Pyridine-based coordination polymeric hydrogel with Cu2+ ion and its encapsulation of a hydrophobic molecule

Article abstract of DOI:10.1039/c0cc05555g

We report the formation of a coordination polymeric hydrogel of a pyridine derivative with Cu²⁺ and its efficiency as a delivery system for curcumin as a model hydrophobic drug. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc05555g

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COMMUNICATION
2+
Pyridine-based coordination polymeric hydrogel with Cu ion and its
encapsulation of a hydrophobic moleculew
a
a
b
b
c
Hyejin Lee, Ji Ha Lee, Sunwoo Kang, Jin Yong Lee,* George John* and
a
Jong Hwa Jung*
Received 14th December 2010, Accepted 11th January 2011
DOI: 10.1039/c0cc05555g
We report the formation of a coordination polymeric hydrogel of
2
+
a pyridine derivative with Cu and its efficiency as a delivery
system for curcumin as a model hydrophobic drug.
The self-assembly of small molecules to form functional materials
is a powerful tool for the development of new technological
devices. In particular, supramolecular self-assembly of low
molecular weight hydrogelators leading to gel formation has
tube method (Fig. 1a and Fig. S1, ESIw). In contrast, compounds
2+
1–8
1 and 2 with Cu cannot gelate water at an acidic condition, due
to protonation of nitrogen atoms of ligands 1 and 2. This result
clearly supported the view that 1 forms the hydrogel mainly by
coordination bonds at pH = 7. In trials with other metal ions,
attracted increasing interest. Among the materials, hydrogels
possess a range of applications in areas such as tissue
9
engineering, controlled-release drug delivery systems
10–12
and
13
medical implants. The design and synthesis of low molecular
weight hydrogelators have received considerable attention in soft
materials research in terms of their potential use in cosmetics,
toiletries, and pharmaceutical formulations.
2
+
2+
2+
1
and 2 did not form hydrogels with Zn , Co or Mn at
pH = 7 (Fig. S2, ESIw). The hydrogels 1 and 2 are pH responsive
and precipitated upon adjustment to acidic and basic pH values.
Furthermore, upon adjusting the pH from acidic to neutral
conditions, the formation of a complex allows the recovery of
the gel structure. 1 could also be gelated with a variety of copper
Very recently, several researchers have successfully incorporated
metal ions into gelators to form coordination polymeric organo-
14–16
gels or hydrogels.
Coordination polymeric gels have also been
2
4
ꢀ
ꢀ
ꢀ
anions such as SO
, NO
3
and Cl (Fig. S3, ESIw), indicating
that the formation of coordination polymeric gel 1 did not
reported to display unusual functional properties such as
18,19
1
7
20,21
redox responsiveness,
catalytic action,
21
and magnetism. However, a study of the literature
absorption,
22–24
emission
strongly depend on the nature of the anion. Fig. 1b shows the
2+
SEM image of Cu coordination polymeric gel 1, which clearly
reveals that there are only limited reports on easily achievable and
efficient low molecular weight materials that are able to form
displays a fibrillar network. The fibers are several micrometres
2+
long with widths in the range 40–65 nm. SEM images of Cu
1
5
coordination polymeric hydrogels. Herein, we report the
coordination polymeric gel 1 with different anions showed a
similar fiber structure with diameters of 40–70 nm (Fig. S4, ESIw).
These findings suggest that the morphology of the coordination
polymeric gel 1 was not dependent on the type of anion.
The absorption and emission properties of sol 1 and
formation of a coordination polymeric gel of simple pyridine
2+
derivative (1) containing Cu ion. We also describe the encap-
sulation of a hydrophobic molecule, curcumin, by 1. Compound 2
without the central nitrogen atom was prepared as a reference. We
believe this approach will give new insights into low molecular
weight hydrogelator-based drug delivery models.
2+
coordination polymeric gel 1 with Cu were extensively studied
(Fig. S5, ESIw). Compound 1 shows a distinct absorption
When acidic aqueous solutions of 1 and 2 (20 mM) were
2
+
spectrum with one prominent peak at 302 nm attributed to
reacted with Cu
ion solution, hydrogels 1 and 2 were
p–p* transition. On the other hand, the UV-vis absorption
formed instantly at pH = 7, as confirmed by the inverted test
a
Department of Chemistry and Research Institute of Natural Science,
Gyeongsang National University, Jinju 660-701, Korea.
E-mail: jonghwa@gnu.ac.kr
Department of Chemistry and Institute of Basic Science,
b
Sungkyunkwan University, Suwon 440-746, Korea.
E-mail: jinylee@skku.edu
Department of Chemistry, The City College of New York,
c
New York, New York 10031, USA. E-mail: john@sci.ccny.cuny.edu
w Electronic supplementary information (ESI) available: Spectro-
scopic data and calculation results for gel 1. See DOI: 10.1039/
c0cc05555g
2
+
Fig. 1 (a) Photograph of 1 (20 mM) in the presence of Cu
3 equiv.) at different pH values. (b) SEM image of gel 1 (20 mM)
(
2+
with Cu (3 equiv.).
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2937–2939 2937

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2
+
25
previously reported literature. Therefore, 1 might form the
band of Cu coordination polymeric gel 1 exhibits a large red
2+
coordination polymeric structure with Cu
shift in energy (Fig. S5A, ESIw), which is similar to previously
.
25
reported results. The fluorescence spectra of the coordination
polymeric gel 1 and sol 1 (lex = 302 nm) were also observed, as
shown in Fig. S5B (ESIw). The sol 1 exhibits a strong blue
emission with a maximum at l = 470 nm. In contrast, the
The solid sample, containing ligand 1 and Cu(ClO ) , was
4
2
prepared to probe the stoichiometry by elemental analysis and
EDX technique. The elemental analysis of the precipitated
sample consists of 52.05% of C, 3.35% of H, 17.91% of N,
4.55% of Cl and 4.09% of Cu. Our DFT calculation also
shows the following results, which is in excellent agreement
with the experimental data; calcd C (53.04%), H (3.38%), O
(16.64%), N (18.20%), Cl (4.61%), Cu (4.11%). These
findings indicate that stoichiometry of the sample is consistent
with a 4 : 1 (1 to Cu) formulation. The EDX observation is
also in agreement with that of the elemental analysis for the
4 : 1 complex (1 : Cu) (Fig. S9, ESIw).
2+
fluorescence emission intensity of the Cu
coordination
polymeric gel 1 decreased drastically compared to sol 1, due to
photoinduced electron transfer (PET) effect with the complex
formation of the interaction between nitrogen atoms of both end
2
+ 26
pyridine groups of ligand 1 and Cu
pyridine groups of 1 are bound to Zn
. It is known that both end
2+ 27
2+
Probably Cu has a
.
tendency to bind to the nitrogen atoms of both end pyridine
groups rather than the nitrogen atom of the center pyridine group.
2+
Interestingly, the absorption intensity of Cu coordination
The strength of the coordination polymeric gel 1 was then
2+
studied by rheology. The linear viscoelastic region (LVR) of Cu
polymeric gel 1 gradually increased up to the addition of
2+
.25 equivalents of Cu
0
and then remained constant upon
coordination polymeric gel 1 was also determined with increasing
ꢀ
1
amplitude of deformation from 0.01% to 200% at 1 rads and
further addition (Fig. S6, ESIw). These results indicate that one
metal ion is bound to 4 gelators. Furthermore, different anions
0
00
storage modulus G and loss modulus G remained flat up to
E1% (Fig. S10a, ESIw). Beyond this level of deformation, drastic
drop in both moduli suggested a catastrophic disruption of the
networks. Fig. S10b (ESIw) shows the frequency response of a gel
ꢀ
ꢀ
+
2ꢀ
such as Cl , NO
3
2
and SO had little effect on the absorption
4
properties of Cu coordination polymeric gel 1, indicating that
the formation of the coordination polymeric gel of ligand 1 was
2
+
0
specific for Cu and was not affected by the anion.
of 2.5 wt%. The elastic modulus G is independent of frequency
00
2
+
The Cu coordination polymeric gel 1 fiber was also examined
independently by elemental mapping with electron energy-loss
spectroscopy. The material contains copper (Fig. S7a, ESIw),
carbon (Fig. S7b, ESIw), nitrogen (Fig. S7c, ESIw) and oxygen
and much higher than the viscous modulus G over the frequency
range. This response is typical of gels as it shows that the sample
0
does not relax over long time scales. The value of G is a measure
of the gel stiffness, and its value here (ca. 3500 Pa) indicates a gel
of moderate strength.
(
Fig. S7d, ESIw) components. The distribution of copper shows a
one-dimensional structure, strongly implying again that Cu had
formed a complex with ligand 1.
2+
To further explore the possible applications of the coordination
polymeric gels, we considered using the hydrophobic pockets
within the gel to encapsulate the hydrophobic molecule curcumin
(Fig. S11 and S12, ESIw). We tested the gel as a delivery vehicle
model. We demonstrate pH-triggered delivery at physiological
conditions, where we encapsulated (solubilized without chemical
modification) a hydrophobic molecule in the coordination
polymeric hydrogel and subsequently released the hydrophobic
molecule by degrading the gel with weak acid. As a model
molecule we chose one of the best-characterized chemopreventive
To obtain an insight into the coordination polymeric structure
2+
of 1 with Cu , we carried out density functional theory (DFT)
calculations using the Becke’s three parameterized Lee–Yang–
Parr exchange functional (B3LYP) with 3-21G* basis sets using a
28
suite of Gaussian 03 programs. The optimized structure of the
complex (Fig. S8a, ESIw) showed two water molecules and four
ligands coordinated to each Cu ion with a possibly octahedral
2+
geometry with the two water molecules in the trans position.
2
9
In addition, two ligands participate as m -ligands that are
agents, curcumin (or diferuloylmethane), extracted from the
2
2+
coordinated to two different Cu
ions at the same time. On
2+
was not coordinated to Cu . It should
root of Curcuma longa, which exhibits strong antioxidative,
30
anti-inflammatory and antiseptic properties.
ꢀ
the other hand, the ClO
4
be noted that there is a spacious cavity surrounded by the two
A schematic representation of curcumin encapsulation and
pH-response release is depicted in Fig. S12 and experimental
section (ESIw). The curcumin molecules were stably encapsulated
2+
2
m -ligands and two Cu ions. A cyclic water tetramer occupies
this cavity and each of the four water molecules is involved in the
2+
hydrogen bonding with the amide nitrogen of the ligands. The
in Cu
coordination polymeric gel 1 (Fig. 2). The curcumin
distance between the two copper(II) cations was calculated to be
˚
molecules might encapsulate by hydrophobic or hydrogen-bond
interactions in the hydrophobic cavity between the ligand and
curcumin molecules. The release of curcumin into the aqueous
solution at pH = 5 was monitored by measuring the curcumin
UV-absorption spectrum (Fig. S13, ESIw). We compared the
absorption spectrum recorded in aqueous gel solution with the
spectrum of curcumin recorded in methanol (the effect of solvent
polarity on the absorbance spectrum of curcumin is minimal).
1
6.25 A, and the distance between the two nitrogen atoms
˚
of the pyridine across the cavity was calculated to be 8.24 A.
Interestingly, when the cyclic water tetramer is located at the
center of the cavity, the hydrogen bonding networks apparently
make the complex very solid, which is similar to a previously
2+
27
reported Zn
complex. As shown in Fig. S8b (ESIw), the
hydrogen bonding distances (OꢁꢁꢁO distances) in the cyclic water
2+
ꢀ3
tetramer inside the cavity of the Cu complex are in the range of
˚
.53–2.57 A, much shorter than those in the free cyclic water
Curcumin at 5 ꢂ 10 M was solubilized in 2.5 wt% hydrogel of 1
3
1
ꢀ8
2
(the reported solubility of curcumin in water is 3 ꢂ 10 M,
B165 000 times less than that in the hydrogel); the resulting gel
was dark yellow in color (Fig. 2A; b), and due to its hydrophobic
nature, curcumin might be located in hydrophobic pockets of the
gel. The absence of any absorbance peak indicated the absence of
tetramer, even though there are four additional hydrogen
bondings between the water tetramer and the ligands. Further-
more, the intermolecular hydrogen-bonding interaction between
amide groups of 1 did not take place, which coincides with a
2
938 Chem. Commun., 2011, 47, 2937–2939
This journal is c The Royal Society of Chemistry 2011

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encapsulation of chemopreventive curcumin in the hydrogel
and the pH-triggered gel dissociation were performed to
release the encapsulated drug into the solution at physiological
temperature. Coordination polymeric gels now offer
a
powerful strategy for developing new molecularly defined
materials in materials and medicinal science.
This work was supported by a grant from World Class
University (WCU) Program (R32-2008-000-20003-0) and NRF
2+
Fig. 2 (A) Photograph of (a) hydrogel 1 (20 mM) with Cu
2+
ꢀ3
(
3 equiv.), (b) hydrogel 1 with Cu
+ curcumin (5 ꢂ 10 M),
c and d) hydrogel 1 with Cu + curcumin + aqueous solution (pH =
, 1 mL) after (c) 10 min and (d) 80 min. (B) UV-vis spectra of hydrogel 1
(2010-0016922) supported by Ministry of Education, Science,
2+
(
and Technology, S. Korea. The work at SKKU was supported
by the NRF grant (20100001630) by MEST, S. Korea.
5
2+
with Cu + curcumin + aqueous solution (pH = 5) after (a) 10 min and
b) 80 min and (c) curcumin solution (5 ꢂ 10ꢀ M).
3
(
Notes and references
curcumin on the gel surface by adsorption. However, 1.0 mL of an
aqueous solution (pH = 5) was added to the preformed gel which
had been kept at 37 1C for 80 min. Initially, the added solution
was colorless (Fig. 2A; c). After 80 min, visual changes occurred
1
G. O. Lloyd and J. W. Steed, Nat. Chem., 2009, 1, 437–442.
2 R. G. Weiss and P. Terech, Molecular Gels: Materials with
Self-Assembled Fibrillar Networks, Springer, Dordrecht, 2006.
3
4
T. Ishi-I and S. Shinkai, Top. Curr. Chem., 2005, 258, 119–160.
N. M. Sangeetha and U. Maitra, Chem. Soc. Rev., 2005, 34, 821–836.
(
Fig. 2A; d), i.e., the gel 1 became soluble, and the top solution
5 R. Hirst, B. Escuder, J. F. Miravet and D. K. Smith, Angew.
Chem., Int. Ed., 2008, 47, 8002–8018.
became yellow in color which indicated that the encapsulated
curcumin had been released into the solution. This possibility was
confirmed by spectroscopic experiments. Aliquots were collected
after addition of aqueous solution (pH = 5) to the hydrogel (after
6
7
8
P. Dastidar, Chem. Soc. Rev., 2008, 37, 2699–2715.
F. Zhao, M. L. Ma and B. Xu, Chem. Soc. Rev., 2009, 38, 883–891.
M.-O. M. Piepenbrock, G. O. Lloyd, N. Clarke and J. W. Steed,
Chem. Rev., 2010, 110, 1960–2004.
9
K. Y. Lee and D. J. Mooney, Chem. Rev., 2001, 101, 1869–1879.
1
0 min and 80 min), and the absorbance spectra were recorded.
1
0 A. Friggeri, B. L. Feringa and J. J. van Esch, J. Controlled Release,
004, 97, 241–248.
Interestingly, initial aliquots (after 10 min) did not show any
absorbance peak (Fig. 2B; a), but aliquots collected after 80 min
showed absorption maxima at 425 nm (Fig. 2B; b), which
corresponded to the absorption peak of curcumin (Fig. 2B; c).
When the pH was adjusted to B5, approximately 100% of
curcumin was efficiently released into the aqueous phase over
2
1
1 (a) Z. Yang, G. Liang, L. Wang and B. Xu, J. Am. Chem. Soc.,
2006, 128, 3038–3043; (b) Z. Yang, H. W. Gu, D. G. Fu, P. Gao,
K. J. K. Lam and B. Xu, Adv. Mater., 2004, 16, 1440–1444;
(
c) Z. Yang and B. Xu, Chem. Commun., 2004, 2424–2425.
1
2 (a) P. K. Vemula, J. Li and G. John, J. Am. Chem. Soc., 2006, 128,
8932–8938; (b) P. K. Vemula, G. A. Cruikshank, J. M. Karp and
G. John, Biomaterials, 2009, 30, 383–393.
80 min. The results strongly indicated that the curcumin that was
1
3 T. Miyata, T. Uragami and K. Nakamae, Adv. Drug Delivery Rev.,
encapsulated in the hydrogel was effectively released by pH control.
2
4 F. Fages, Angew. Chem., Int. Ed., 2006, 45, 1680–1682.
002, 54, 79–98.
2+
In order to investigate the binding mode of the Cu complex
with the curcumin molecule, we carried out density functional
1
15 (a) W. L. Leong, S. K. Batabyal, S. Kasapis and J. J. Vittal,
Chem.–Eur. J., 2008, 14, 8822–8829; (b) S. K. Batabyal,
W. L. Leong and J. J. Vittal, Langmuir, 2010, 26, 7464–7468.
28
theory (DFT) calculations. The optimized structure was shown
in Fig. 3. In the complex, the curcumin molecule can be inserted
1
1
1
6 S. Zhang, S. Yang, J. Lan, Y. Tang, Y. Xue and J. You, J. Am.
Chem. Soc., 2009, 131, 1689–1691.
7 K. Tsuchiya, Y. Orihara, Y. Kondo, N. Yoshino, T. Ohkubo, H. Abe
and M. J. Sakai, J. Am. Chem. Soc., 2004, 126, 12282–12283.
8 T. Tu, W. Assenmacher, H. Peterlik, R. Weisbarth, M. Nieger and
2+
perpendicularly into the cavity of the Cu complex, and it tightly
binds through the hydrogen inside the cavity. The NHꢁꢁꢁO
˚
distances were calculated to be 1.883 and 1.877 A, respectively.
In addition to the hydrogen bonding inside the cavity, the –OCH
3
¨
K. H. Dotz, Angew. Chem., Int. Ed., 2007, 46, 6368–6371.
19 B. Xing, M.-F. Choi and B. Xu, Chem.–Eur. J., 2002, 8, 5028–5032.
and –OH functional groups of the curcumin molecule are
also involved in hydrogen bonding with the water molecule
2
0 K. Kuroiwa, T. Shibata, A. Takada, N. Nemoto and N. Kimizuka,
J. Am. Chem. Soc., 2004, 126, 2016–2021.
(
–CH
3
OꢁꢁꢁHOH) and oxygen of the amide moiety of the complex
2
1 O. Roubeau, A. Colin, V. Schmitt and R. Clerac, Angew. Chem.,
Int. Ed., 2004, 43, 3283–3286.
22 M. Shirakawa, N. Fujita, T. Tani, K. Kaneko, M. Ojima, A. Fujii,
˚
(
–OHꢁꢁꢁO) with the distances of 1.544 and 1.848 A, respectively.
2+
The binding energy between the curcumin and Cu complex was
ꢀ
1
M. Ozaki and S. Shinkai, Chem.–Eur. J., 2007, 13, 4155–4162.
3 W. Weng, J. B. Beck, A. M. Jamieson and S. J. Rowan, J. Am.
Chem. Soc., 2006, 128, 11663–11672.
4 W. L. Leong, A. Y.-Y. Tam, S. K. Batabyal, L. W. Koh, S. Kasapis,
V. W.-W. Yam and J. J. Vittal, Chem. Commun., 2008, 3628–3630.
5 T. H. Kim, J. Seo, S. J. Lee, S. S. Lee, J. Kim and J. H. Jung, Chem.
Mater., 2007, 19, 5815–5819.
calculated to be 77.3 kcal mol
.
2
2
2
2
2
2
2
In conclusion, we have demonstrated that the formation of
a coordination polymeric gel can be facilitated. A pyridine-
appended ligand was shown to efficiently produce a hydrogel
2
+
by simple mixing with Cu . We also showed that the
6 A. W. Varnes, R. B. Dodson and E. L. Wehry, J. Am. Chem. Soc.,
1
972, 94, 946–950.
7 Y. W. Shin, T. H. Kim, K. Y. Lee, K.-M. Park, S. W. Han, S. S. Lee,
J. S. Kim and J. Kim, Bull. Korean Chem. Soc., 2005, 26, 473–475.
8 M. J. Frisch, et al., Gaussian 03 (Revision A1), Gaussian Inc.,
Pittsburgh, PA, 2003.
9 A. Duvoix, B. Romain, D. Sylvie, S. Michael, M. Franck,
H. Estelle, D. Mario and D. Marc, Cancer Lett. (Shannon, Irel.),
2
005, 223, 181–190.
0 M. Hergenhahn, S. Ubaldo, W. Annette, P. Axel, H. Chih-Hung,
3
2+
Fig. 3 The B3LYP/3-21G* optimized structure for the curcumin–Cu
C. Ann-Lii and R. Frank, Mol. Carcinog., 2002, 33, 137–145.
sson and T. Loftsson, Int. J. Pharm., 2002,
244, 127–135.
4ꢀ
complex. (H-bonds were denoted as green dotted lines.) The ClO
31 H. H. Tønnesen, M. Ma
´
2+
uncoordinated to Cu was omitted in the complex structure.
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2937–2939 2939