Bioapplications for Molecularly Imprinted Polymers | Analytical

Review pubs.acs.org/ac

Bioapplications for Molecularly Imprinted Polymers Romana Schirhagl*

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Physics Department, ETH-Zurich, Schafmattstrasse 16, 8046 Zurich

CONTENTS

Introduction to Bioimprinting Polymers and Imprinting Strategies Template Removing the Template “Traditional” Applications Chromatography and Electrophoresis Bulk Polymer Grinded Bulk Polymers Regularly Shaped Micro- And Nanoparticles Separation Surface Chemical Sensing Optical Read Out Electrical Read Out Mass Sensitive Devices Catalysis New Applications Drug Delivery Crystallization MIP Particles As Biomimetic Antibodies Drug Discovery Cell Culturing Conclusion and Outlook Author Information Corresponding Author Notes Biography References

The resulting polymers are promising, since they are relatively cheap, straightforward to make, and remarkably robust.11 Additionally, due to the high number of different monomers that are commercially available (more than 4000 polymerizable compounds),12 their properties can be tuned. During the last years, the field of molecular imprinting has grown rapidly and become very broad. However, there are still entirely new fields where imprinted polymers have been used just recently. While molecularly imprinted polymers with great selectivities have been synthesized for small molecules,13 imprinting with large macromolecules remains challenging.14 This review includes recent advances that have been made in this field, focusing on the discussion of similarities and differences of applications and requirements concerning the imprinted polymers. This encompasses a broad overview of the topic, using the most important or recent illustrative examples.

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POLYMERS AND IMPRINTING STRATEGIES The choice of the right polymer is one of the most critical factors in molecular imprinting. While many requirements to the polymer are application specific, there are a few generally applicable points (see Table 1 for a few common polymer examples). The most important requirement is that the monomer needs to have functional groups that can interact with the template. These groups can be any groups that form noncovalent interactions as charges,15,16 dipoles,17,18 van der Waals interactions,19,20 or π−π interactions.21 Which groups are best-suited is thus directed by groups that are available on the template molecule. An additional requirement to the polymer is that it is not reactively polymerizing with the template. This for example poses a problem for imprinting biomolecules into polyurethanes. One of the monomeric units is an isothiocyanate that is reacting with alcohol or amine groups present in most biomolecules. Furthermore, the polymer needs to be cross-linked enough to guarantee that the binding sites stay intact after the template is removed. If the binding sites are too flexible, they might also bind similar molecules. It has been found that targeting smaller molecules works best with highly cross-linked polymers.37 In contrast, often targeting larger molecules is achieved with more flexible polymers.38,39 Furthermore, it is desirable to use nontoxic polymer building blocks. Additionally, to ease optimization for different templates, it is favorable if the viscosity of the polymer can easily be tuned. While this article is about imprinted polymers, it is worth mentioning that there are alternative methods for molecular imprinting that do not use polymers. Such alternatives are, for example, self-assembled

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INTRODUCTION TO BIOIMPRINTING Molecules or coatings with high selectivities, as antibodies or enzymes, are of great importance in chemistry, diagnostics,1,2 and biology.3 However, these natural receptors are expensive or difficult to produce. Furthermore, since they are biomolecules their lifetime and applicability is limited.4 Molecular imprinting is one technique that was developed to overcome these limitations. To generate imprints with certain selectivity, a prepolymer is simply polymerized in the presence of the desired target molecule (see Figure 1).5−7 When the polymer is cured, two things happen simultaneously. First, functional groups in the prepolymer orient toward their counteracting partners in the template. This complex formation has been theoretically investigated in several articles.8−10 Second, the polymer is cross-linked, resulting in “freezing” the orientation of the functional groups. This orientation remains even when the template is removed. As a result, the remaining cavities reproduce size, shape, and surface chemistry of the template molecules. As a consequence, molecules of the template species will be incorporated preferentially later on. © 2013 American Chemical Society

Special Issue: Fundamental and Applied Reviews in Analytical Chemistry 2014 Published: August 14, 2013 250

dx.doi.org/10.1021/ac401251j | Anal. Chem. 2014, 86, 250−261

Analytical Chemistry

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Figure 1. Imprinting mechanism. (a) When the polymer is cured in the presence of the template, two things happen simultaneously. First, functional groups within the prepolymer (green) are oriented toward functional groups in the template they can interact with (red circles). Second, polymer chains (gray lines) are formed and cross-linked. (b) When the template is removed, the binding sites remain in shape.

template directly. Figure 2c shows substructure imprinting.59,60 This method uses small characteristic substructures instead of the whole molecule. This is similar to natural antibodies which target epitopes instead of whole molecules. This is especially favorable, if the analyte has a surface where the arrangement of functional groups is changing. This, for example, applies to cells where membrane proteins can change their relative position within the membrane. This leads to a decrease in binding affinity if the whole structure is used and limits the selectivity that can be generated for large flexible structures. In contrast, this does not affect the epitope approach, which is more promising in those cases (see Figure 3).

Table 1. Most Commonly Used Polymer Systems and Examples for Applications polymer

application

methods

literature

polyacrylate/ polymethacrylates/ polymethylmethacrylate polyacrylamide

sensors, chromatography, drug delivery chromatography, crystallization sensors

bulk imprinting, surface imprinting, imprinted particles bulk imprinting

22−24

surface imprinting, sacrifice layers surface imprinting bulk imprinting

28−31

polyurethane siloxanes solgels

chromatography chromatography, sensors, catalysts

25−27

32 33−36

monolayers that are assembled in the presence of a template40−43 or molten gallium44 that can also be imprinted.

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TEMPLATE Although the template is usually dictated by the problem that one wants to solve, there are some interesting alternatives. Figure 2 summarizes these for creating molecularly imprinted polymers. For a specialized review article on different methods, refer to ref 45.

Figure 3. The traditional and the epitope approach for large flexible analytes.

46−48

Figure 2. (a) Traditional bulk imprinting, (b) surface imprinting,49−51 (c) substructure imprinting,52 (d) structural analog imprinting, (e) antibody replicae,53,54 and (f) sacrifice layers.55,56

A difficulty of the method is that one needs to know which substructure of an analyte is present on the surface, which is often nontrivial.61−64 Another alternative are structural analogues that can be used instead of the target molecule.65 This can be favorable if the target itself is rare or toxic or not stable under the imprinting conditions. Additionally, this is an interesting approach if the template molecule is hard to remove from the polymer or otherwise inconvenient to use. Another method that was also determined in the Dickert group is antibody replicae (Figure 2e).66 The slightly more complicated method uses natural antibodies for the desired target molecule

Figure 2a shows the traditional bulk imprinting, where a template molecule is simply added to the prepolymer.57 As a result, selective cavities are distributed all over the bulk. When the template is very big, it might not be possible to diffuse through the cross-linked polymer. For such large templates (e.g., cells or viruses), surface imprinting with stamps (Figure 2b) was developed by the group of Prof. Dickert.58 The rest of the methods that are summarized in Figure 2 are alternative imprinting strategies, where the target molecule is not used as a 251



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order to achieve the properties, several strategies have been used and are reviewed in the following sections. Figure 4 summarizes the different options and shows examples for the different column materials.

as the starting material. These antibodies are imprinted into a polymer, which is then used to imprint another polymer. This results in receptors that mimic the structure of the initial antibody material. Since the receptors mimic natural antibodies, they also target epitopes instead of the whole structure. Another advantage is that the procedure is easily adaptable to other analytes by changing the starting material to an antibody with a different selectivity. This way, selectivity for large viruses or hormone molecules, for example, could be generated. Disadvantages of the method are that it is more complicated than the standard imprinting technique and that the antibody is needed as the starting material. Using a sacrifice layer allows the use of a polymer that would otherwise react with the template. So instead of imprinting with the biomolecule directly, one can cover the template with a monolayer of molecules. These both interact with the template and form the binding site and are covalently bound to the polymer. This way, the recognition can be further tuned. This approach was successfully used by Shi et al. to generate imprinted receptors.48

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REMOVING THE TEMPLATE Especially for large biological samples, template removal is one of the most critical problems in imprinting. To facilitate template removal, the imprinted polymer is usually either washed in solvents,67−69 acids or bases,70,71 or detergents.72,73 The polymer can also be heated for template removal.74−76 Another elegant method for template removal is the addition of digesting enzymes like proteases.77 For complex biosamples, cell osmosis, for example, can be used. Remaining template cells shrink when the surface is washed with high ionic strength solution and can thus be removed from the surface. Flushing the surface with an excess of ions or molecules that can compete with the template for binding sites might also be successful.78 Also, ultrasonic treatment has shown to be useful.42 However, care has to be taken since some polymers might be sensitive to the treatment. Furthermore, some molecules that can potentially be used for template removal or recovery of the imprinted polymer can adhere to the polymer. As a result, the template removal might be successful, but binding sites are blocked by removal molecules. This has been shown for some detergents as SDS79 and can be circumvented by changing the removal procedure or extensive washing.

Figure 4. Different options for MIP materials in chromatography. Bulk Polymer: (a) the stationary phase is a highly porous polymer,81 (b) regularly shaped particles,83 (c) irregularly shaped particles,82 and (d) surface imprinting on the wall of the column.84 Reprinted with permission from ref 81. Copyright 2011 Elsevier B.V. Reprinted with permission from ref 82. Copyright 2000 Elsevier B.V. Reprinted with permission from ref 83. Copyright 2011 Royal Society of Chemistry. Reprinted from ref 84. Copyright 2009 American Chemical Society.

Bulk Polymer. One approach to generate an imprinted stationary phase for separation is a porous polymer material. This approach was used by Deng et al., who used imprinted polymers to separate proteins.74 They used an acrylamide-based monomer solution containing the template proteins. After the addition of the cross-linker, the solution was cooled in an ice bath and a cooled radical starter was added. The mixture was then polymerized at −20 °C for 24 h. After the polymerization was completed, the frozen monoliths were thawed at room temperature and washed to remove the template. The result was a monolithic porous polymer that was used in HPLC systems to separate hemoglobin from bovine serum albumin. Li et al. used a similar method to generate selectivity toward enrofloxacin (a commonly used antibiotic).85 To allow the mobile phase to pass through, the authors used a porogen to increase porosity within the polymer. Using such a nonpolymerizing solvent, which leads to pores within the polymer, is a commonly used strategy.86 Interestingly, the authors found that the addition of a “crowding agent” can positively alter the formation of the imprints. They used polystyrene beads for this purpose and stated that the addition of crowding agents in the prepolymerization mixture can shift the rate of polymerization and/or the kinetics of phase separation between the MIP and the solvent. The main disadvantage of this method is that the bulk material is only feasible for small molecules. For large templates, template removal poses a problem and the bulk material can hinder the analytes to pass the stationary phase during separation. Grinded Bulk Polymers. An alternative method to allow template molecules to diffuse through the stationary phase is using particles. Such particles can simply be generated by

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“TRADITIONAL” APPLICATIONS Chromatography and Electrophoresis. Chromatography was the first application where imprinted polymers were used. Separating components of complex mixtures is a crucial step in analysis and preparation of samples. Since they are relatively easy to make and have high selectivities toward their template, imprinted polymers are good separation materials. Another part of separation science where MIPs have proven to be useful is electrophoresis. During electrophoresis the analyte mixture is forced through a stationary phase by an electric field (instead of gravity or pressure in chromatography). A specialized review on this application can be found in ref 80. Since there are many similarities between chromatography and electrophoresis (especially concerning the requirements for the imprinted material), these two methods are discussed here in one section. To allow a flow of the mobile phase passing through the material, it needs to be to some extent porous. Furthermore, the density of binding sites should be maximal. In 252



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Figure 5. Different methods to synthesize regularly shaped particles: (a) precipitation polymerization, (b) emulsion polymerization or suspension polymerization, (c) core−shell polymerization, and (d) U-tube polymerization.

synthesizing a bulk material and grinding it to particles.87,88 While for the monolithic approach, a very porous material needs to be used. The choice of polymer in the particle approach is more flexible. As a consequence, the polymer material can be fine-tuned for a certain template easier. However, the resulting particles usually have an irregular shape and a wide particle size distribution.89,90 This leads to broad peaks and worse reproducibilities. To improve these two properties, the particles are often sieved and only the desired size fraction is taken for the separation.91 Walshe et al. used this approach to separate enantiomers by electrophoresis.92 To this end, the authors synthesized bulk MIPs using N-acryloylalanine and ethylene glycol dimethacrylate (EDMA) as functional monomers. The bulk material was then crushed and sieved to obtain irregular particles 20−30 μm in size. Using these particles imprinted against (S)-propranolol, a separation of the enantiomers of propranolol was obtained. Solutions of reference polymer (prepared without a template) were tested and found not to achieve any chiral resolution. Regularly Shaped Micro- And Nanoparticles. A widely used approach is using regularly shaped particles for separation. Over grinded material with random shapes, they have the striking advantage to be more reproducible and to produce narrower bands. This is due to their monodispersity and regular shape. Such particles can be generated by precipitation polymerization,93 emulsion polymerization,94 or can be forced through a porous membrane95 (see Figure 5). To perform a precipitation polymerization, the monomers and all ingredients are simply stirred in a solution where they are not well soluble. When the polymer is formed, the particles containing the template will precipitate. As an additive to support the droplet formation within such a solution, a detergent can be used, which will enclose the particle ingredients. This process is called emulsion polymerization. For particle sizes above 1 μm, this method, which was historically the first method used to generate regularly shaped MIP particles, is called suspension polymerization.96 Alternatively, a particle can be used as a core, which can also support the formation of a polymer shell around it.97−99 A recent review article on particle synthesis can be found in ref 100. Alternatively, an imprinted polymer can be synthesized on the surface of a nonimprinted particle.101 Regularly shaped polymer particles with selectivity toward 2,4-dichlorophenoxyacetic acid (2,4-D, a common herbicide) were used by Fang et al.76 The MIP microspheres were prepared via precipitation polymerization, using a complex mixture containing 4-[(4-

methacryloyloxy)phenylazo]pyridine (MAzoPy), 2,4-D, ethylene glycol dimethacrylate (EGDMA), azobisisobutyronitrile (AIBN), and acetonitrile as the functional monomer, template, cross-linker, initiator, and porogenic solvent, respectively. The most interesting feature of this polymer material is its photoresponsive affinity toward the template, which decreased upon UV light irradiation. This is caused by the azo groups that undergo photoreaction and thus alter binding sites. The initial binding properties could be recovered by heat treatment. Furthermore, the authors were able to separate the template molecule from structural analogues. The disadvantage of using regularly shaped particles is that the procedure is more complicated and particle size control is often nontrivial.102 This makes adapting the method to different templates more challenging. Separation Surface. One drawback of all the abovementioned methods to generate a stationary phase is that it takes a long time to force the mobile phase through a densely packed column. Additionally, if very large particles should be separated, densely packed columns cannot be used since the analyte would simply get stuck. An interesting alternative is providing the binding sites only on the surface of the column. Qu et al. implemented that technique into a microfluidic chip, which could be used for enantiomeric separation of L and 77 D forms of tert-butoxycarbonyl-tryptophan (BOC-Trp). They inserted the prepolymer mixture consisting of acrylamide as a functional monomer and ethylene glycol dimethacrylate as the cross-linker into a microfluidic system. There, the mixture was polymerized covering the walls of the chip that was used for separation. They optimized the polymeric composition and were able to sort standard analytes for enantiomeric separation (Boc-D-Trp, Boc-L-Trp) within 75 s. Recently, this method was used to allow a chromatographylike separation for bacteria.72 The authors were able to separate different strains of cyanobacteria using a microfluidic channel, where the floor was imprinted with the respective bacteria strains. Remarkably, even strains that could not be separated by FACS sorting could be separated by the polydimethylsiloxanebased imprinted polymer. Ren et al. used the same method to generate surface imprinted channels for the separation of different clinically relevant bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Staphylococcus epidermidis).103 They found that the imprinted polymer channels preferentially incorporated template bacteria over other species. As a consequence, the template cells were trapped in the chip and thus could be depleted from the cell suspension. 253



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Figure 6. Different electrical readout schematics: (a) conductometric sensor, (b) ISFET, and (c) voltammetric or amperometric sensor.

group of Prof. Gauglitz.115 RIfS is based on the reflectance of white light at thin layers. A characteristic interference spectrum is observed, which gets shifted as a result of the uptake of template molecules by the sensitive layer. This shift corresponds to changes of the optical thickness (product of physical thickness and refractive index) of the sensitive layer.116,117 As a result, the method is label-free and applicable to molecules that are not fluorescent. The authors used a nanoparticle film imprinted with L-Boc-phenylalanine anilide. They were able to detect concentrations down to 60 μM of their template. Electrical Read Out. Electrical read out is especially useful for charged template molecules that can be detected electrically. However, it has a clear disadvantage for the detection of neutral analytes. Detailed review articles about electrical sensors based on imprinted polymers can be found in refs 118−120. In addition, I would like to refer to an excellent book about MIP sensors covering that topic.121 Conductometric, impedimetric, ion-selective field effect transistor (ISFET), amperometric, and voltammetric transduction have been explored, which will be discussed in the following (see Figure 6 for a scheme). Conductometric and Impedimetric Sensors. Measurements are performed by imposing an alternating voltage between two electrodes, two Pt electrodes for conductometric devices, and one reference electrode and the sensor for an impedimetric system. As a result, one obtains an alternating current as the response. In order to carry out conductometric or impedimetric sensing, conductivity has to be carried out through a membrane. Therefore, it is necessary to prepare the imprinted polymer as a membrane, which can be challenging. This approach was used by Sergeyev et al. to generate an atrazine (a common pestiside) sensor.122 MIP membranes were prepared using atrazine as a template, methacrylic acid as a functional monomer, and tri(ethylene glycol) dimethacrylate as a cross-linker. To fabricate a membrane, the mixture was sandwiched between two glass plates at a fixed distance of 60− 120 μm. Cross-sensitivity toward structural analogues was tested and found to be about a factor of 8 smaller than the signal for the template. Furthermore, sensitivity was found to be quite high (detection limit in buffer was 5 nM). ISFET. An ion-selective field-effect transistor or ISFET is a field-effect transistor that is sensitive to ions in a solution. It consists of a source and a drain made of an n-doped semiconducting material that are separated by a p-doped semiconductor. The p-doped semiconductor is separated by an insulating layer from the gate where the imprinted polymer is mounted. If charges are generated in the polymer due to the incorporation of the template, moving of charge carriers is allowed within the p-doped semiconductor.123 This allows a

Furthermore, the authors investigated the mechanism of the capturing. To this end, they coated the binding sites by a thin film of silanes. This treatment alters the surface chemistry but hardly affects the shape of the cavities. They found that after silanization, nearly no selectivity was observed. The authors concluded that the separation was mostly due to chemical interactions and not solely based on different shapes. A drawback of the method is that the channels have to be fairly small to minimize diffusion ways and thus achieve reasonable separation. Consequently, the method requires fabrication of microfluidic devices. Additionally, packed columns usually provide a larger separation surface and thus are better suited for small template molecules. Chemical Sensing. Since there is only one capturing event, selectivity is even more crucial in sensing applications than in chromatography. MIP-based biosensors have been generated for different templates, ranging from molecules 104 to proteins,105 viruses,106 or even entire cells.107,108 Recent specialized reviews on chemical sensing can be found in refs 109−111. The techniques and requirements to imprint polymer receptors are substantially different, depending on the read-out methods. Thus, different methods are discussed in the following sections. Optical Read Out. Optical read out is relatively straightforward. There are very little requirements to the polymer material. It simply has to be nonfluorescent at the detection wavelengths. If light has to pass the polymer to reach the detector, the polymer has to be transparent too. The template has to be either naturally fluorescent or absorbing or it has to be stained in a separate step. This restriction to a certain subset of possible analytes is a disadvantage of the method. Fukazawa et al. used UV fluorescence imaging to detect proteins that were captured on the surface of their imprinted polymers.112 They used a surface-imprinting approach but immobilized the proteins first on particles and then created the imprints. That way they were able to increase the density of receptors on the surface and thus the sensitivity of the sensor. Furthermore, they used a layer of sodium dodecyl sulfate (SDS) in analogy to the previously described sacrifice layer to form the binding sites. As polymer matrix, a quite complex photoreactive phospholipid polymer was used, providing several different functional groups. The authors reported a good selectivity toward bovine serum albumin over the structurally similar ovalbumin. Some authors developed methods where the polymer itself in fluorescing instead of the template molecule.113,114 Incorporation of the template can be verified since the fluorescence of the polymer is quenched when the cavities are occupied. An interesting approach using reflectometric interference spectroscopy (RIfS) has been used for optical sensing in the 254



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Figure 7. Comparison between quartz crystal microbalance (top) and surface acoustic wave resonators (bottom). Both techniques are based on the detection of a frequency change caused by an increase in mass. However, they use different oscillations, leading to different appearance and properties.

current to flow between the source and gate, which is used as a measuring signal. This method was used by Tsai et al.124 who generated a sensor for creatinine (a clinically relevant byproduct of muscle metabolism). The imprinted polymer was based on poly(ethylene-co-vinyl alcohol) that was surface imprinted simply by dropping the template solution onto the prepolymer film (drop-coating). The authors were able to measure concentrations down to 0.2 mg/mL, within a fairly short time of 20 min. Amperometric Sensor and Voltammetric Sensors. In this type of sensor, measurements are performed by applying a potential (variable in voltammetric and fixed in amperometric devices) between the sensor and a reference electrode. The current that flows through the counter electrode and the sensor is continuously monitored and used as a signal. Alizadeh et al. used such a voltammetric sensor to detect promethazine in plasma samples.125 To generate selectivity, they synthesized MIP particles. These were then embedded in a carbon paste electrode in order to prepare the MIP electrode. The detection limit was found to be relatively low (2.8 × 10−12 M), and no sample preparation was necessary. Kriz et al. have generated an amperometric sensor for morphin.126 Their detection method of morphine involves two steps. In the first step, morphine binds selectively to the molecularly imprinted polymer in the sensor. In the second step, an electroinactive competitor (codeine) is added in excess. As a result, some of the bound morphine is released and can be detected amperometrically. To fabricate the MIP electrode, the authors used a platinum wire, which was melted into a glass tube. Then the wire was dipped into a suspension containing MIP particles in agarose solution. Finally, the agarose is crosslinked, and the template is removed. With this method, they were able to achieve a remarkably low detection limit of 0.1 μg/ mL. Mass Sensitive Devices. To detect an analyte with a mass sensitive device, the imprinted polymer is simply coated onto the surface of a quartz crystal microbalance or a surface acoustic

wave resonator. A comparison between the two techniques is shown in Figure 7. Since an increase in the mass load results in a resonance frequency drop, one can very accurately measure the incorporation of an analyte. Since every analyte has a mass, this is the most generally applicable detection method. However, there are some requirements to the template and the polymer material that need to be fulfilled. First, in order to generate a frequency shift that is proportional to the analyte concentration, the analyte molecules need to be to some extent rigid and mounted to the resonator surface. Second, the polymer has to be rigid127 and fairly thin to have linear concentration dependency. For very thick128 or too flexible polymer layers 129,130 or analytes that are not tightly bound,131,132 unexpected frequency increases have been reported. In addition, care has to be taken when measuring in liquid phase. Since the frequency response also depends on viscosity and ionic strength133 of a measured solution, references have to be measured under the same conditions. An additional drawback of mass sensitive devices is that heavy contaminants can lead to high unspecific responses. Quartz Crystal Microbalance (QCM). A QCM consists of a quartz plate that is sandwiched between two electrodes (see Figure 7). When a voltage is applied, an oscillation is induced in the quartz material that is sensitive to a mass change. Where the imprinted polymer coating can be applied depends on the sample. If the sample is a gas, both electrodes can be coated and exposed to the sample during the measurement.134 If the sample is liquid, the backside cannot be exposed to a sample to prevent shortings in the electronics. The imprinted polymer is then mounted on one electrode while the voltage is applied from the other side. As an alternative to this simplest electrode geometry, several alternative designs have been realized. For example, the group of Prof. Dickert designed more than one electrode on each side of the quartz. This allows them to include a reference coated with a nonimprinted polymer and a measuring electrode coated with the MIP.135,136 Up to four electrodes have been implemented on each side, allowing them 255



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to sense with an array of four different coatings simultaneously.137 There are also different possibilities for choosing a quartz resonator. Although the mass sensitivity increases with the resonance frequency of the quartz resonator, there are practical limitations. For higher frequency resonators, the thickness of the quartz plate is smaller. As a consequence they are more fragile and thus harder to handle. Good compromises are resonators with resonance frequencies between 5 and 20 MHz, which are normally used.138 In order to mount the imprinted polymer onto the gold electrode, one can either coat the prepolymer directly on the gold139,140 or apply an additional coating. Such coatings, that facilitate binding, usually have a functional group (e.g., a thiol group) that binds to the gold and a high affinity to the polymer material. Such an adhesion layer might also contain groups that form covalent bonds to the prepolymer.141 A quartz crystal microbalance was used by Zhou et al. to fabricate a sensor for domoic acid, an amino acid neurotoxin.142 To this end, the authors coated the gold electrode of a quartz crystal microbalance with the prepolymer (based on dopamine as monomer units). They achieved an excellent selectivity toward the template over structural analogs. Zhou et al. also obtained remarkably high sensitivities and were to detect 5 ppb of domoic acid. A similar quartz microbalance sensor was used by Alenus et al.143 However, instead of an imprinted polymer layer, they used microparticles, obtained by crushing a bulk imprinted polymer, which were then immobilized on thin films of polyvinyl chloride on the surface of a QCM. Surface Acoustic Wave Resonators (SAWs). Compared to QCMs, SAWs usually have an order of magnitude of higher resonance frequencies leading to an increase in mass sensitivity. As a result, SAWs are perfectly suited for trace gas detection.144−146 This was used by Dickert et al., for example, who fabricated a MIP-based sensor for the detection of volatile organic compounds in air.147,148 It was observed that MIPcoated 433 MHz SAW devices exhibited a very low detection limit of 0.1 ppm, for o-xylene vapors. These coatings were further optimized to differentiate between different isomers of xylene. Cao et al. achieved excellent sensitivity (19.4 ppb) toward dimethylmethyl phosphonate DMMP with imprinted 2,5(thioalkyl-alkoxy)-p-tert-butylcalix[4]arene.149 DMMP is a highly relevant substance for chemical sensing due to its analogy to chemical warfare agents. They also tested several vapors and attributed remarkable selectivity of their sensing layer to the molecular imprinting effect. A disadvantage of SAWs is that the propagation of surface acoustic waves require the analyte medium to be moved (see Figure 7). As a result, the method is more affected by damping and less applicable for detection in viscous, liquid media than in QCM detection. Specialized review articles on mass sensitive devices150 or SAW resonators151 have recently been published. Catalysis. Catalysts are materials that can alter the velocity of chemical reactions without being consumed. They usually achieve that by lowering the activation energy by forming a complex which is stabilizing an intermediate. To achieve this with an imprinted polymer, one has to generate a cavity where an important intermediate fits in and thus can be stabilized.152 Furthermore, the cavities of an imprinted polymer can protect functional groups or orient two areas where a reaction should happen toward each other. See Figure 8 for a schematic summary of the different options to achieve catalysis. These

Figure 8. Options to catalyze a chemical reaction using an imprinted polymer (the structure that fits into the cavity is circled and the respective polymer is depicted on the right). One option is to remove the favored end product from the equilibrium with an imprint that represents the shape of the end product. Another option is orienting groups toward each other that should react or protect groups that should not react with cavities resembling a starting product. The third option is to stabilize an intermediate state.

approaches share the disadvantage that one has to have quite a detailed knowledge of the reaction mechanism. Bonomi et al. achieved catalytic activity by using this approach.153 There, cavities were able to catalyze the so-called Kemp elimination that is shown in Figure 9.

Figure 9. Kemp elimination: indole imprinted cavities are thought to catalyze the ring-opening by building a complex with the intermediate. (XH or Cl).

To this end, they used a vinylpyrollidone-based polymer, which can form hydrogen bonds with the N-atom in Figure 9. A slightly different approach was used by Zhang et al. to catalyze a regioselective huisgen 1,3-dipolar cycloaddition reaction.154 Huisgen 1,3-dipolar cycloaddition of azides and alkynes has drawn great attention because of its efficiency and versatility to provide fast access to an enormous variety of medicinally interesting triazoles.155 However, it usually leads to a mixture of two isomers. To direct the reaction toward the preferred isomer, they imprinted a polymer with the preferred end product isomer. As a result, the cavities were catalyzing the formation of the preferred isomer, whereas the wrong isomer formation was sterically hindered. This method was used by Katz et al. who used microporous silica as a polymer material.156 Their material was found to act as shape-selective base catalysts. The formation of their desired product was monitored by gas chromatographic analysis. 256



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NEW APPLICATIONS Drug Delivery. Many drugs that are known to be effective against cancer, for example, cannot be used due to their severe side effects. Other drugs have very low solubility in body fluids or are degraded by the immune system and thus never reach the area in the body where they are needed. Drug delivery is looking for materials that incorporate the drug, can deliver it to the area where it is needed, and release it there. Molecularly imprinted polymers can reversibly incorporate a template molecule. This property is highly desired in drug delivery, which makes them interesting candidates for that field. To be suitable for drug delivery, the polymer material has to meet several additional requirements. While for the previously described applications, it is desirable to have a stable polymer, drug delivery polymers should be biodegradable. Additionally, toxicity of the polymer or any building block is much more critical. Specialized review articles on MIPs for drug-delivery applications are available from refs 157 and 158. Puoci et al. used MIPs for the delivery of 5-fluorouracil, which is a widely used anticancer drug.159 To obtain drug delivery particles, the authors first performed bulk imprinting using cross-linked methylmethacrylic acid. Then the polymer was grinded and sieved to obtain uniformly sized particles. In their study, they achieved a sustained release of the drug. This means that the MIP particles slowly released a constant level of the drug. This behavior is highly favorable, since the drugs have to be taken less frequently. This was evaluated by in vitro release studies in gastrointestinal and in plasma simulating fluids. An interesting alternative to drug delivery particles is used for therapeutic contact lenses. A review about this topic can be found in ref 160. To obtain such contact lenses, AlvarezLorenzo et al. prepared a hydroxyethyl methacrylate-based prepolymer, which was injected into a mold.161 The prepolymer contained the template molecule timolol which is used in eye drops to treat glaucomas. The authors investigated different polymer compositions and were able to achieve sustained release of timolol from their bulk imprinted polymer. This was evaluated in vitro using artificial lacrimal fluid. Similar imprinted polymer-based contact lenses were tested in vivo by Hiratani et al.162 The results of animal experiments (with rabbits) indicate that their imprinted polymers provide greater and more sustained drug concentrations in tear fluid with lower doses than conventional eye drops. An interesting approach was used by Sreenivasan.163 His drug-delivery particles release a drug in response to certain molecules. This was achieved by using a hydrocortisonimprinted polymer that was loaded with testosterone that functions as a drug. When the imprinted polymer particles come in contact with their template (hydrocortison), the weakly bound testosterone is released. As a result, the release of testosterone can be triggered by hydrocortisone. Suedee et al. generated a polymer membrane that was able to perform a differential release of enantiomers, whereby the release of the more therapeutically active enantiomer is promoted, while the release of the less or nonactive enantiomer is retarded.164 This approach is interesting for racemic drugs, which are often considerably cheaper to produce than the pure enantiomer. The incorporation of MIPs within delivery systems is of potential value in the administration of chiral drugs, where significant pharmacological activities are associated with only one enantiomer.

They developed a transdermal patch for controlled delivery of the active S-enantiomer from racemic propranolol and tested their performance in vivo on rats. A molecularly imprinted polymer (MIP) thin-layer composited cellulose membrane with selectivity for S-propranolol was employed as the enantioselective-controlled release system. The membrane was found to preferentially deliver the desired enantiomer. In comparison with conventional drugs, drug-delivery particles (based on MIPs and other materials) have the disadvantage that they are quite complex. This not only poses a problem in particle synthesis but also can cause difficulties when the particle should be approved for the clinic since every building block has to be tested. As a consequence, drug delivery particles, although having nice advantages over conventional drugs, are only used where they are really necessary. Crystallization. Structure determination of proteins is limited by their ability to form well-diffracting and largeenough crystals. Unfortunately, many proteins have irregular shapes and thus cannot easily be crystallized. Thus, a whole field of crystallography has emerged to solve that problem. A very new application for imprinted polymers is initiating protein crystallization.165,166 The ability of MIPs to control crystallization was first demonstrated in refs 167 and 168. The authors showed that polymers imprinted with calcite are able to induce the nucleation of calcite under conditions favoring the growth of aragonite (another polymorph of calcium carbonate). Saridakis et al. were the first who used molecularly imprinted polymers to facilitate protein crystallization.169 They found that molecularly imprinted polymers can initiate protein crystal growth for several different proteins (lysozyme, trypsin, catalase, hemoglobin, intracellular xylanase IXT6-R217W, alpha crustacyanin, and human macrophage migration inhibitory factor). Among them were also proteins that are difficult to crystallize and thus had not been crystallized before. Furthermore, imprinted polymers have also increased the speed of crystal formation significantly. The same group also investigated the crystal formation ability as a measure for the affinity between different polymers and protein templates.153 They compared acrylamide (AA), Nhydroxymethylacrylamide (NHMA), and N-isopropylacrylamide (NiPAM) as functional monomers for protein imprinting. They found that the crystal formation was improved in the order of NiPAM < AA < NHMA. They concluded that the affinity to the target proteins were in the same order. MIP Particles As Biomimetic Antibodies. In this section, the use of MIP particles as artificial antibodies is discussed. The idea is to generate particles with certain selectivity that could be given to patients and replace natural antibodies in an immune response. Many authors name their imprinted polymers, artificial antibodies when used in sensing. However, a specific application is addressed here and the respective articles about sensing applications are discussed there. First attempts toward achieving this goal were made by the Shea group.170 The authors designed their particles to bind a toxic protein called mellitin. This is a hemolytic peptide that lyses red blood cells. They investigated different acrylamidebased imprinted nanoparticles. The hemolytic behavior was used to determine the success of the binding reaction. To this end, the imprinted particles were mixed with red blood cells and melittin. When the melittin bound, it could not lyse the blood cells anymore. Remarkably the authors where able to increase blood cell survival in vitro from 0 to almost 80% (after 257



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addition of 30 μg/mL imprinted polymer). This detoxification from melittin poisoning was also demonstrated in vivo.171,172 To test the detoxification with imprinted polymer particles, mice were intoxicated with melittin. The authors showed that survival rate of mice was significantly improved when they were treated with the melittin-imprinted particles. This effect was not observed with nonimprinted reference particles. Additionally, they found that the particles and the enclosed melittin is directed to the liver (which is the organ where particles are naturally cleared from the bloodstream to be excreted). The Shea group also tested potential toxicity of the artificial antibodies independently and found no adverse effects on the mice after injection. The same group also generated artificial receptors that were able to bind the Fc fragment of natural antibodies.38 These results establish that engineered synthetic polymer particles can be formulated with an affinity to a specific domain of a large biomacromolecule. To achieve that goal, the authors used an iterative approach using different polymer compositions to obtain the optimal binding affinity. The affinity of such artificial antibodies toward their target can even be increased by affinity chromatography. Hoshino et al. have demonstrated that they can select particles with high affinity.173 To achieve this goal, they used a column with immobilized target proteins. While low affinity particles get eluted first, high affinity particles remain on the column longer. Drug Discovery. The affectivity of drugs is mostly based on their ability to bind to certain receptors and trigger or inhibit a reaction. Inhibitors are of great interest since they are often potential drugs or have other biological relevance. Review articles about molecular imprinting in drug discovery can be found in ref 174. The group of Prof. Mosbach has found that molecularly imprinted polymers can be used to find potential inhibitors for receptors.175 The inhibitors they were interested in are kallikrein inhibitors. Kallikrein is an enzyme with physiological significance in transforming hormone precursors into their active form. Kallikrein is also believed to play a role in cancer and thus can be used as a cancer marker. For inhibitor screening, they self-assembled new inhibitor structures within the reactive sites of the native enzyme (strategy 1 in Figure 10). The assembled products were removed from the enzyme and their ability to inhibit the enzyme activity was tested. As an alternative strategy, they used a double imprinting strategy (strategy 2 in Figure 10). To this end, they first imprinted a known kallikrein inhibitor to generate an artificial enzyme (based on a cross-linked divinylbenzene). After extracting the template inhibitor, cavities remain that are similar in structure to the natural enzyme. Then the authors performed a condensation reaction within the cavities of the MIP. The products of this second imprinting step were evaluated for their ability to inhibit kallikrein. The striking advantage of this technique is that there is no need for detailed structural information or isolation of the natural biological target. Both approaches lead to the formation of new kallikrein inhibitors and thus potential drugs. Cell Culturing. Surfaces with defined patterns and roughness have been found to improve cell culturing.176,177 Since size, density, and even surface chemistry of such patterns can be tuned in molecular imprinting, molecularly imprinted polymers are an interesting material for this application. DePorter et al. have demonstrated the growth promotion of three different cell types.178 HeLa cells (cells from an immortal cancer cell line), HEK-293T (human embryonic kidney cells), and MRC-9

Figure 10. Strategies to screen for new inhibitors discovered in the Mosbach group.160 New inhibitors can be self-assembled within the natural enzyme (strategy 1) or generated by double imprinting (strategy 2). In the double-imprinting approach, an imprinted polymer is molded around a known inhibitor, leading to a cavity that represents the active site of the enzyme. The new inhibitor is then self-assembled within the cavity in a second imprinting step.

(human embryonic lung cells) grow significantly better on an imprinted polymer. In order to create the imprints, cells were incubated in a premixed solution consisting of acrylamide, bisacrylamide, tetramethylethylene-diamine (TEMED), and ammonium persulfate (radical starter) at room temperature for 20 min. They performed several careful control experiments to guarantee that the improved adhesion is caused by imprinting and not simply residues of cell debris on the surface. The authors also showed that the imprinted surfaces adhere more to the respective template cells than to other cells. Zehua et al. also used molecular imprinting for cell growth.179 However, instead of a cell imprinted polymer, they used sugar fibers as templates. They report that grooves remaining from sugar fiber imprinting direct cell growth (MC3T3-E1) in the same direction. They observed that the cell viability is not negatively affected by the imprinted polymer.

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CONCLUSION AND OUTLOOK Molecularly imprinted polymers have been highly optimized for the traditional applications as chemical sensing or chromatography reaching record selectivities. Starting from small molecules, the field of molecularly imprinted polymers has been extended to large biomolecules as proteins, viruses, or even entire cells. However, the selectivities and sensitivities that have been achieved still differ a lot, depending on the template. Selectivities that have been achieved for large biomolecules are still a lot worse than what was reported for small molecules. Some success has been achieved for viruses that have a repetitive surface structure or for cells with a relatively rigid cell wall, for example. However, too flexible surface structures as on cells with “fluid” cell membranes, for example, are a serious problem for imprinting that has so far not been solved. Several promising new technologies are starting to make use of the high affinities provided by molecularly imprinted polymers. These have been successfully used for drug discovery and drug delivery applications, as enzymelike catalysts, for cell culturing and crystal growth and even as artificial antibodies. There are many applications, mainly in the fields of biology and 258



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medicine, where MIPs have just been discovered very recently. Consequently, there is most likely room for improvement and new innovations in this field.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biography Romana Schirhagl studied chemistry at the University of Vienna, where she received her Ph.D. degree in 2009. She worked for one year as a postdoctoral researcher in the Department of Chemistry at Stanford University. Currently, she does research at the ETH in Zurich, where her main research focus is in micro- and nanofabrication and surface chemistry for nanometer scale magnetic imaging, bioanalysis tools, and biosensors. She is a nationally ranked chess player.

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