Table S1 in the ESI†) indicated fabricated by the SAA approach was visualized by introducing a
that the DABA NG3 particles were spherical, with a controllable stimuli-responsive fluorescent agent, 2-[4-(3-hydroxy-4-oxo-4H-
average hydrodynamic diameter of around 119 nm in water. chromen-2-yl)phenoxy]ethylacrylamide (3HF-AM), into the DABA
The combination of these characterization data demonstrated nanogels (as shown in Fig. 4a). This fluorescent probe displayed
that the targeted DABA NGs had been successfully prepared a dual-band emission with a predominantly green fluorescence
through the SAA approach. The glucose and pH responsiveness in hydrophobic environments, while it exhibited a blue emis-
of the DABA NGs was investigated by DLS measurements and sion in hydrophilic environments, as described in our recent
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TEM observation. As the pK of the AAPBA monomer was reported publication. The glucose responsiveness of DABA NGs was
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to be B8.2, DABA NG3 remained virtually unchanged under due to the hydrophobic-to-hydrophilic equilibrium shift of the
acidic conditions when glucose was added into the solution. PAAPBA chains. Therefore, after the introduction of 3HF-AM into
Meanwhile, at pH = 7, the nanogels exhibited a slight volume the DABA NGs, we anticipated that the resultant NGs would
exhibit glucose-responsive fluorescence. The detailed synthetic
procedure for preparing the fluorescent FDABA NG is described
in the ESI.†
The properties of the fluorescent FDABA NG were charac-
terized using DLS, TEM and fluorescence spectroscopy. As
shown in Fig. 4b, the FDABA NGs possessed a spherical shape
with an average hydrodynamic diameter of B239 nm. Although
the variation of the FDABA NG diameters in response to glucose
was less pronounced, possibly due to the crosslinked structure
of these NGs (Table S2 in ESI†), their fluorescence spectra did
indeed change upon glucose addition. As shown in Fig. 4c,
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Fig. 2 FT-IR (a) and H NMR (b) spectra of DABA NG3 samples.
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474 Chem. Commun., 2013, 49, 9473--9475
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Scholars Award of SJTU, and the Scientific Research Foundation
for Returned Overseas Chinese Scholars provided by the State
Education Ministry for their financial support, and thanks the
Instrumental Analysis Center of SJTU for their support in
measurements. Dr C. Chen is thankful for the financial support
from NSC100-2113-M-002-010-MY3.
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Fig. 4 Schematic illustration showing the fabrication of FDABA NG (a). TEM
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This journal is c The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 9473--9475 9475