(S)-(+)-Ibuprofen-based hydrogelators: an approach toward anti-inflammatory drug delivery

Article abstract of DOI:10.1016/j.tetlet.2006.08.002

We have synthesized (S)-(+)-ibuprofen-based hydrogelators that feature dipeptide linkages. In aqueous media, one of these hydrogelators formed robust gels that were stable for several months. Enzyme-mediated hydrolysis offers a route toward the sustained

Full text of DOI:10.1016/j.tetlet.2006.08.002

Tetrahedron Letters 47 (2006) 7153–7156
(S)-(+)-Ibuprofen-based hydrogelators: an approach toward
anti-inflammatory drug delivery
Sankarprasad Bhuniya, Young Jun Seo and Byeang Hyean Kim*
National Research Laboratory, Department of Chemistry, BK School of Molecular Science,
Pohang University of Science and Technology, Pohang 790-784, Republic of Korea
Received 3 July 2006; revised 29 July 2006; accepted 1 August 2006
Available online 22 August 2006
Abstract—We have synthesized (S)-(+)-ibuprofen-based hydrogelators that feature dipeptide linkages. In aqueous media, one of
these hydrogelators formed robust gels that were stable for several months. Enzyme-mediated hydrolysis offers a route toward
the sustained release of this anti-inflammatory agent.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The preparation of small organic molecules that are
capable of gelling aqueous solvents (i.e., hydrogelators)
is a rapidly expanding area of research,1,2 especially
because of these materials’ possible practical applica-
tions in tissue engineering, as vehicles for controlled
drug release,3 and for the capture and removal of pollu-
tants. A formidable challenge for controlled drug release
is finding suitable biodegradable materials, which are
usually polymeric in nature;4 the use of small molecule
gelators may overcome this problem because they can
be derived from biocompatible components and because
their gels are held together through noncovalent forces,5
making them easier to degrade in vivo. In addition, the
diversity of functionality, that is, available for the syn-
thesis of such gelators opens up the possibility of incor-
porating drugs directly into the gelling component
through covalent bonding, that is, without the need
for physical entrapping. A further challenge for drug-
based low-molecular-weight hydrogels6 is the ability to
facilitate drug delivery to targeted regions. In this letter,
we report the synthesis of hydrogelators incorporating
the anti-inflammatory drug (S)-(+)-ibuprofen, their
gelation, and the drug’s recovery through enzymatic
cleavage, which may be beneficial for self-rendered
anti-inflammatory activity. In addition, these hydrogela-
tors may serve as carriers of other therapeutic agents
because the arrest of inflammatory response is one of
the most important prerequisites for biomaterials.
Scheme 1 illustrates our approach toward the synthesis
of the (S)-(+)-ibuprofen-based gelators. Starting from
commercially available (S)-(+) ibuprofen, we obtained
the final products in overall yields of 60–70% after two
successive coupling reactions with various amino acids.7
Of the six compounds that we prepared, only gelator 2a
had the ability to restrict the flow of water; its minimum
gelation concentration (MGC) of 0.9% (w/w) suggests
that one molecule of gelator 2a traps 2000 water mole-
cules (Table 1). In a mixed solvent system of water and
ethanol, the MGC of gelator 2a reached its minimum
value (0.25%) at a H2O-to-EtOH ratio of 80:20; that is,
the MGC of this particular gelator depends on the polar-
ity of the co-solvent system. In addition to 2a, gelator 2f
also formed a gel in the 80:20 H2O/ethanol co-solvent
system (MGC = 0.5%). Gelator 2a formed a translucent
gel for each solvent system, whereas that of gelator 2f
was opaque; these gels were stable for several months.
In case of gelators 2a and 2f, the balance between hydro-
phobic and hydrophilic forces is sufficient to form
secondary structure (nano- to micrometer scale), that
is, defined as the gel morphology; however, in other cases
(2b–e) these forces are insufficient to stabilize secondary
and tertiary structure of gelator in aqueous medium.8
Scanning electron micrograph (SEM) images (Fig. 1) of
the cryo-dried hydrogels9 of gelators 2a and 2f indicate
that they existed as entangled irregular fibers having
widths of 60–100 nm.
Keywords: Hydrogelator; Anti-inflammatory; Self-delivery.
*
In both cases, these nanofibers were bundles of supramo-
lecular polymer chains, suggesting that the intermolecular
Corresponding author. Tel.: +82 54 279 2115; fax: +82 54 279
3399; e-mail: bhkim@postech.ac.kr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.002

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S. Bhuniya et al. / Tetrahedron Letters 47 (2006) 7153–7156
H
H
H
i) glycine methyl ester,
EDC, DMAP, rt. 10 h
N
COOH
OH
O
ii) 1N NaOH, MeOH
rt, 4 h
O
1a
1
i) L-aminoacid methyl ester,
EDC, DMAP, rt. 10 h
ii) 1N NaOH, MeOH, rt. 4 h
O
H
H
O
N
C
H
N
H
N
COOH
COOH
C
2a
H
N
H
COOH
2d
O
H
O
N
O
N
H
H
O
C
H
N
N
C
H
N
2b
N
H
COOH
H
2e
2f
O
O
OH
O
C
O
H
H
N
H
H
COOH
N
C
N
H
N
COOH
2c
Scheme 1. Synthesis of potential hydrogelators.
H
O
O
interactions between the two types of gelators were
similar.
20% H2O content, reveal that the hydrogen bonding
with DMSO-d6 (CD3)2SOÁ Á ÁHN replaces that with
H2O(H2OÁ Á ÁHN).10,11 Furthermore, the upfield shift
of the amide NH signal at H2O concentrations higher
To determine the roles played by the amide linkages and
the carboxylic acid groups during the self-assembly, we
recorded the FTIR spectra of gelator 2a in both its solid
amorphous and xerogel states.7 The carbonyl stretching
band of the carboxylic acid moiety shifted significantly
(ca. 1733 cmÀ1) in the gel state relative to its location
in the solid amorphous state (ca. 1737 cmÀ1). Similarly,
the C@O stretching frequency of the amide group also
decreased in the xerogel state when compared with that
in its solid amorphous state. These spectral changes sug-
gest that hydrogen bonding interaction of the carboxylic
acid and the amide groups were one of the driving forces
for gelation.
To obtain further information about the intermole-
cular hydrogen bonding interactions between amide
groups, we measured the 1H NMR spectra of 2a in
DMSO-d6 containing various amounts of H2O.7 We
found that upon increasing the H2O content up to
20%, the signal for the amide proton initially shifted
to lower field, but then shifted upfield at 30% H2O.
The changes in the chemical shifts of the amide pro-
tons, to lower fields in the aqueous solutions up to a
Table 1. Gelation properties of hydrogelator 2a in various solvent
systems at 25 ꢁC
H2O:Ethanol
MGCa (w/w) %
Concentration (mmol)
100:00
95:05
90:10
85:15
80:20
75:25
70:30
0.90
0.60
0.40
0.30
0.25
0.40
0.50
28.00
18.75
12.50
9.35
7.80
12.50
15.60
a The MGC is the lowest gelator concentration at which gelation was
observed to restrict the flow of the medium.
Figure 1. SEM images of the xerogels of gelators: (a) 2a and (b) 2f.

S. Bhuniya et al. / Tetrahedron Letters 47 (2006) 7153–7156
7155
than 20% suggests that intermolecular hydrogen bond-
ing occurred between the gelator molecules. In addi-
tion to these hydrogen bonds, we believe that
hydrophobic interactions and van der Waals forces
also play important roles during the gelation processes
and in determining the architecture of the gel state.
hence, release the desired drug—through the action of
an enzyme in vitro.
Acknowledgments
We thank the National Research Laboratory Program
(Laboratory for Modified Nucleic Acid Systems)
and Gene Therapy R&D program(M10534000011-
05N3400-01110).
To study the release of the drug, that is, (S)-(+)-ibupro-
fen, from gelator 2a, we added a solution of carboxypep-
tidase Y (1 lmol, 0.02 mL) to a colloidal solution12 of
gelator 2a (6 lmol, 2 mg). After incubation for 2 h at
37 ꢁC, we acidified the solution to pH 2 and extracted
it with EtOAc. We analyzed the organic extract using
HPLC: the chromatogram we obtained was similar to
that of ibuprofen itself (Fig. 2). This result encouraged
us to attempt the release of the anti-inflammatory drug
from its gel. Thus, we added a solution of carboxypepti-
dase Y (1 lmol; 0.02 mL) to the gel of gelator 2a; after
24 h the gel became very weak—unstable with respect
to inversion of the container (Fig. 3)—suggesting that
the gel had been degraded by the enzyme.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.08.002.
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anti-inflammatory drug-based hydrogelators through
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Figure 2. HPLC traces of (a) (S)-(+)-ibuprofen and (b) the organic
extract of gelator 2a after enzyme treatment. The HPLC mobile phase
was held isocratically for 20 min with acetonitrile at a flow rate of
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7. See the Supplementary Data.
S. Bhuniya et al. / Tetrahedron Letters 47 (2006) 7153–7156
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