Advanced Drug Delivery Reviews 57 (2005) 1733 – 1741

www.elsevier.com/locate/addr

Commentary

Molecularly imprinted polymers: A bridge to

advanced drug delivery B
Börje Sellergren a,*, Chris J. Allender b
a
INFU, Universität Dortmund, D-44221 Dortmund, Germany
b
Welsh School of Pharmacy Cardiff University, Cardiff XCF10 3XF, UK
Received 20 March 2005; accepted 29 July 2005
Available online 25 October 2005

Abstract

Specific molecular recognition is a fundamental requirement of living systems on which processes as diverse as neural
transmittance, respiration, immune defence, cellular differentiation and nutrition rely. It is therefore not surprising that scientists
have invested huge amounts of time and effort into harnessing, and more recently mimicking, biological function. A number of
synthetic approaches have been developed and one of the most promising of these is molecular imprinting. Molecular imprinted
polymers have routinely been used, as robust and effective synthetic molecular receptors, in a diverse range of technologies. But
it is perhaps in the area of drug delivery, in particular dintelligent drug releaseT and dmagic bulletT drug targeting, that significant
future opportunities lie.
D 2005 Elsevier B.V. All rights reserved.

Keywords: Molecularly imprinted polymers; Controlled drug delivery; Targeted drug delivery; Magic bullet; Synthetic receptors

1. Introduction cesses of life, information transfer and reaction cata-

Specific molecular recognition is a fundamental
requirement of living systems and, through millions
of years and countless rounds of evolutionary optimi-
zation, dbiologyT has become a master of the art. At the
cellular and sub-cellular level the fundamental pro-
B
This commentary is part of the Advanced Drug Delivery
Reviews theme issue on bMolecularly imprinted polymers: Technol-
ogy and applicationsQ, Vol. 57/12, 2005.
* Corresponding author. Tel.: +49 231 755 4082; fax: +49 231
7554084.
E-mail address: borje@infu.uni-dortmund.de (B. Sellergren).
0169-409X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2005.07.010
lysis, rely on the specific interaction of low molecular
weight molecules with macromolecular dhosts.T In the
majority of such events the macromolecule is a pro-
tein. Processes as diverse as neural transmittance,
respiration, immune defence, cellular differentiation
and nutrition all rely on the basic principle of specific
molecular recognition. It is therefore not surprising
that scientists have invested huge amounts of time
and effort, initially into harnessing the potential of
biological molecular recognition, antibodies and en-
zymes, and more recently in trying to mimic these
properties in synthetic materials. A number of syn-
thetic approaches have been developed that aim to
1734 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741

Fig. 1. Schematic generalisation of the molecular imprinting process.

mimic the dynamic non-covalent molecular recogni-
tion approach favored by biology. Inherently, all of
these approaches aim to solve the problem in the same
way, by creating a binding cavity or binding frame-
work within which functional chemical groups can be
positioned so that reciprocal non-covalent interactions
between the binding site and a specific target analyte
are favored. One of the most promising of these
approaches is molecular imprinting.
Molecularly imprinted polymers (MIPs) are poly-
mers prepared in presence of a template (Fig. 1) [1,2]
that serves as a mould for the formation of template
complementary binding sites. Thus, MIPs can be
programmed to recognize a large variety of target
structures with antibody-like affinities and selectiv-
ities. These properties, in addition to the robustness
and ease of preparation of these artificial receptors,
have made them extremely attractive for problem
solving in the areas of preparative chemical separa-
tions [3], solid phase extraction [4,5] and sensing [6].
In addition, proof of concept of their use as scaven-
gers to remove undesirable compounds from foods or
biological fluids [7], and as screening tools in drug
discovery [8] has also been demonstrated (Fig. 2).
2. A brief history of imprinting
Molecular imprinting is not a new science. The
earliest reports of imprinting go back to the early
1930s when a Soviet chemist M.V. Polyakov [9] pre-
pared a number of silica gels and observed that when
prepared in the presence of a solvent additive the
resulting silica demonstrated preferential binding
capacity for that solvent. Although Polyakov contin-
ued with this work until the1950s his findings were

Fig. 2. Scheme outlining the main applications envisaged for MIPs.

 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741
seldom cited outside of Eastern Europe. A later study,
also using silica, was to have more of an impact. In
1949 a senior student of Linus Pauling, Frank Dickey,
published the results of experiments where silica gels
had been prepared in the presence of dyes [10]. Dickey
observed that after removal of the dpatterningT dye the
silica would rebind the same dye in preference to the
others. Silica imprinting continued during the 1950s
and 1960s but the number of publications in the area
remained low. However, in 1972 a step change in
molecular imprinting occurred when the group of
Guenter Wulff reported that they had successfully
prepared a molecularly imprinting organic polymer
[11]. Wulff used what is now termed a dcovalent
approachT to prepare an organic molecularly imprinted
polymer capable of discriminating between the enan-
tiomers of glyceric acid. Subsequently, throughout the
1970s and 1980s, Wulff’s group published extensively
using this approach. The second major break through
in organic polymer imprinting occurred in 1981 when
Mosbach and Arshady reported that they had prepared
an organic MIP using non-covalent interactions only
[12]. This approach was termed the dnon-covalent
approach,T as opposed to the covalent approach
favored by Wulff, and it was this approach, with its
simple, seemingly trivial methodology, that triggered
the explosion in molecular imprinting that was to occur
during the 1990s. To this day the non-covalent versus
covalent debate continues with both sides being cham-
pioned. However, it is generally accepted that there
are pros and cons to both approaches and in 1995
Whitcombe et al. reported an intermediate approach
that appeared to combine the advantages of both
approaches [13]. This approach relies on covalent
interaction during the polymerization stage but non-
Fig. 3. Intelligent dallostericT drug release from MIP carrier.
1735
covalent interactions during rebinding. Importantly, in
order to improve subsequent non-covalent binding
geometry, Whitcombe’s approach incorporated a sacri-
ficial spacer group that was designed to be lost during
template removal.
The noncovalent approach however is still by far
the most widely used approach in MIP synthesis.
Several of its drawbacks can be overcome by the use
of stoichiometrically associating monomer-template
systems [33–35,49]. This has resulted in a range of
receptors exhibiting high capacity and effective recog-
nition properties in aqueous media.
3. Molecular imprinting in drug delivery
Synthetic molecularly selective receptors such as
MIPs have broad application in many areas of science
but perhaps the area of greatest potential, and probably
an area of greatest challenge, is that of therapeutics and
medical therapy. Examples of robust near real-time
diagnostic sensors, as discussed within this issue in
an article by Hillberg et al., and MIPs with ddrug-
likeT effects, such as a cholesterol selective MIPs devel-
oped for use as oral adsorbers [14] and imprinted bile
acid sequestrants [15,16], have triggered widespread
interest in MIPs as fully synthetic molecularly selective
materials. In addition MIPs incorporated into mem-
branes are being increasingly investigated in the con-
text of bioseparations and biopurification [17]. For
instance, biocompatible membranes imprinted with
uric acid have been developed for use in selective
blood purification [18], whilst the area of drug separa-
tion and analysis is fully reviewed in an article by
Richard Ansell contained in this issue. But it is in the
1736 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741

Fig. 4. Targeted drug delivery using a molecularly imprinted carrier.

area of drug delivery that some of the most significant
opportunities lie, and what is particularly exciting is
that to date, researchers have barely scratched the sur-
face as to the potential of molecular imprinting.
But MIPs are not entirely new in the area of drug
delivery. They have been applied usefully as excipi-
ents in controlled release delivery systems and this is
discussed in detail by Cunliffe at al. later on in this
issue. A number of publications report that MIPs have
been used to modify drug release from solid dosage
forms and that by modifying MIP composition release
can be tuned. Although this work is of obvious value,
it does not exploit the real benefit of molecular
imprinting and that is selectivity. The MIP drug
release profiles reported in the literature are not excit-
ing, similar profiles could have been obtained by
simple modification of a non-imprinted polymer.
However, there is huge potential in drug delivery for
technologies that can bring about intelligent drug
release or can target a therapeutic pay-load to a parti-
cular site of action. Intelligent drug release refers to
the release, in a predictable way, of a therapeutic agent
in response to specific stimuli such as the presence of
another molecule, whilst drug targeting is best exem-
plified by the dmagic bulletT approach where a drug
conjugated to a targeting vector, such as an antibody
or a peptide, interacts with specific sites of interac-
tions. A good example of this might be a cell surface
epitope. In both of these areas molecular imprinting
has very real potential. For instance, intelligent con-
trolled release could be achieved by the competitive
displacement of a drug by a structurally related cross-
reactant. This type of direct displacement is probably
the simplest way of generating a release profile in
response to a second analyte but other dallosteric-likeT
phenomenon are also plausible (Fig. 3).

Fig. 5. Targeted drug delivery and facilitated internalisation using a MIP.

 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741
Using MIPs to target drug delivery is also an
exciting concept (Fig. 4). The drug, coupled either
covalently or non-covalently to the MIP, would be
released when the MIP binds to its target on the
surface of a cell. This concept could be extended so
that the binding of the MIP to the cell surface would
bring about internalisation of the MIP–drug complex
and subsequent drug release (Fig. 5).
Although these targeting applications are certainly
someway-off in terms of in vivo evaluation, molecular
imprinting technology is close to the point where an in
vitro demonstration would be plausible. Currently, a
wide range of polymers are being studied for con-
trolled drug delivery, including a number of biocom-
patible acrylates and vinyl polymers, so the step
change from current best practice is not great. In
addition, biodegradable polymers, and the potential
for biodegradable MIPs, would provide further flex-
ibility in polymer morphology and the resulting
dosage form. It is therefore feasible that a working
system might comprise a surface imprinted (refer to
the article by Mayes and Whitcombe in this issue)
nanoparticulate MIP, selective for some cell surface
epitope, conjugated to the active drug.
Already chemically responsive gels have been
reported that release drug loads only in response to
specific chemical stimuli [19,20], whilst chemically
responsive materials [21,22] could also be envisaged
to act as smart valves in microfluidic systems, clos-
ing or opening channels in response to chemical
signals [23]. Although MIPs are good at binding
specific target molecules they have been less suc-
cessful in catalysing chemical reactions. However,
using stable transition state analogues as templates,
recent advances indicate that there is potential in the
future for MIPs to compete with their biological
counterparts [24].
4. Molecular imprinting: the challenges
However, before some of these ideas can be further
developed a number of technology issues need to be
more fully addressed and these include the perfor-
mance of MIP in fully aqueous environments,
imprinting of very polar molecules and bio-macromo-
lecules, mass transfer, binding site population, capa-
city and template bleed. But in order to appreciate the
1737
origin of some of these issues it is important to under-
stand some background.
The majority of MIPs reported in the literature are
highly reticulated network polymers consisting of a
common matrix structure and binding sites formed
by a template present during the polymer synthesis
(Fig. 1). The three dimensional arrangement of the
binding functional groups in MIPs is obtained by
linking the functional monomers covalently or non-
covalently to the template during polymerization
(Fig. 6). Removal of the template from the formed
polymer then generates a structure complementary to
the template structure. These sites can be reoccupied
by the template or an analogous structure by refor-
mation of the binding interactions present during
synthesis or, alternatively, weaker kinetically more
favorable interactions.
4.1. Imprinting approaches
Essentially, three approaches currently exist to gen-
erate high fidelity imprinted sites, these are distin-
guishable by the nature of the linkage during
synthesis and during rebinding.
The first example of molecular imprinting of
organic network polymers introduced by Wulff et al.
later followed by Shea et al. was based on a covalent
attachment strategy, i.e., covalent monomer–template,
covalent polymer–template [25,26]. This approach has
the advantage of a known stoichiometry between the
functional monomer and the template. Provided that
the template can be recovered in high yields, a high
density of well defined sites can be expected. One
problem with this approach is the limited number of
covalent linkages that satisfy these criteria. Further-
more, considerable synthetic effort may be required to
prepare the template and slow kinetics is often
observed for rebinding by reformation of the covalent
bond. This approach is therefore difficult to combine
with applications where fast on-off kinetics is required.
In this respect, the use of sacrificial spacers has found
more widespread use [13]. Here the functional mono-
mer is bound to the template through a disposable
spacer that is removed after polymerization is com-
pleted. This results in a disposition of the functional
groups allowing rebinding to occur through hydrogen
bonding interactions. Therefore, this approach can be
more amenable to chromatographic applications and
1738 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741
Fig. 6. Strategies used to place binding or catalytic functional groups at defined positions in imprinted sites of network polymers.
furthermore allows more freedom in the choice of
polymerization conditions (vide infra).
However, the most widely used approach in
imprinting involves functional monomers that are
chosen to associate non-covalently with the template
[27,28]. Here the template is directly mixed with one
or several functional monomers followed by polymer-
ization. It can thereafter be easily extracted from the
polymer and recycled. Generally, the resulting materi-
als can be directly used to perform separations with
high affinity and selectivity for instance as chromato-
graphic stationary phases. This approach is very
attractive since it is simple, it delivers MIPs showing
high affinity for its target and it is broadly applicable.
Thus, using essentially the same procedure, MIPs
targeting a large variety of small lipophilic targets
can be obtained. Conceivably, a simple commodity
monomer such as methacrylic acid (MAA) can be
used to create good binding sites for a large variety
of template structures containing hydrogen bond- or
proton-accepting functional groups [29]. Commonly,
these binding sites are capable of discriminating
subtle structural differences in the template, similar
to the selectivity displayed by antibodies.
4.2. Solutions to the problems
Advances made in the areas of host–guest chem-
istry, polymer and materials chemistry and analytical
chemistry, each associated with the different steps
in the MIP synthesis schemes, have guided the
way to much improved imprinting protocols. Thus
approaches to generate MIPs tailored not only for
static molecular recognition but also for rapid binding
and release possibly associated with a secondary func-
tion, i.e., a measurable signal such as in sensors or a
mechanical work such as in stimuli-responsive gels,
are now available.
4.2.1. High throughput synthesis and computational
techniques
The optimization of the molecular recognition
properties under equilibrium conditions has been
aided by computational [30] and high throughput
 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741
synthesis (HTS) and screening techniques [31]. These
techniques have mainly been used to rapidly identify
suitable functional monomers for a given template but
are equally useful for optimizing ratios of monomers
in co- or higher polymers. Recently, an HTS technique
was successfully used to optimize terpolymers for
minimal nonspecific binding of lipophilic targets in
biological fluids [32].
4.2.2. New host monomers
Commonly, the monomers used in the above pro-
tocols are commercially available and individually
provide typically only weak interactions with the
template molecule. This leads to site heterogeneity,
low saturation capacity and nonspecific binding. In
order to address this issue, the monomer tool box may
be extended drawing inspiration from the area of
host–guest chemistry. Thus designed functional
monomers are capable of stoichiometrically associat-
ing with the template in the imprinting step and sub-
sequently to allow strong binding in the rebinding step
[33–35]. This minimizes site heterogeneity due to the
functional monomer–template complex distribution.
4.2.3. The polymer matrix
The polarity and functionality of the material sur-
face need to be matched to the matrix environment for
which the materials are designed. As mentioned above
water compatibility can be achieved by tuning the
composition of terpolymers including hydrophilic
comonomers or the use hydrophilic crosslinkers
[32,50]. Alternatively the organic polymer matrix
may be entirely replaced by an inorganic one. Thus
sol–gel imprinting is growing in importance and sev-
eral impressive examples of molecular recognition in
aqueous systems using these materials have been
reported [36,37].
4.2.4. Polymer beads and nanoparticles
The development of bead polymerization techni-
ques serves a twofold objective. First it addresses the
technical issues related to the conventional monolith
procedure to produce MIPs, e.g., low yields of useful
particles, irregular particle sizes, time-consuming
crushing sieving techniques. Secondly, packed beds
of monodisperse spherical particles will exhibit less
band broadening effects than corresponding beds of
irregular particles. If the particles are sufficiently
1739
small, the binding kinetics can also be expected to
strongly improve. Recently developed precipitation
polymerization techniques [38] and microemulsion
polymerization techniques [39] appear very promising
in this regard.
4.2.5. Composites
In order to decouple the binding site formation
from the generation of a particular morphology,
grafting techniques may be applied. Thus starting
from a support (e.g., a porous membrane [40], por-
ous particles [41]) thin layers of imprinted polymers
may be grafted on its surface. Combining the graft-
ing with controlled radical polymerization techniques
offers a mean to perform this grafting in a controlled
manner leading to a tunable polymer film thickness
[42]. In contrast to the polymer beads the thin film
composites have shown strongly improved mass
transfer properties.
4.2.6. Interfacial imprinting techniques
By confining the binding sites to accessible sur-
faces, mass transfer may be considerably enhanced
and the sites may be accessed by larger target mole-
cules or when surface–surface recognition is required
as would be the case when using MIP-nanoparticles to
target drug delivery (Fig. 4). This is possible by
employing interfacial imprinting techniques where
the template is confined at the interface between a
monomer rich and a monomer poor phase [43,44]. If
the template penetrates into the monomer rich phase a
surface imprint is generated which would be directly
associated with a pore or a void tunable by the choice
of monomer poor phase. In this regard, the immobi-
lized template approach, making use of template mod-
ified porous silica, appears particularly promising
[45–47]. Here, the template is coupled to the silica
surface whereafter the pore system is filled with the
imprint monomer mixture. Polymerization and subse-
quent removal of the silica by etching leave behind an
organic polymer corresponding to the replica of the
original silica pore system. In a recent extension of the
protocol, peptides were synthesised by solid phase
synthesis techniques on the silica surface [47]. The
resulting material could recognize the peptide used as
template but more importantly it also exhibited a high
affinity for larger peptides. Again this is an important
marker for future drug targeting studies.
1740 B. Sellergren, C.J. Allender / Advanced Drug Delivery Reviews 57 (2005) 1733–1741
5. Conclusions
With no ambition to be comprehensive, the above
examples and discussion show that molecular imprint-
ing is alive and well. Recent enabling techniques are
likely to open the door to a range of exciting applica-
tions in the near future. Particularly important is the
ability to engineer binding sites and the material
morphology in a relatively simple and controlled fash-
ion. The future will tell how far the imprinting engi-
neers can take MIPs, and whether the fully synthetic
antibody is destined to become fact or fiction. This
current issue complements the recent Advanced Drug
Delivery Review issue edited by Nicholas Peppas on
bIntelligent Therapeutics: Biomimetic systems and
nanotechnology in drug deliveryQ [48].
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