biomolecule_sensitive glucose hydrogels
TRANSCRIPT
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
1/20
Advanced Drug Delivery Reviews 54 (2002) 7998www.elsevier.com/ locate/ drugdeliv
Biomolecule-sensitive hydrogelsa , a b*Takashi Miyata , Tadashi Uragami , Katsuhiko Nakamae
aUnit of Chemistry, Faculty of Engineering and High Technology Research Center, Kansai University, Suita, Osaka 564-8680, Japan
bDepartment of Chemical Science and Engineering, Faculty of Engineering, Kobe University, Rokko, Nada, Kobe 657-8501, Japan
Received 1 August 2001; accepted 17 August 2001
Abstract
Stimuli-sensitive hydrogels have attracted considerable attention as intelligent materials in the biochemical and biomedical
fields, since they can sense environmental changes and induce structural changes by themselves. In particular, biomolecule-
sensitive hydrogels that undergo swelling changes in response to specific biomolecules have become increasingly important
because of their potential applications in the development of biomaterials and drug delivery systems. This article provides an
overview of the important and historical research regarding the synthesis and applications of glucose-sensitive hydrogels
which exhibit swelling changes in response to glucose concentration. Enzymatically degradable hydrogels and antigen-
sensitive hydrogels are also described in detail as protein-sensitive hydrogels that can respond to larger biomolecules. The
synthetic strategies of other biomolecule-sensitive hydrogels are summarized on the basis of molecular imprinting and
specific interaction. The biomolecule-sensitive hydrogels reviewed in this paper are expected to contribute significantly to the
exploration and development of newer generations of intelligent biomaterials and self-regulated drug delivery systems.
2002 Elsevier Science B.V. All rights reserved.
Keywords: Stimuli-sensitive hydrogel; Biomolecule-sensitive hydrogel; Glucose-sensitive hydrogel; Antigen-sensitive hydrogel; Enzymati-
cally degradable hydrogel; Biomolecular interaction
Contents
1. Introduction ............................................................................................................................................................................ 80
2. Glucose-sensitive hydrogels ..................................................................................................................................................... 80
2.1. Glucose oxidase-loaded hydrogels.... .................... .................... ................... .................... .................... ................... ........... 81
2.2. Lectin-loaded hydrogels .................. .................... .................... ................... .................... .................... ................... ........... 82
2.3. Hydrogels with phenylboronic acid moieties ................... ................... .................... .................... .................... ................... . 85
3. Protein-sensitive hydrogels .................. .................... ................... .................... .................... ................... .................... .............. 87
3.1. Enzyme-sensitive hydrogels.......... .................... ................... .................... .................... ................... .................... .............. 873.2. Antigen-sensitive hydrogels.............................................................................................................................................. 89
4. Other molecule-sensitive hydrogels ................... .................... ................... .................... .................... .................... ................... . 93
4.1. Molecular imprinting of hydrogels .................... ................... .................... .................... ................... .................... .............. 93
4.2. Other biomolecule-sensitive hydrogels.................. .................... ................... .................... .................... ................... ........... 93
5. Conclusions ............................................................................................................................................................................ 95
Acknowledgements...................................................................................................................................................................... 95
References .................................................................................................................................................................................. 95
*Corresponding author. Tel.: 1 81-6-6368-0949; fax: 1 81-6-6330-3770.
E-mail address: [email protected] (T. Miyata).
0169-409X/ 02/ $ see front matter 2002 Elsevier Science B.V. All rights reserved.
P I I : S 0 1 6 9 - 4 09 X ( 0 1 ) 0 0 2 4 1 - 1
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
2/20
80 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
1. Introduction [1722] and temperature- [2327] sensitive hydro-
gels have been prepared from polyelectrolyte and
The most important biosystems required to main- poly(N-isopropylacrylamide) (PNIPAAm), respec-
tain life are closely associated with natural feedback tively, for application in self-regulated drug delivery,
system functions such as homeostasis. For example, as temperature and pH are the most widely utilizedhormone release from secretory cells is regulated by triggering signals for modulated intelligent systems.
physiological cycles or specific input signals. Such Organs must respond to the presence of specific
natural feedback systems perceive specific ions or molecules, as well as physicochemical changes, such
biological molecules, such as hormones (sensor as pH and temperature, to maintain life. The next
function), and induce conformational changes or generation of biomaterials and drug delivery systems
rearrange their constitutional biomolecules to elicit will require biomolecule-sensitive hydrogels that
biological functions (effector function). Therefore, by recognize specific biomolecules and respond to them.
combining their functions in polymeric materials, For example, glucose-sensitive hydrogels that under-
natural feedback systems can be mimicked, thus go swelling in response to glucose can provide the
enabling us to fabricate intelligent systems that can tools for constructing self-regulated insulin delivery
be applied in the biomedical and biochemical fields. systems, in which a necessary amount of insulin canPolymeric materials, having both sensor and effector be administered in response to the blood glucose
functions, will contribute significantly to the con- concentration. Even though most biomolecule-sensi-
struction of the next generation of biomaterials and tive hydrogels still require further research before
drug delivery systems. practical application, they are likely to become quite
Hydrogels that exhibit both liquid-like and solid- important materials in the near future. This article
like behavior have a variety of functional properties, provides an overview of current research in the fields
such as swelling, mechanical, permeation, surface of synthesis and application of biomolecule-sensitive
and optical properties. Such properties have provided hydrogels which undergo swelling in response to
many potential applications of hydrogels in fields specific biomolecules, such as glucose, enzymes,
such as medicine, agriculture, biotechnology, etc. antigens, etc.
[1,2]. In addition, hydrogels have the unique proper-
ty of undergoing abrupt volume changes from theircollapsed and swollen states in response to environ-
mental changes [310]. The stimuli-sensitive hydro- 2. Glucose-sensitive hydrogels
gels that undergo volume changes in response to
environmental stimuli are intelligent materials, hav- Diabetes is caused by the inability of the pancreas
ing both sensor and effector functions. They can to control the blood glucose concentration. During
sense a stimulus as a signal and induce structural the treatment of diabetes, a necessary amount of
changes by themselves. With these points in view, insulin, a hormone which is secreted from the
various stimuli-sensitive hydrogels that respond to Langerhans islets of the pancreas and controls glu-
pH [7], temperature [6,8,9,11,12], electric field cose metabolism, must be administered while con-
[13,14], and other stimuli [15,16] have been studied stantly monitoring the blood glucose concentration.
experimentally and theoretically. Due to the fascinat- Many researchers have tried to develop self-reg-ing properties of the stimuli-sensitive hydrogels it is ulated insulin delivery systems in which insulin can
certain that they will have many future applications be released in response to the blood glucose con-
as suitable materials for the design of intelligent centration. Glucose-sensitive hydrogels are very
biomaterials and self-regulated drug delivery sys- useful for the development of self-regulated insulin
tems. Therefore, a variety of stimuli-sensitive hydro- delivery systems and enable us to construct an
gels have been developed for use in switches, artificial pancreas that can administer the necessary
sensors, mechanochemical actuators, drug delivery amount of insulin in response to the blood glucose
devices, specialized separation systems, bioreactors, concentration. The following subsections focus on
and artificial muscles. For example, a variety of pH- three types of glucose-sensitive hydrogels.
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
3/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 81
2.1. Glucose oxidase-loaded hydrogels
Combining glucose oxidase with pH-sensitive
hydrogels to sense glucose and regulate insulin
release is the method that many researchers haveused to develop glucose-sensitive insulin delivery
systems. Within the pH-sensitive hydrogels contain-
ing glucose oxidase, glucose is converted to gluconic
acid by glucose oxidase, thus lowering the pH in the
hydrogels. Insulin can be released by the pH-sensi-
tive swelling of the hydrogels. Thus, the pH-sensitive
hydrogels containing glucose oxidase can control
insulin release in response to the glucose concen-
tration.
Ishihara et al. [28] combined a copolymer mem-
brane ofN
,N
-diethylaminoethyl methacrylate (DEA)and 2-hydroxypropyl methacrylate (HPMA) with a
cross-linked poly(acrylamide) membrane, in which
glucose oxidase was immobilized. The presence of
glucose enhanced insulin permeability through the
membrane containing glucose oxidase (Fig. 1). The
glucose-sensitive insulin permeation was achieved
based upon the combination of an enzymatic reaction
with a pH-sensitive swelling (Fig. 2). In this system,
glucose diffuses into the membrane and is catalyzed Fig. 2. Schematic representation of the glucose-sensitive hydrogelby glucose oxidase, resulting in the conversion of membrane consisting of a poly(amine) and glucose-oxidase-loaded
membrane.glucose to gluconic acid. The microenvironmental
pH in the membrane becomes low, due to the
production of gluconic acid. As the membrane
swells, resulting from ionization of the amine groups
by the lower pH, insulin permeability through the
membrane is enhanced. Thus, insulin permeation
through the membrane is strongly dependent upon
the glucose concentration. Further, Ishihara et al.
[29] investigated insulin release from polymer cap-
sules containing insulin and glucose oxidase, which
were prepared by a conventional interfacial precipi-
tation method. Insulin release was inhibited in theabsence of glucose, but was strongly enhanced in the
presence of glucose.
Horbett et al. [3032] entrapped glucose oxidase
within hydroxyethyl methacrylate-N,N-di-Fig. 1. Permeation profile of insulin through a glucose-sensitive methylaminoethyl methacrylate copolymer hydrogelpolymer membrane consisting of a poly(amine) and glucose membranes to construct a glucose-sensitive insulinoxidase-immobilized membrane. Glucose concentration: (m) 0 M;
delivery system. To obtain a high insulin permeabili-(d) 0. 1 M; (s) 0. 2 M; (n) 0.2 M without glucose oxidase.
ty, the hydrogel membranes were made porous via(Reprinted, with permission, from Ref. [28]. Copyright 1984 TheSociety of Polymer Science, Japan.) preparation under conditions that induced a phase
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
4/20
82 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
separation during polymerization. The addition of Thus, the poly(MAAc-g-EG) hydrogels containing
glucose resulted in swelling of the membranes and glucose oxidase showed a glucose-sensitivity re-
an enhanced permeation of insulin from a reservoir sulting from the combination of the catalytic reaction
via diffusion through the swollen hydrogel mem- of glucose oxidase and the pH-sensitive complex
branes. Furthermore, to examine pH changes in the formation between carboxyl and etheric groups.glucose-sensitive hydrogel membranes, pH indicator Consequently, glucose-sensitive insulin release can
dyes that convert a pH change to a color change be achieved by using pH-sensitive hydrogels con-
were introduced into the membranes. Based on the taining insulin and glucose oxidase.
results of the experiments, a mathematical model
was developed to describe the steady-state behavior 2.2. Lectin-loaded hydrogels
of the glucose-sensitive hydrogel membranes. Theo-
retical and experimental studies demonstrated that Lectins, which are carbohydrate-binding proteins,
glucose-sensitive hydrogel membranes containing interact with glycoproteins and glycolipids on the
glucose oxidase can achieve a maximum response at cell surface and induce various effects, such as cell
sub-physiological glucose concentrations and not agglutination, cell adhesion to surfaces, and hor-
respond to higher glucose concentrations. The model mone-like action. The unique carbohydrate-bindingrevealed that the glucose-sensitive hydrogel mem- properties of lectins are very useful for the fabrica-
branes with sufficiently low glucose oxidase loading tion of glucose-sensitive systems. Therefore, some
show a progressive response to glucose concen- researchers have focused on the glucose-binding
trations in the physiological range. properties of concanavalin A ( Con A), a lectin
Peppas et al. [33,34] copolymerized methacrylic possessing four binding sites.
acid (MAAc) with poly(ethylene glycol) mono- Brownlee et al. [35] and Kim et al. [36,37] were
methacrylate in the presence of activated glucose pioneers in the development of glucose-sensitive
oxidase in order to prepare glucose-sensitive poly- insulin release systems using Con A. Their strategy
(methacrylic acid-g-ethylene glycol) (poly(MAAc-g- was to synthesize a stable, biologically active glyco-
EG)) hydrogels. Carboxyl groups of MAAc formed a sylated insulin derivative able to form a complex
complex with etheric groups of EG at a low pH, but with Con A. The glycosylated insulin derivative
the complex dissociated at a high pH, due to could be released from its complex with Con A inionization of the carboxyl groups. Therefore, the the presence of free glucose, based on the competi-
poly(MAAc-g-EG) hydrogels collapsed at a low pH, tive and complementary binding properties of glyco-
due to complexation between carboxyl groups and sylated insulin and glucose to Con A. Furthermore,
etheric groups, but were swollen at a high pH. Thus, Kim et al. [38] bound the self-regulated insulin
poly(MAAc-g-EG) hydrogels showed pH-sensitivity delivery systems, enclosed in polymer membranes, to
caused by formation and dissociation of the complex soluble, bead immobilized or cross-linked Con A.
in response to pH changes. The glucose oxidase- Polymer membranes or microcapsules containing
loaded poly(MAAc-g-EG) hydrogels showed a Con A and succinyl-amidophenyl-glucopyranoside
slower swelling rate at high glucose concentrations insulin (SAPG-insulin) quickly controlled the release
as seen in hyperglycemic conditions (200500 mg/ of SAPG-insulin in response to changes in the
dl) than that at the lower glucose concentrations of glucose concentration (Fig. 3), based on the mecha-normal blood (80 mg / dl). As glucose oxidase in the nism of the competitive and complementary binding
poly(MAAc-g-EG) hydrogels catalyzed glucose oxi- properties of SAPG-insulin and glucose to Con A.
dation, the microenvironmental pH in the hydrogels Polymer membranes and microcapsules containing
decreased, due to the production of gluconic acid. Con A and SAPG-insulin were used as self-regulated
Lowering the pH made the poly(MAAc-g-EG) hy- insulin release devices in vitro and could be opti-
drogels collapse caused by a complexation between mized for use in in vivo studies. Their studies
carboxyl and etheric groups. It is postulated that the provided new concepts with regard to the competi-
poly(MAAc-g-EG) hydrogels squeeze out insulin tive and complementary binding properties of glu-
during their collapse in the presence of glucose. cose derivatives and glucose to Con A, as well as
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
5/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 83
that Con A can recognize pendant glucose groups of
PGEMA and that the PGEMACon A complex is
sensitive to monosaccharides. Therefore, the
PGEMACon A complex is a promising develop-
ment for the fabrication of a novel glucose sensor ora glucose-sensitive insulin release system.
Novel glucose-sensitive hydrogels were prepared
using complex formation between Con A and the
pendant glucose groups of PGEMA to produce cross-
linked points in the hydrogels [41,42]. The Con
A-entrapped PGEMA hydrogels were obtained by
copolymerization of a monomer with a pendant
glucose (GEMA) and a divinylmonomer in the
presence of Con A. The density of cross-linkage of
the resultant Con A-entrapped PGEMA hydrogels
increased with increasing Con A, suggesting thatCon A acts as a cross-linking agent. The immersion
of Con A-entrapped PGEMA hydrogels in an aque-
ous glucose solution resulted in their swelling and
the swelling ratios were strongly dependent upon theFig. 3. Release of SAPG-insulin in response to stepwise changes
glucose concentration. Compressive modulus mea-in the glucose concentration. (Reprinted, with permission, from
surements revealed that the cross-linking density ofRef. [38]. Copyright 1990 Elsevier Science B.V.)Con A-entrapped PGEMA hydrogels decreased with
increasing glucose concentration. Therefore, the
their suitability for the fabrication of glucose-sensi- glucose-sensitive swelling of Con A-entrapped
tive hydrogels. PGEMA hydrogels was due to the presence of free
A variety of polymers containing saccharide res- glucose, which resulted in the dissociation of the
idues have been synthesized because of their high complex via competitive exchange (Fig. 4). Mannosepotential as promising biomaterials for biochemical caused the swelling of Con A-entrapped PGEMA
and biomedical applications [39]. Some synthetic hydrogels more effectively than glucose and the
polymers with well-defined saccharide residues have swelling ratio did not change in the presence of
been used for the investigation of saccharide-recog- galactose (Fig. 5). As mannose is a stronger inhibitor
nition processes in proteins. Nakamae et al. [40] of PGEMACon A complex formation than glucose,
investigated the complex formation between Con A the former can induce the dissociation of the com-
and a polymer with pendant glucose groups, poly(2- plex more effectively than the latter. A change in the
glucosyloxyethyl methacrylate) (PGEMA). Aqueous swelling ratio of Con A-entrapped PGEMA hydro-
PGEMA was flocculated by the addition of Con A, gels in an aqueous galactose solution was not
due to the complex formation between Con A and observed, because Con A was not able to form
the pendant glucose groups of PGEMA. The turbid complexes with galactose. Thus, the Con A-entrap-PGEMACon A complex solution became transpar- ped PGEMA hydrogels are able to recognize a
ent on the addition of free glucose or mannose, but specific monosaccharide and induce structural
not on the addition of free galactose. This is because changes. These results suggest that Con A-entrapped
free glucose and mannose act as inhibitors, thereby PGEMA hydrogels have many potential applications
inducing the dissociation of the PGEMACon A as a novel glucose sensor and as new closed-loop
complexes. The effect of these monosaccharides on insulin delivery systems.
the dissociation of the PGEMACon A complexes Park et al. [43,44] prepared a new type of hydro-
can be explained by the difference in affinity of Con gel capable of solgel phase-reversible transitions
A for the monosaccharides. These results suggest based upon changes in the glucose concentration. It
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
6/20
84 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
Fig. 4. Schematic representation of glucose-sensitive swelling changes in a poly(GEMA)Con A hydrogel. ( Reprinted, with permission,
from Ref. [41]. Copyright 1996 WileyVCH.)
concentration of free glucose in the environment had
to be at least four times that of pendant glucose to
induce the phase transition from gel to sol. The
solgel phase transition in response to the free
glucose concentration was repeated more than 10
times without any problems. The hydrogel was able
to sense changes in the glucose concentration of the
environment and respond to them in a reversible
manner. Park et al. [45] also investigated the release
of lysozyme and insulin as model proteins throughglucose-sensitive hydrogel membranes using a diffu-
sion cell. Porous poly(hydroxyethyl methacrylate)
(PHEMA) membranes were used to sandwich
glucose-containing polymers and Con A between the
donor and receptor chambers of the cell. The release
rate of the proteins from the receptor chamber to the
donor chamber was strongly dependent upon the free
glucose concentration (Fig. 6). Their studies demon-Fig. 5. Swelling ratio changes of a PGEMACon A gel as a strated that the glucose-sensitive solgel phase tran-function of time when the gel was immersed in a buffer solution
sition can be used to regulate insulin release incontaining 1 wt% of monosaccharide: (s) glucose; (j) mannose;
response to the free glucose concentration in the(d) galactose. (Reprinted, with permission, from Ref. [41].environment.Copyright 1996 WileyVCH.)
Kokufuta et al. [46] combined the carbohydrate-
binding properties of Con A with the temperature-
was shown that the mixture of a vinylpyrrolidinone- sensitive property of poly(N-ispropylacrylamide)
allylglucose copolymer with Con A led to the (PNIPAAm) to prepare saccharide-sensitive hydro-
immediate formation of hydrogels, due to complex gels. Con A was loaded on a cross-linked PNIPAAm
formation between pendant glucose groups and Con hydrogel that underwent a volume phase transition at
A. The addition of free glucose led to a phase 348C. The Con A-loaded PNIPAAm hydrogel was
transition of the hydrogel into the sol state. The shown to swell abruptly in the presence of the ionic
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
7/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 85
Fig. 6. Release of lysozyme through a glucose-sensitive hydrogel at initial glucose concentrations of 1 mg/ ml (d) and 4 mg/ml (s).
(Reprinted, with permission, from Ref. [45]. Copyright 1997 Elsevier Science B.V.)
saccharide dextran sulphate at temperatures close to means that complex formation between phenylboron-
the volume phase transition point. The abrupt swell- ic acid and a polyol compound has many potential
ing of the Con A-loaded PNIPAAm hydrogel caused applications as a glucose-sensitive material.
by the ionic saccharide dextran sulphate was attribu- Kitano et al. [47,48] synthesized copolymers with
ted to the ionic osmotic pressure exerted by the phenylboronic acid moieties (poly(NVP-co-PBA))
ionized saccharide. The replacement of the ionic by copolymerizing N-vinyl-2-pyrrolidone (NVP) and
saccharide dextran sulfate with a non-ionic sac- 3-(acrylamido)phenylboronic acid (PBA). Due to the
charide led to the collapse of the hydrogel to its reversible complex formation between phenylboronicnative volume. The temperature-sensitive property of acid of poly(NVP-co-PBA) and poly(vinyl alcohol)
PNIPAAm in the hydrogel contributed to a dramatic (PVA), the competitive binding of phenylboronic
change in the swelling ratio, due to a shift in volume acid with glucose and PVA could be utilized to
phase transition by complex formation. construct a glucose-sensitive system. The formation
and dissociation of the poly(NVP-co-PBA)/PVA2.3. Hydrogels with phenylboronic acid moieties complex could be investigated by observing the
change in viscosity.Viscosity measurements revealed
All of the preceding studies utilized proteins, such that poly(NVP-co-PBA) formed a complex with PVA
as glucose oxidase or lectins, for the fabrication of in the absence of glucose, however the complex
glucose-sensitive hydrogels. This section focuses on dissociated in the presence of glucose. These results
the preparation of glucose-sensitive hydrogels with- led to the concept of a glucose-sensitive insulinout biological components such as proteins, but release system using poly(NVP-co-PBA) and PVA
instead complex formation between a phenylboronic (Fig. 7) [48]. An electrode coated with the poly-
acid group and glucose. (NVP-co-PBA)/PVA complex is an example of the
Phenylboronic acid and its derivatives form com- potential of this system for the development of
plexes with polyol compounds, such as glucose in glucose-sensitive devices [49]. The presence of free
aqueous solution. The complex between phenylbor- glucose resulted in swelling of the poly(NVP-co-
onic acid and a polyol compound can be dissociated PBA) / PVA complex hydrogel, due to complex dis-
in the presence of a competing polyol compound sociation. Thus, the electrode coated with poly(NVP-
which is able to form a stronger complex. This co-PBA)/PVA complex hydrogel could be utilized as
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
8/20
86 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
complex as a glucose-sensitive insulin release sys-
tem, because of its intrinsic instability at a physio-
logical pH of 7.4. To stabilize complex formation
between phenylboronic acid and glucose at a physio-
logical pH of 7.4, amino groups were introducedeither into the polymer or in the vicinity of the
phenylboronic acid moiety [50]. Furthermore, a
glucose-sensitive hydrogel possessing both phenyl-
boronic acid and amino groups was prepared for the
development of a novel glucose-sensitive insulin
delivery system at physiological pH [51]. This
glucose-sensitive insulin delivery system was based
upon the complex formation between gluconated
insulin and the phenylboronic acid groups in the
hydrogel. The gluconated insulin was released from
the hydrogel in the presence of free glucose, whichinduced the dissociation of the complex. This system
was able to achieve an insulin release in response to
the glucose concentration at a physiological pH.
PBA exists in equilibrium between the uncharged
and the charged form (Fig. 8). Complex formation
between the uncharged form and glucose was shown
to be unstable because of its high susceptibility to
hydrolysis, while charged phenylboronic acid groups
were able to form a stable complex with glucose.
Complex formation between the charged phenyl-Fig. 7. Concept of a glucose-sensitive insulin release system using boronic acid groups and glucose caused a shift in the
PVA/poly(NVP-co-PBA) (polymer capsule type). equilibrium towards an increase of charged phenyl-boronic acid groups. Therefore, the total amount of
a glucose sensor, as the current changes were charged phenylboronic acid groups increased and
proportional to the glucose concentration. uncharged groups decreased when glucose was
It is difficult to use the poly(NVP-co-PBA)/ PVA added. A change in the ratio of the uncharged to
Fig. 8. Equilibria of (alkylamido)phenylboronic acid ( 1).
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
9/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 87
charged forms by the addition of glucose influenced
the solubility of the polymer in water. The change in
solubility indicated that the shift in the equilibrium
between the uncharged and charged forms of the
phenylboronic acid groups can be used to developglucose-sensitive systems. Kataoka et al. [50] pre-
pared a copolymer of N,N-dimethylacrylamide and
PBA, which had a low critical solution temperature
(LCST) of about 278C, in a buffer solution of pH
7.4. The fact that a copolymer without the phenyl-
boronic acid groups had no LCST suggested that the
phenylboronic acid groups played an important role
in the appearance of LCST. LCST of the copolymer
with the phenylboronic acid groups increased con-
tinually with the addition of glucose. This change in
the glucose-sensitive LCST was attributed to anincrease in hydrophilic, charged phenylboronic acidFig. 9. Temperature dependence of swelling curves for PNIPAAm
groups caused by complex formation between thecopolymer gel with phenylboronic acid moieties at different
phenylboronic acid groups and glucose. glucose concentrations. ( Reprinted, with permission, from Ref.This fascinating property of phenylboronic acid [53]. Copyright 1998 American Chemical Society.)
was combined with the temperature-sensitive proper-
ty of PNIPAAm to improve the glucose-sensitive
LCST of copolymers containing phenylboronic acid 3. Protein-sensitive hydrogels
groups [52]. A ternary polymer was synthesized by
copolymerizing NIPAAm, PBA, and N-(2-di- 3.1. Enzyme-sensitive hydrogels
methylaminopropyl)acrylamide) (DMAPAA). LCST
of the ternary polymer with phenylboronic acid Biodegradable polymers have become increasingly
groups was influenced by the glucose concentration. important in biomedical fields because of their highThis indicates that the solubility of the polymer chain potential for tissue engineering, drug delivery sys-
is strongly dependent upon the glucose concentration tems, etc. [54,55]. Since some biodegradable poly-
at a constant temperature. Based on the glucose- mers can be digested by specific enzymes, enzyme-
sensitive solubility change, Kataoka et al. [53] sensitive hydrogels can be prepared from such
prepared totally synthetic hydrogels (from NIPAAm biodegradable polymers. Some enzymes are used as
and phenylboronic acid) showing glucose sensitivity. important signals for diagnosis to monitor several
These hydrogels underwent a sharp transition in the physiological changes, and specific enzymes in spe-
swelling ratio in response to the external glucose cific organs have become useful signals for site-
concentration (Fig. 9). No insulin was released from specific drug delivery. Therefore, the enzyme-sensi-
the hydrogel in a buffer solution containing less than tive hydrogels are promising candidates as enzyme
1 g / l glucose, but a remarkable release of insulin sensors and enzyme-sensitive drug delivery systems.took place with a glucose concentration of 3 g/ l. The microbial enzymes that are predominantly
Onoff regulation of insulin release from the hydro- present in the colon can be used as signals for
gel was successfully repeated in response to stepwise site-specific delivery of drugs to the colon. Hovgaard
changes in the glucose concentration (Fig. 10). et al. [56] focused on the fact that microbial enzymes
These results suggest that a glucose-sensitive insulin in the colon, such as dextranases, can degrade the
release system can be constructed by exploiting the polysaccharide dextran. They prepared dextran hy-
complex formation properties of phenylboronic acid drogels cross-linked with diisocyanate for colon-
groups and glucose, without the use of biological specific drug delivery. The dextran hydrogels were
components, such as proteins. degraded in vitro by a model dextranase, as well as
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
10/20
88 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
Fig. 10. Repeated on off release of FITC-insulin from a glucose-sensitive hydrogel at 288C, pH 9.0, in response to the external glucose
concentration. (Reprinted, with permission, from Ref. [53]. Copyright 1998 American Chemical Society.)
in vivo in rats and in a human colonic fermentation in the stomach, due to their low swelling ratio at a
model. Release of a drug from the dextran hydrogels low pH. However, when the hydrogels pass through
can be controlled by the presence of dextranase. the gastrointestinal tract they swell due to ionization
Drug release from the dextran hydrogels in the of carboxylic acid groups. In the colon, azoreductase
absence of dextranase was observed to be based on becomes accessible to the cross-links in the swollen
simple diffusion processes, however in the presence hydrogels and can degrade the matrix to release the
of dextranase it was mainly governed by the degra- protein drugs. These studies are examples showing
dation of the dextran. Thus, it follows that dextran that the combination of enzyme sensitivity with pH
hydrogels are dextranase-sensitive and may hold sensitivity enables site-specific drug delivery.promise as intelligent systems for colon-specific drug Some potential applications of stimuli-sensitive
delivery. hydrogels in the medical field require the ability to
Azoreductase is also useful for colon-specific drug sense physiological changes from several diseases at
delivery as it is an enzyme produced by the micro- the same time. Yui et al. [63,64] prepared dual-
bial flora of the colon. To construct colon-specific stimuli-sensitive hydrogels that can be degraded in
drug delivery systems, a few researchers used the presence of two enzymes as biological stimuli.
azoaromatic bonds, which can be degraded by The dual-stimuli-sensitive hydrogels consisted of
azoreductase [5762]. Kopecek et al. [5862] used interpenetrating polymer networks (IPNs) of
azoaromatic bonds as cross-linking agents to prepare oligopeptide-terminated poly(ethylene glycol) (PEG)
azoreductase-sensitive hydrogels for colon-specific and dextran. Only the presence of both papain and
drug delivery. The hydrogels were pH-sensitive and dextranase could induce the degradation of the IPNbiodegradable as they contained both acidic hydrogels, while the presence of only one of the two
comonomers and azoaromatic cross-links. The hy- enzymes was ineffective. Such a dual-stimuli sen-
drogels were based on biocompatible copolymers of sitivity of the IPN hydrogels could act as a fail-safeN,N-dimethylacrylamide (DMAAm), as well as tert- mechanism for guaranteed drug delivery to a certain
butylacrylamide (BAAm) to improve mechanical diseased tissue (Fig. 11). Further, dual-stimuli-sensi-
properties, acrylic acid (AAc) to introduce pH sen- tive hydrogels were prepared by sequential cross-
sitivity, and cross-linking agents containing linking of gelatin and methacryloylated dextran
azoaromatic bonds. The hydrogels can protect pro- below the solgel transition temperature (T ) oftrans
tein drugs against digestion by proteolytic enzymes gelatin [65]. The gelatindextran IPN hydrogels
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
11/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 89
Fig. 12. Lipid microsphere release from a gelatin/ dextran IPN
hydrogel in phosphate buffer at 378C. (s) 5 U / m l a-chymo-
trypsin1 0.5 U/ml dextranase; (n) 5 U/ml a-chymotrypsin; (h)
0.5 U /ml dextranase. ( Reprinted, with permission, from Ref. [65].Copyright 1998 Elsevier Science B.V.)
Fig. 11. Concept of dual-stimuli-sensitive drug release by IPN-
structured hydrogel.
structing a fail-safe system for guaranteed drug
prepared below T showed an enzymatic degra- delivery and medical micromachines.trans
dation in the presence of both a-chymotrypsin and
dextranase, however those prepared above T did 3.2. Antigen-sensitive hydrogelstrans
not. This result suggests that the degradation be-
havior of dual-stimuli-sensitive IPN hydrogels is An antibody has recognition sites to bind with a
strongly governed by the IPN structure, i.e. physical specific antigen through multiple noncovalent bonds,
entanglements between chemically different polymer such as electrostatic interactions, hydrogen bonds,
networks. Lipid microspheres, acting as drug mi- hydrophobic interactions, and van der Waals interac-croreservoirs, were released from the dual-stimuli- tions. Such unique features of antibodies are associ-
sensitive hydrogels in the presence of both a-chymo- ated with the immune responses to protect the
trypsin and dextranase, however their release was organism from infection. Antibodies have been em-
completely hindered in the presence of either enzyme ployed in a variety of immunological assays which
alone (Fig. 12). Another type of dual-stimuli-sensi- utilize their specificity and versatility in order to
tive hydrogel was also prepared by combining the detect biological substances [68]. Thus, the specific
temperature-sensitivity of PNIPAAm with enzymatic antigen-recognition function of an antibody can
degradation [66,67]. These hydrogels, consisting of provide the basis for constructing sensors with
NIPAAm, DMAAm, butyl methacrylate (BMA) and various uses for immunoassays and antigen sensing.
a novel biodegradable cross-link, exhibited tem- This section describes novel antigen-sensitive hydro-
perature-sensitive biodegradation. The hydrogels gels that undergo swelling changes in response to awere degraded by an enzyme at low temperatures, specific antigen.
but not at higher temperatures. At higher tempera- Antigen-sensitive hydrogels were prepared by
tures, the formation of an enzymesubstrate complex using antigenantibody bonds at cross-linking points
was sterically hindered by the increased cross-linking in the hydrogels [69,70]. For example, rabbit im-
density of the hydrogels. Therefore, temperature- munoglobulin G (IgG), the antigen, was chemically
sensitive changes in the cross-linking density enabled modified by coupling it with N-succinimidylacrylate
an onoff switch of enzymatic degradation of the (NSA) in phosphate buffer solution to introduce
hydrogels. Hydrogels that are dual-stimuli sensitive vinyl groups into the rabbit IgG. The resultant vinyl-
for enzyme and temperature can be used for con- rabbit IgG was mixed with the antibody, goat anti-
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
12/20
90 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
rabbit IgG (GAR IgG), to form an antigenantibody BIAcore system using surface plasmon resonance
complex. The vinyl-rabbit IgG was then copoly- [71,72]. Measurements of the affinity constant re-
merized with acrylamide (AAm) as a comonomer vealed that the binding of the antibody with polymer-
and N,N9-methylenebisacrylamide (MBAA) as a ized antigen was much weaker than that with the
cross-linker in the presence of GAR IgG, resulting in native antigen. Therefore, the addition of free, nativea hydrogel containing antigenantibody bond sites antigen can induce the dissociation of the complex
(antigenantibody entrapment hydrogel). between antibody and antigen grafted to the hydrogel
After the swelling ratio attained equilibrium in a network. Furthermore, determination of the hydrogel
buffer solution without rabbit IgG, the antigenanti- modulus clarified that the cross-linking density of the
body entrapment hydrogel was immersed in a buffer antigenantibody entrapment hydrogel decreased
solution containing rabbit IgG as a free antigen [69]. gradually in proportion to the increasing free antigen
In the presence of a free rabbit IgG, the antigen concentration in a buffer solution. Consequently, the
antibody entrapment hydrogel showed signs of swell- antigen-sensitive swelling of the antigenantibody
ing. The equilibrium swelling ratio of the antigen entrapment hydrogel can be explained by the com-
antibody entrapment hydrogel was strongly depen- plex exchange mechanism as follows: in the antigen
dent upon the antigen concentration of the buffer antibody entrapment hydrogel in a buffer solutionsolution (Fig. 13). Furthermore, the presence of a containing a free antigen, the free antigen induces
free rabbit IgG resulted in a dramatic increase in the the dissociation of the antigenantibody bonds
swelling ratio of the antigenantibody entrapment grafted to the network, due to the stronger affinity of
hydrogel, but the presence of free goat IgG did not. the antibody for the free antigen than for the antigen
To determine the mechanism responsible for the grafted to the network. Therefore, the hydrogel
antigen-sensitive swelling, the affinity of the anti- underwent swelling in the presence of the free
body for modified antigen was investigated by the antigen because the dissociation of the antigen
antibody bonds resulted in a decrease in the cross-
linking density. Thus, the antigenantibody entrap-
ment hydrogel showed antigen-sensitive behavior on
the basis of the competitive binding properties of the
free antigen and network-grafted antigen to antibody.In general, most potential applications of stimuli-
sensitive hydrogels require a reversible behavior in
response to environmental stimuli changes. In the
case of the antigenantibody entrapment hydrogel,
however, the antibody entrapped in the network
leaked out of the hydrogel, while it underwent
swelling in response to a specific antigen. As a result
of the leak of the antibody, the antigenantibody
entrapment hydrogel did not show reversible swell-
ingshrinking behavior in response to stepwise
changes in the antigen concentration. Therefore, suchhydrogel structures must be designed to prepare
reversible antigen-sensitive hydrogels. To do this, the
antibody must be immobilized within the network so
that it can build a complex with the antigen graftedFig. 13. Effect of the antigen concentration in a phosphate buffer to the network in a buffer solution without a freesolution on the equilibrium swelling ratio of a PAAm hydrogel antigen. With this in view, a reversible, antigen-(s) and an antigenantibody entrapment hydrogel (d), after
sensitive hydrogel was prepared by the fabrication ofswelling equilibrium was attained in a phosphate buffer solution
a semi-interpenetrating polymer network (semi-IPN)containing Rabbit IgG. ( Reprinted, with permission, from Ref.[69]. Copyright 1999 American Chemical Society.) structure, consisting of a linear polymer containing
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
13/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 91
the antibodies and a network containing the antigens polymerized GAR IgG. The linear polymerized
[70]. The synthetic strategy and structure of the antibody interpenetrated the antigen-containing net-
antigenantibody semi-IPN hydrogel are shown in work, resulting in an antigenantibody semi-IPN
Fig. 14. As shown in Fig. 14b, both rabbit IgG hydrogel. The linear polymerized antibody did not
(antigen) and GAR IgG (antibody) were chemically leak out of the semi-IPN hydrogel because it wasmodified by coupling them to NSA to produce a entangled with the network.
vinyl-antigen and a vinyl-antibody. The resultant Similar to the antigenantibody entrapment hydro-
vinyl-GAR IgG was copolymerized with AAm to gel, the antigenantibody semi-IPN hydrogel was
create a polymerized GAR IgG that acts as the linear also able to swell immediately after the addition of
chain in a semi-IPN hydrogel. Then, the antigen free rabbit IgG to the buffer solution [70]. The
antibody semi-IPN hydrogel was prepared by the antigenantibody semi-IPN hydrogel possessed the
copolymerization of the vinyl-rabbit IgG, AAm, and antigen-sensing function, as its swelling ratio was
MBAA as a cross-linker in the presence of the strongly dependent upon the antigen concentration in
Fig. 14. Strategy for the preparation of an antigen-sensitive hydrogel with a semi-IPN structure. (Reprinted, with permission, from Ref.
[70]. Copyright 1999 Nature Publishing Group.)
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
14/20
92 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
Fig. 15. Swelling ratio changes of the antigenantibody semi-IPN
hydrogel following the addition of goat IgG (s) and rabbit IgG
(d) after the swelling equilibrium had been attained in phosphate
buffer solution at 258C. The concentration of the antigen in the
phosphate buffer solution was 4 mg/ml. (Reprinted, with permis-
sion, from Ref. [70]. Copyright 1999 Nature Publishing Group.)
Fig. 16. Reversible swelling changes and antigen-sensitive per-the buffer solution. Furthermore, the antigenanti- meation profiles of hemoglobin through a PAAm semi-IPNbody semi-IPN hydrogel responded only to rabbit hydrogel (s) and an antigenantibody semi-IPN hydrogel (d) in
response to stepwise changes in the antigen concentration betweenIgG, but not other IgG (Fig. 15). These results imply0 and 4 mg/ ml. (Reprinted, with permission, from Ref. [70].that the antigenantibody semi-IPN hydrogel is alsoCopyright 1999 Nature Publishing Group.)
antigen-sensitive. Compressive modulus measure-
ments of the antigenantibody semi-IPN hydrogel
demonstrated that its cross-linking density decreased antigen, thus differing from the antigenantibody
with increasing rabbit IgG concentration in a buffer entrapment hydrogel. In addition, the cross-linking
solution. Therefore, the antigen-sensitive swelling of density of the antigenantibody semi-IPN hydrogel
the antigenantibody semi-IPN hydrogel was caused showed a reversible behavior in response to stepwise
by a decrease in its cross-linking density, due to the changes in the antigen concentration. Therefore, by
dissociation of the antigenantibody bonds in the introducing a semi-IPN structure the hydrogel was
presence of the free antigen. Consequently, the able to undergo reversible swelling changes in
antigenantibody semi-IPN hydrogel was able to response to the antigen concentration, most likelyrecognize a specific antigen and induce structural with the following mechanism (Fig. 14a). The an-
changes. tigenantibody semi-IPN hydrogel swelled in the
The reversibility of the antigen-sensitive swelling presence of a free antigen, due to the dissociation of
shrinking behavior of the antigenantibody semi-IPN the antigenantibody bonds, acting as cross-linking
hydrogel was investigated to reveal the effect of the points. In the swollen semi-IPN hydrogel, polymer-
semi-IPN structure [70]. As shown in Fig. 16, the ized antibody could not leak out of the hydrogel as it
antigenantibody semi-IPN hydrogel was able to was trapped in the network containing grafted an-
swell immediately in the presence of a free antigen, tigen. Therefore, the hydrogel was able to shrink
however it shrunk gradually in the absence of reversibly in the buffer solution without free antigen,
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
15/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 93
because the complex between the polymerized anti- molecular cavity in order to memorize the print
body and grafted antigen was able to form anew. molecule. Recently, it was reported that temperature-
Consequently, the antigenantibody semi-IPN hy- sensitive hydrogels, prepared using a small amount
drogel exhibits a reversible antigen-sensitive be- of cross-linker, could memorize a print molecule in
havior. their collapsed state via molecular imprinting [78To investigate the possibility of an antigen-sensi- 80].
tive hydrogel as an intelligent system for novel drug Watanabe et al. [78] synthesized temperature-
delivery applications, the permeation of a model sensitive hydrogels by copolymerizing NIPAAm and
drug through an antigenantibody semi-IPN hydro- acrylic acid (AAc) with a cross-linker in the presence
gel membrane was investigated in the presence and of a print molecule and then removing the print
absence of rabbit IgG as a free antigen [70]. The molecule from the resultant hydrogel. The NIPAAm-
model drug permeated through the antigenantibody AAc hydrogel exhibited swelling at a low tempera-
semi-IPN hydrogel membrane in the presence of ture and collapsed at a high temperature. The swol-
rabbit IgG, but not in its absence. As shown in Fig. len NIPAAm-AAc hydrogel at a low temperature
16, the antigenantibody semi-IPN hydrogel mem- showed no change in swelling after the addition of
brane enabled the pulsatile permeation of a model an excess of print molecule, however the hydrogelsdrug in response to stepwise changes in the antigen in the collapsed state at high temperatures showed an
concentration. The antigen-sensitive hydrogel could increase in swelling ratio with increasing print
lead to a novel drug delivery system, in which a drug molecule concentration in water. This suggests that
can be released in the presence of a specific antigen the imprinted hydrogel in the collapsed state can
and the drug release can be stopped in its absence. memorize the print molecule but that in the swollen
Thus, the antigen-sensitive hydrogel is a promising state it cannot. For example, the NIPAAm-AAc
candidate for the fabrication of an intelligent device hydrogel prepared using norephedrine as a print
to modulate drug release in response to a specific molecule was able to swell with increasing nor-
antigen. ephedrine concentration in water, but exhibited no
change in swelling after increasing the adrenaline
concentration (Fig. 17). This implies that the
4. Other molecule-sensitive hydrogels NIPAAm-AAc hydrogel prepared using norephedrineas a print molecule is norephedrine-sensitive. It is
4.1. Molecular imprinting of hydrogels noticeable that the preparation conditions strongly
affected the memorization of the hydrogel prepared
Some proteins, such as enzymes and antibodies, by molecular imprinting. The NIPAAm-AAc hydro-
can recognize specific substrates, based upon the gel prepared in 1,4-dioxane in the presence of a print
correct fit of guest molecules in their molecular molecule underwent a specific volume change in
cavities via noncovalent interactions. Molecular im- response to the print molecule, but when prepared in
printing is an attractive technique to create water it did not. These results were supported by
biomimetic polymers possessing such molecular studies on a general approach for creating hydrogels
cavities for molecular recognition [7377]. In molec- that are able to recognize and capture a target
ular imprinting, some functionalized monomers are molecule by multiple-point interaction, as reportedprearranged around a print molecule via noncovalent by Tanaka et al. [79,80]. Consequently, molecular
interactions and then polymerized. Afterwards, the imprinting is a very useful method to synthesize
print molecule is removed from the resultant poly- molecule-sensitive hydrogels that undergo changes in
mer, resulting in a molecular cavity. The polymer swelling in response to a specific molecule.
with the molecular cavity can thus recognize the
print molecules by a combination of reversible 4.2. Other biomolecule-sensitive hydrogels
binding and shape complementarity. In most molecu-
lar imprinting approaches, a large amount of cross- Deoxyribonucleic acid (DNA) and ribonucleic
linker has been necessary to fix the structure of the acid (RNA) are composed of the nucleotides
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
16/20
94 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
between uracil moieties at a lower temperature, but
became water-soluble above an upper critical solu-
tion temperature (UCST). In addition, the presence
of adenosine resulted in a shift of its UCST to a
lower temperature, because of complex formationbetween the uracil moiety and complementary
adenosine. The effect of the addition of adenosine on
the UCST of PAU was different from that of
guanosine, due to the different interaction of uracil
moieties with adenosine and guanosine. Therefore,
PAU is a nucleic acid base-sensitive polymer, as its
solubility in water changes in response to the species
of additive nucleic acid base and could be used for
the fabrication of a novel nucleic acid base-sensitive
hydrogel for drug delivery purposes.
In addition, Aoki et al. [82] synthesized a tem-perature-sensitive copolymer composed ofN-(S)-sec-
-butylacrylamide ((S)-sec-BAAm) and NIPAAm,
which exhibited hydration changes in response to
foreign, optically active compounds. The LCST
(23.18C) of the resultant poly((S)-sec-BAAm-co-
NIPAAm) with a (S)-sec-BAAm content of 50 mol%
was shifted to 28.7 and 34.58C in the presence of
D-tryptophan (D-Trp) and L-Trp, respectively. The
shift of LCST was strongly dependent upon theL-Trp concentration. The remarkable shift in LCST
of poly((S)-sec-BAAm-co-NIPAAm) in the presence
of L-Trp could be attributable to the stereospecificinteraction between the optically active (S)-sec-
BAAm in the copolymer and L-Trp. These results led
to the concept that a temperature-sensitive polymer
with optically active moieties can respond to enantio-
mers. Based upon this concept, optically active
poly(N-(L)-(1-hydroxymethyl)propylmethacrylamideFig. 17. Equilibrium swelling ratios at 508C as a function of the(L-PHMPMA) and DL-PHMPMA were synthesized,concentration of either norphedrine (d) or adrenaline (s) in
water for molecular recognition gels prepared in the presence of which had optically active moieties and a chemicalnorphedrine (A) and adrenaline (B). (Reprinted, with permission, structure similar to PNIPAAm [83]. An aqueousfrom Ref. [78]. Copyright 1998 American Chemical Society.)
PHMPMA solution exhibited quite a different be-
havior in the temperature-sensitive phase transitionbetween L- and DL-PHMPMA. This indicates that
L-PHMPMA has a unique temperature sensitivity,
adenine, cytosine, guanine, thymine and uracil, and due to the optically active moieties and might
form double or triple strands with their complemen- respond to enantiomers on the basis of this specific
tary base pairs via hydrogen bonding and stacking of interaction. Therefore, enantiomer-sensitive hydro-
their bases. Focusing on complementary hydrogen gels such as poly((S)-sec-BAAm-co-NIPAAm) hy-
bonding between nucleic acid bases, Aoki et al. [81] drogel and L-PHMPMA hydrogel can be prepared
synthesized poly(6-(acryloyloxymethyl)uracil) from such temperature-sensitive polymers with opti-
(PAU) containing uracil moieties as side chains. PAU cally active moieties [84]. The temperature-sensitive
was insoluble in water, due to the complex formation swelling behavior of these hydrogels was strongly
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
17/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 95
influenced by the addition of L-Trp. Consequently, from the Ministry of Education, Science, Sports, and
they are enantiomer-sensitive hydrogels that can Culture, Japan.
recognize the difference between L- and D-Trp and
initiate structural changes in response. Such enantio-
mer-sensitive hydrogels are useful for constructing Referencesintelligent systems to sense enantiomers.
[1] N.A. Peppas, Hydrogels in Medicine and Pharmacy, CRC
Press, Boca Raton, FL, 1987.5. Conclusions
[2] D. DeRossi, K. Kajiwara, Y. Osada, A. Yamauchi, Polymer
Gels, Fundamentals and Biomedical Applications, Plenum,
The fascinating properties of stimuli-sensitive New York, 1991.[3] K. Dusek, Responsive Gels: Volume Transitions I, Advanceshydrogels suggest that they will have many future
in Polymer Science, Vol. 109, Springer, Berlin, 1993.applications as the next generation of materials for[4] K. Dusek, Responsive Gels: Volume Transitions II, Ad-
biological and biomedical applications. Furthermore,vances in Polymer Science, Vol. 110, Springer, Berlin, 1993.
fundamental research of such stimuli-sensitive be- [5] T. Okano, Biorelated Polymers and Gels, Academic Press,
havior also contributes significantly to our under- Boston, 1998.[6] T. Tanaka, Collapse of gels and the critical endpoint, Phys.standing of the biological functions of biomolecules.Rev. Lett. 40 (1978) 820823.There have been many studies on stimuli-sensitive
[7] T. Tanaka, D. Fillmore, S.-T. Sun, I. Nishio, G. Swislow, A.hydrogels that exhibit changes in swelling in re-Shah, Phase transitions in ionic gels, Phys. Rev. Lett. 45
sponse to physicochemical stimuli, such as pH,(1980) 16361639.
temperature, etc. Recently, biomolecule-sensitive [8] Y. Hirokawa, T. Tanaka, Volume phase transition in ahydrogels that respond to specific biomolecules, such nonionic gel, J. Chem. Phys. 81 (1984) 63796380.
[9] T. Amiya, Y. Hirokawa, Y. Hirose, Y. Li, T. Tanaka,as saccharides and proteins, have become increasing-Reentrant phase transition of N-isopropylacrylamide gels inly important, since saccharides and proteins aremixed solvents, J. Chem. Phys. 86 (1987) 23752379.
useful as markers to monitor several physiological[10] M. Annaka, T. Tanaka, Multiple phases of polymer gels,
changes as well as for site-specific drug delivery. Nature 355 (1992) 430432.Some researches have demonstrated that molecular [11] G. Chen, A.S. Hoffman, Graft copolymers that exhibit
temperature-induced phase transitions over a wide range ofinteractions, such as lectinglucose, phenylboronicpH, Nature 373 (1995) 4952.acidglucose, and antigenantibody interactions, can
[12] R. Yoshida, K. Uchida, T. Kaneko, K. Sakai, A. Kikuchi, Y.provide the tools for creating biomolecule-sensitiveSakurai, T. Okano, Comb-type grafted hydrogels with rapid
hydrogels for the development of self-regulated drug deswelling response to temperature changes, Nature 374delivery systems. Combining the functions of bio- (1995) 240242.molecules, such as enzymes, with pH- or tem- [13] T. Tanaka, I. Nishio, S.-T. Sun, S. Ueno-Nishio, Collapse of
gels in an electric field, Science 218 (1982) 467469.perature-sensitive polymers can also lead to the[14] Y. Osada, H. Okuzaki, H. Hori, A polymer gel withconstruction of biomolecule-sensitive systems. Even
electrically driven motility, Nature 355 (1992) 242244.though most biomolecule-sensitive hydrogels still
[15] M. Irie, Stimuli-responsive poly(N-isopropylacrylamide).require further research, they are likely to become Photo- and chemical-induced phase transitions, Adv. Polym.quite important biomaterials in the near future. Some Sci. 110 (1993) 4965.
[16] A. Suzuki, T. Tanaka, Phase transition in polymer gelsof the studies described in this paper will surely lead, induced by visible light, Nature 346 (1990) 345347.not only to a better understanding of the structures[17] R.A. Siegel, Hydrophobic weak polyelectrolyte gels: studiesand functions of biomolecule-sensitive hydrogels,
of swelling equilibria and kinetics, Adv. Polym. Sci. 109but also to promising strategies for the development (1993) 233267.of novel stimuli-sensitive hydrogels. [18] L.B. Peppas, N.A. Peppas, Solute and penetrants diffusion in
swellable polymers. IX. The mechanisms of drug release
from pH-sensitive swelling controlled systems, J. Controlled
Release 8 (1989) 267274.Acknowledgements[19] C.S. Brazel, N.A. Peppas, Synthesis and characterization of
thermo- and chemomechanically responsive poly(N-iso-Our work cited in this review was partially propylacrylamide-co-methacrylic acid) hydrogels, Macro-
supported by a Grant-in-Aid for Scientific Research molecules 28 (1995) 80168020.
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
18/20
96 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
[20] L.-C. Dong, A.S. Hoffman, A novel approach for preparation [37] S.W. Kim, C.M. Pai, K. Makino, L.A. Seminoff, D.L.
of pH-sensitive hydrogels for enteric drug delivery, J. Holmberg, J.M. Gleeson, D.E. Wilson, E.J. Mack, Self-Controlled Release 15 (1991) 141152. regulated glycosylated insulin delivery, J. Controlled Release
[21] T. Miyata, K. Nakamae, A.S. Hoffman, Y. Kanzaki, Stimuli- 11 (1990) 193201.sensitivities of hydrogels containing phosphate groups, Mac- [38] K. Makino, E.J. Mack, T. Okano, S.W. Kim, A microcapsule
romol. Chem. Phys. 195 (1994) 11111120. self-regulating delivery system for insulin, J. Controlled[22] K. Nakamae, T. Nizuka, T. Miyata, M. Furukawa, T. Release 12 (1990) 235239.
Nishino, K. Kato, T. Inoue, A.S. Hoffman, Y. Kanzaki, [39] T. Miyata, K. Nakamae, Polymers with pendant saccharidesLysozyme loading and release from hydrogels carrying Glycopolymers, Trends Polym. Sci. 5 (1997) 198206.pendant phosphate groups, J. Biomater. Sci. Polym. Ed. 9 [40] K. Nakamae, T. Miyata, A. Jikihara, A.S. Hoffman, Forma-(1997) 4353.
tion of poly(glucosyloxyethyl methacrylate)concanavalin A[23] A.S. Hoffman, Application of thermally reversible polymers
complex and its glucose-sensitivity, J. Biomater. Sci. Polym.and hydrogels in therapeutics and diagnostics, J. Controlled
Ed. 6 (1994) 7990.Release 6 (1987) 297305.
[41] T. Miyata, A. Jikihara, K. Nakamae, A.S. Hoffman, Prepara-[24] T. Okano, Molecular design of temperature-responsive poly-
tion of poly(2-glucosyloxyethyl methacrylate)concanavalinmers as intelligent materials, Adv. Polym. Sci. 110 (1993)
A complex hydrogel and its glucose-sensitivity, Macromol.179197.
Chem. Phys. 197 (1996) 11351146.[25] L.-C. Dong, A.S. Hoffman, Synthesis and application of
[42] T. Miyata, A. Jikihara, K. Nakamae, T. Uragami, A.S.thermally reversible heterogels for drug delivery, J. Con-Hoffman, K. Kinomura, M. Okumura, Preparation of
trolled Release 13 (1990) 2131. glucose-sensitive hydrogels by entrapment or copolymeriza-[26] T. Okano, Y.H. Bae, H. Jacobs, S.W. Kim, Thermally on offtion of concanavalin A in a glucosyloxyethyl methacrylateswitching polymers for drug permeation and release, J.hydrogel, in: N. Ogata, S.W. Kim, J. Feijen, T. Okano (Eds.),Controlled Release 11 (1990) 255265.Advanced Biomaterials in Biomedical Engineering and Drug[27] H. Katono, A. Maruyama, K. Sanui, N. Ogata, T. Okano, Y.Delivery Systems, Springer, Tokyo, 1996, pp. 237238.Sakurai, Thermo-responsive swelling and drug release
[43] S.J. Lee, K. Park, Synthesis and characterization of sol gelswitching of interpenetrating polymer networks composed ofphase-reversible hydrogels sensitive to glucose, J. Mol.poly(acrylamide-co-butyl methacrylate) and poly(acrylicRecogn. 9 (1996) 549557.acid), J. Controlled Release 16 (1991) 215228.
[44] A.A. Obaidat, K. Park, Characterization of glucose depen-[28] K. Ishihara, M. Kobayashi, N. Ishimaru, I. Shinohara,dent gelsol phase transition of the polymeric glucoseGlucose induced permeation control of insulin through aconcanavalin A hydrogel system, Pharm. Res. 13 (1996)complex membrane consisting of immobilized glucose oxi-989995.dase and a poly(amine), Polym. J. 16 (1984) 625631.
[45] A.A. Obaidat, K. Park, Characterization of protein release[29] K. Ishihara, K. Matsui, Glucose-responsive insulin release
through glucose-sensitive hydrogel membranes, Biomaterialsfrom polymer capsule, J. Polym. Sci. Polym. Lett. Ed. 2418 (1997) 801806.(1986) 413417.
[46] E. Kokufuta, Y.-Q. Zhang, T. Tanaka, Saccharide-sensitive[30] G. Albin, T.A. Horbett, B.D. Ratner, Glucose sensitivephase transition of a lectin-loaded gel, Nature 351 (1991)membranes for controlled delivery of insulin: insulin trans-302304.port studies, J. Controlled Release 2 (1985) 153164.
[47] S. Kitano, K. Kataoka, Y. Koyama, T. Okano, Y. Sakurai,[31] G.W. Albin, T.A. Horbett, S.R. Miller, N.L. Ricker, Theoret-Glucose-responsive complex formation between poly(vinylical and experimental studies of glucose sensitive mem-alcohol) and poly(N-vinyl-2-pyrrolidone) with pendentbranes, J. Controlled Release 6 (1987) 267291.phenylboronic acid moieties, Makromol. Chem. Rapid Com-[32] S. Cartier, T.A. Horbett, B.D. Ratner, Glucose-sensitivemun. 12 (1991) 227233.membrane coated porous filters for control of hydraulic
[48] S. Kitano, Y. Koyama, K. Kataoka, T. Okano, Y. Sakurai, Apermeability and insulin delivery from a pressurized reser-novel drug delivery system utilizing a glucose responsivevoir, J. Membr. Sci. 106 (1995) 1724.polymer complex between poly(vinyl alcohol) and poly(N-[33] C.M. Hassan, F.J. Doyle III, N.A. Peppas, Dynamic behaviorvinyl-2-pyrrolidone) with a phenylboronic acid moiety, J.
of glucose-responsive poly(methacrylic acid-g-ethylene gly- Controlled Release 19 (1992) 162170.col) hydrogels, Macrmolecules 30 (1997) 61666173.[49] A. Kikuchi, K. Suzuki, O. Okabayashi, H. Hoshino, K.[34] R.S. Parker, F.J. Doyle III, N.A. Peppas, A model-based
Kataoka, Y. Sakurai, T. Okano, Glucose-sensing electrodealgorithm for blood glucose control in type I diabeticcoated with polymer complex gel containing phenylboronicpatients, IEEE Trans. Biomed. Eng. 46 (1999) 148157.acid, Anal. Chem. 68 (1996) 823828.[35] M. Brownlee, A. Cerami, A glucose-controlled insulin
[50] K. Kataoka, H. Miyazaki, T. Okano, Y. Sakurai, Sensitivedelivery system: semisynthetic insulin bound to lectin,
glucose-induced change of the lower critical solution tem-Science 206 (1979) 11901191.
perature of poly[N,N-dimethylacrylamide-co-3-[36] L.A. Seminoff, G.B. Olsen, S.W. Kim, A self-regulating
(acrylamido)phenylboronic acid] in physiological saline,insulin delivery system. I. Characterization of a synthetic
Macromolecules 27 (1994) 10611062.glycosylated insulin derivative, Int. J. Pharm. 54 (1989)
241249. [51] D. Shiino, Y. Murata, A. Kubo, Y.J. Kim, K. Kataoka, Y.
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
19/20
T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998 97
Koyama, A. Kikuchi, M. Yokoyama, Y. Sakurai, T. Okano, swelling behavior, Macromol. Chem. Phys. 199 (1998) 705
Amine containing phenylboronic acid gel for glucose-respon- 709.
sive insulin release under physiological pH, J. Controlled [67] K.M. Huh, J. Hashi, T. Ooya, N. Yui, Synthesis andRelease 37 (1995) 269276. characterization of dextran grafted with poly(N-iso-
[52] T. Aoki, Y. Nagao, K. Sanui, N. Ogata, A. Kikuchi, Y. propylacrylamide-co-N,N-dimethylacrylamide), Macromol.
Sakurai, K. Kataoka, T. Okano, Glucose-sensitive lower Chem. Phys. 201 (2000) 613619.critical solution temperature changes of copolymers com- [68] E.P. Diamandis, T.K. Christopoulos, Immunoassay, Academ-posed of N-isopropylacrylamide and phenylboronic acid ic Press, New York, 1996.moieties, Polym. J. 28 (1996) 371374. [69] T. Miyata, N. Asami, T. Uragami, Preparation of an antigen-
[53] K. Kataoka, H. Miyazaki, M. Bunya, T. Okano, Y. Sakurai, sensitive hydrogel using antigenantibody bindings, Macro-Totally synthetic polymer gels responding to external glu- molecules 32 (1999) 20822084.cose concentration: their preparation and application to on [70] T. Miyata, N. Asami, T. Uragami, A reversibly antigen-off regulation of insulin release, J. Am. Chem. Soc. 120 responsive hydrogel, Nature 399 (1999) 766769.(1998) 1269412695. [71] T. Natsume, T. Koide, S. Yokota, K. Hirayoshi, K. Nagata,
[54] M. Chasin, R. Langer (Eds.), Biodegradable Polymers as Interactions between collagen-binding stress protein HSP47Drug Delivery Systems, Marcel Dekker, New York, 1990. and collagen: analysis of kinetic parameters by surface-
[55] J.O. Hollinger (Ed.), Biomedical Applications of Synthetic plasmon resonance biosensor, J. Biol. Chem. 269 (1994)
Biodegradable Polymers, CRC Press, Boca Raton, FL, 1995. 3122431228.
[56] L. Hovgaard, H. Brndsted, Dextran hydrogels for colon- [72] N. Murai, H. Taguchi, M. Yoshida, Kinetic analysis of
specific drug delivery, J. Controlled Release 36 (1995) 159 interactions between GroEL and reduced a-lactalbumin:
166. effect of GroES and nucleotides, J. Biol. Chem. 270 (1995)
[57] M. Saffran, G.S. Kumar, C. Savariar, J.C. Burnham, F. 1995719963.
Williams, D.C. Neckers, A new approach to the oral [73] G. Wulff, A. Sarhan, K. Zabrocki, Enzyme-analogue built
administration of insulin and other peptide drugs, Science polymers and their use for the resolution of racemates,233 (1986) 10811084. Tetrahedron Lett. 44 (1973) 43294332.
[58] P.-Y. Yeh, P. Kopeckova, J. Kopecek, Biodegradable and [74] B. Sellergren, M. Lepisto, K. Mosbach, Highly enantioselec-
pH-sensitive hydrogels: synthesis by crosslinking of N,N- tive and substrate-selective polymers obtained by molecular
dimethylacrylamide copolymer precursors, J. Polym. Sci. imprinting utilizing noncovalent interactions. NMR and
Part A Polym. Chem. 32 (1994) 16271637. chromatographic studies on the nature of recognition, J. Am.
[59] P.-Y. Yeh, P. Kopeckova, J. Kopecek, Degradability of Chem. Soc. 110 (1988) 58535860.
hydrogels containing azoaromatic crosslinks, Macromol. [75] K. Mosbach, Molecular imprinting, Trends Biochem. Sci. 19
Chem. Phys. 196 (1995) 21832202. (1994) 914.
[60] H. Ghandehari, P. Kopeckova, P.-Y. Yeh, J. Kopecek, Bio- [76] K. Shea, Molecular imprinting of synthetic network poly-degradable and pH sensitive hydrogels: synthesis by a mers: the de novo synthesis of macromolecular binding and
polymerpolymer reaction, Macromol. Chem. Phys. 197 catalytic sites, Trends Polym. Sci. 2 (1994) 166173.
(1996) 965980. [77] G. Wulff, Molecular imprinting in cross-linked materials with
[61] H. Ghandehari, P. Kopeckova, J. Kopecek, In vitro degra- the aid of molecular templates a way towards artificial
dation of pH-sensitive hydrogels containing aromatic azo antibodies, Angew. Chem. Int. Ed. Engl. 34 (1995) 1812
bonds, Biomaterials 18 (1997) 861872. 1832.
[62] E.O. Akala, P. Kopeckova, J. Kopecek, Novel pH-sensitive [78] M. Watanabe, T. Akahoshi, Y. Tabata, D. Nakayama, Molec-
hydrogels with adjustable swelling kinetics, Biomaterials 19 ular specific swelling change of hydrogels in accordance
(1998) 10371047. with the concentration of guest molecules, J. Am. Chem.
Soc. 120 (1998) 55775578.[63] N. Yamamoto, M. Kurisawa, N. Yui, Double-stimuli-respon-
sive degradable hydrogels: interpenetrating polymer net- [79] G.Q. Wang, K. Kuroda, T. Enoki, A. Grosberg, S.
works consisting of gelatin and dextran with different phase Masamune, T. Oya, Y. Takeoka, T. Tanaka, Gel catalysts that
separation, Macromol. Rapid Commun. 17 (1996) 313318. switch on and off, Proc. Natl. Acad. Sci. USA 97 (2000)
98619864.[64] M. Kurisawa, M. Terano, N. Yui, Double-stimuli-responsive
degradation of hydrogels consisting of oligopeptide-termi- [80] T. Oya, T. Enoki, A.Y. Grosberg, S. Masamune, T.
nated poly(ethylene glycol) and dextran with an interpenet- Sakiyama, Y. Takeoka, K. Tanaka, G.Q. Wang, Y. Yilmaz,
rating polymer network, J. Biomater. Sci. Polym. Ed. 8 M.S. Feld, R. Dasari, T. Tanaka, Reversible molecular
(1997) 691708. adsorption based on multiple-point interaction by shrinkable
gels, Science 286 (1999) 15431545.[65] M. Kurisawa, N. Yui, Dual-stimuli-responsive drug release
from interpenetrating polymer network-structured hydrogels [81] T. Aoki, K. Nakamura, K. Sanui, A. Kikuchi, T. Okano, Y.
of gelatin and dextran, J. Controlled Release 54 (1998) Sakurai, N. Ogata, Adenosine-induced changes of the phase
191200. transition of poly(6-(acryloyloxymethyl)uracil) aqueous so-
lution, Polym. J. 31 (1999) 11851188.[66] M. Kurisawa, Y. Matsuo, N. Yui, Modulated degradation of
hydrogels with thermo-responsive network in relation to their [82] T. Aoki, T. Nishimura, K. Sanui, N. Ogata, Phase-transition
-
7/22/2019 Biomolecule_sensitive Glucose Hydrogels
20/20
98 T. Miyata et al. / Advanced Drug Delivery Reviews 54 (2002) 7998
changes of poly(N-(S)-sec-butylacrylamide-co-N-iso- [84] T. Aoki, M. Muramatsu, K. Sanui, Volume-phase transition
propylacrylamide) in response to amino acids and its chiral of an optically active hydrogel in response to external
recognition, React. Funct. Polym. 37 (1998) 299303. environmental changes, Polym. Prep. Jpn. 48 (1999) 3124
[83] T. Aoki, M. Muramatsu, T. Torii, K. Sanui, N. Ogata, 3125.
Thermosensitive phase transition of an optical active poly-
mer in aqueous milieu, Macromolecules 34 (2001) 31183119.