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Increasing the Local Concentration of Drugs by Hydrogel Formation.

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Bioactive Hydrogelators
Increasing the Local Concentration of Drugs by
Hydrogel Formation**
Joerg C. Tiller*
antibiotics · drug design · gels · hydrogelators ·
During the last decade the development of drugs and other bioactive agents
for medicine, agriculture, infection control, and biotechnology has been greatly
sped up particularly by using combinatorial approaches as well as computer
modeling.[1] Although specificity and
activity of new agents could be improved, most still show severe side
effects. Therefore, an important consideration is that the agents must be
directed to the target site with sufficient
but nontoxic concentrations. A solution
to this problem can be an increased local
concentration of agents on the surfaces
of cells and in organs or other tissue. The
concentration drugs on surfaces of synthetic materials, such as catheters, implants, and even water pipes, is of great
interest too. The immobilization of lowand high-molecular-weight agents, coating with drug-loaded gels, and the application of bioadhesive polymer–drug
conjugates are commonly used approaches to obtain increased local drug
concentrations.[2] A very recent approach is the local concentration of
bioactive agents by hydrogel formation.
The first example of converting an
agent into its analogous hydrogelators
by means of chemical modification was
recently reported by Xing et al.[3] The
authors derivatized the antibiotic van[*] Dr. J. C. Tiller
Freiburger Materialforschungszentrum
Albert-Ludwigs-Universit%t Freiburg
Stefan-Meier-Strasse 21
79 104 Freiburg (Germany)
Fax: (+ 49) 761-203-4700
[**] The author thanks the Deutsche Forschungsgemeinschaft (Emmy-NoetherProgramm) and the Fonds der Chemischen Industrie for financial support.
comycin (1 a) with a pyrene group to
form 1 b. Already 0.36 wt % of 1 b dissolved in water led to the formation of a
gel without additional heating. The gel is
composed of interconnected helical fibers, as verified by analysis by CD and
fluorescence spectroscopy and transmission electron microscopy. Remarkably,
the modified vancomycin 1 b exhibits up
to 11-fold higher activity than 1 a against
different bacteria.
The authors suggested that this effect might originate from the local
concentration of the antibiotic analogue
1 b on the bacterial surfaces. Two different mechanisms are possible. In the first,
it is possible that the drug forms a gel
locally on bacterial surfaces, even
though the concentration in the solution
used was up to 30 times lower than the
minimal gelation concentration (MGC).
The process would start with the specific
adhesion of 1 b to a surface, in the case
of vancomycin by formation of hydrogen bonds between the Lys-d-Ala-d-Ala
peptide backbone of the drug to compatible domains on the bacterial surface.[4] (Vancomycin acts by specific
binding to the bacterial cell surface
and thereby inhibiting the formation of
a new cell wall.) The adhered hydrogelforming drug, which is now concentrated on the surface (eventually above
MGC), starts to self-assemble. The resulting organized structure attracts more
drug molecules from the surrounding
solution, which leads to the amplification of the concentration of the drug on
the surface (Figure 1).
DOI: 10.1002/anie.200301647
Angew. Chem. Int. Ed. 2003, 42, 3072 – 3075
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. Idealized structure of a bioactive hydrogelator that has formed a gel on a surface.
The second possible mechanism involves the adhesion of fiberlike structures of the hydrogel-forming drug,
which are formed in the surrounding
solution. In both cases, the concentration of the gelating antibiotic at the
surface would be significantly higher
than that of the analogous nongelating
agent. If this concept can be further
proven, it might be the basis of a new
method to enhance the activity of numerous drugs and to coat surfaces such
as catheters or wounds with bioactive
To investigate the proposed principle, it would be useful to find a model
system that could also provide information on the functions that can be used for
modifying other bioactive agents. As 1 b
is a low-molecular-weight hydrogelator,
other reported molecules of this kind
that could serve as model systems will be
briefly reviewed in the following section. The basis of the increased activity
of a hydrogel-forming bioactive agent
seems to be:
* no significant decrease in biological
activity relative to the original
* a low MGC and formation of a
stable solution below the MGC;
* a specific affinity for the target site
or surface.
In contrast to organogelators, the
number of low-molecular-weight hydrogelators is rather limited. The structure
of 3D networks of these gelators consists
of helical fiberlike, rodlike, or micellar
shapes, which are interconnected, for
example, by hydrogen bonds. Most of
the described hydrogelators form gels
only in the presence of 1–10 % of an
organic solvent such as dimethyl sulfoxide or methanol.[5] These compounds
can hardly be used as models for biological systems. There are only a few
that form gels in plain water or aqueous
buffer without additional solvents.
Estroff and Hamilton have reported
based on bisurea dicarboxylic acid.[6] A
series of these compounds showed a
strongly pH-dependent gel formation in
water at very low concentrations
(0.3 wt %). For example, a mixture of 2
with phosphate buffer was a homogeneous solution at pH 7.9, whereas it
became a rigid gel at pH 6.7. Scanning
Angew. Chem. Int. Ed. 2003, 42, 3072 – 3075
electron microscope pictures of the
hydrogel revealed the same fibrous
structure described for the above-mentioned hydrogelating vancomycin derivative. Gel formation only occurred after
heating the solutions.
Readily water-soluble, gel-forming,
low-molecular-weight, dendritic bolaamphiphiles, so-called [9]-n-[9] arborols, were described by Newkome et al.[7]
The gels were formed by heating aqueous solutions of this substance
(2–8 wt %) at 80 8C, which is the phasetransition temperature of such systems,
and cooling them to room temperature.
Compound 3 formed gels over a wide
range of pH values (2–11) in buffers of
varying ionic strengths.
Recently, water-soluble hydrogelators based on lysine derivatized with
fatty acids (with neutral and positively
charged end groups) were reported to
have an MGC of less than 0.3 wt %.[8] In
contrast to other hydrogelators, 4, for
example, is soluble in water and need
not be boiled or sonicated as it readily
dissolves at 40 8C and forms a clear
hydrogel with a nanoscale fibrous structure upon cooling to room temperature.
Glycolipids are a large group of
gelators for organic solvents and, in a
few cases, for water. Fuhrhop et al. as
well as PfannemAller and Welte investigated hydrogels of n-octylgluconamides, which were formed by cooling
the boiling aqueous solutions to room
temperature (typical for saccharidebased hydrogelators or glycolipids).[9] It
was shown that only pure stereoisomers
form gels (GMC 0.5 wt %), but not
racemic mixtures. Dilution of the solutions or gels below 0.5 wt % led to
precipitation. Shinkai and co-workers
investigated benzylidene derivatives of
monosaccharides as water-soluble hydrogelators and showed that the stereochemistry of the gelator has a strong
influence on the gel-forming potential of
the derivatives.[10] Whereas the d-mannose-based structure 5 forms a strong
hydrogel, compounds based on d-glucose or d-galactose do not. Shinkai and
co-workers found a similar effect for the
gelation of glucose- and galactose-derivatized azo dyes.[11] In this case, only the
glucose derivative formed a hydrogel.
Kiyonaka et al. described the first
combinatorial approach for the screening of hydrogelators.[12] The authors
derivatized N-acetylgalactosamine with
various amino acids on solid supports.
The compounds prepared in this way are
mostly water-soluble, and some form
hydrogels at concentrations of 4 mm that
surprisingly shrink with increasing temperature.
Hamada et al. synthesized a number
of azo dyes that form hydrogels in water
without further heating.[13] These compounds are intensely colored and exhibit
a high GMC value of about 5 wt %.
Pang and Zhu reported that the
CF3(CF2)5CH2COOH forms a hydrogel
in water at a concentration of about
8 wt %.[14] The gel was formed by sonicating the suspension of the insoluble
compound in water. Owing to the high
MGC and the insolubility of the semifluorinated acids, however, such com-
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
pounds do not fulfill the required conditions for a model system for hydrogelating drugs.
Besides of the synthetic hydrogelators, a number of relatively small peptides (11–20 amino acid residues) can
act as hydrogelators.[15] For hydrogelation, the peptides must form b sheets in
water. Although these compounds are
water-soluble, exhibit GMC values of
1 wt % and lower, and form gels without
additional heating, they can hardly be
used for the modification of drugs as the
complex structure will most likely inhibit the biological activity of the drug.
Another problem in medicine is the
local concentration of bioactive agents,
which is of particular interest in the field
of cancer therapy, because most cytostatics unfortunately still have many
side-effects. This drug concentration is
possible by spontaneous local gel formation, during which the drug is trapped. To ensure that gelation occurs at
the right place and time, it should be
triggered by a specific parameter such as
a change in temperature.
Westhaus and Messersmith recently
reported a thermally triggered gel-forming system, which allows the formation
of hydrogels with entrapped agents
when the temperature is increased from
room to body temperature.[16] This system, illustrated in Figure 2, is based on
two-compound hydrogelators (calcium ions
and alginates). To separate the calcium ions
from the alginate, the
metal ions were trapped as CaCl2 within
temperature-sensitive bilayer lipid vesicles (90 % dipalmitoylphosphatidylcholine and 10 % dimyristoylphosphatidylcholine). An aqueous solution of such
vesicles, alginate, and a drug is stable at
room temperature. Upon injection into
the body, the lipid vesicles disintegrate
as a result of the rise in temperature and
the calcium ions were released, thus
causing a spontaneous gelation of the
alginates with concomitant trapping of
the bioactive drug.
As injection of a nondegradable
polymer into body tissue is a problem,
the application of degradable polymers
would be ideal.[17] However, only a few
are available, and these are not suited to
hydrogel formation. A good alternative
would be low-molecular-weight hydrogelators instead of polymers. Recently
reported low-molecular-weight twocomponent systems could have the same
gel-forming properties as the Ca alginate system. Kimizuka and Nakashima
described the gel formation of cationic
glutamate amphiphiles 6 with anions
such as naphthylsulfonate.[18] After the
Figure 2. Thermally triggered formation of an alginate drug hydrogel.
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
addition of the anionic compounds to
stable aqueous solutions of the cations,
clear hydrogels were formed within a
few minutes. Huc and co-workers used
so-called gemini surfactants for a watergelling system.[19] The gel-forming mixture consists of N,N’-dicetyl-N,N,N’,N’tetramethylethylenediamine dichloride
and tartrates. An aqueous solution of
these compounds forms a gel at room
temperature at concentrations as low as
1 mm.
The synthesis of the first hydrogelforming bioactive agent could open a
new field of drug design based on the
transformation of effective bioactive
agents into their hydrogelator analogues. The challenge is the modification
of the drug without affecting its biological activity. Furthermore, all compounds must be nontoxic. The basis for
this field will be the development of a
larger number of low-molecular-weight
hydrogelators to obtain a variety of
structural motifs, which can be use
either as model systems or as functional
groups for drug modification. The use of
combinatorial synthesis will be helpful
for this purpose. The same is true for
two-component hydrogelating systems,
which need to be optimized, particularly
with respect to rapid gel formation and
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