Molecularly imprinted polymer

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A molecularly imprinted polymer (MIP) is a polymer that has been processed using the molecular imprinting technique which leaves cavities in the polymer matrix with an affinity for a chosen "template" molecule. The process usually involves initiating the polymerization of monomers in the presence of a template molecule that is extracted afterwards, leaving behind complementary cavities. These polymers have affinity for the original molecule and have been used in applications such as chemical separations, catalysis, or molecular sensors. Published works on the topic date to the 1930s.

Contents

Molecular imprinting techniques (state of the art and perspectives)

Molecular imprinting is the process of generating an impression within a solid or a gel, the size, shape and charge distribution of which corresponds to a template molecule (typically present during polymerisation). The result is a synthetic receptor capable of binding to a target molecule, which fits into the binding site with high affinity and specificity. The interactions between the polymer and the template are similar to those between antibodies and antigens, consisting of electrostatic interactions, hydrogen bonds, Van der Waals forces, and hydrophobic interactions.

One of the greatest advantages of artificial receptors over naturally occurring receptors is freedom of molecular design. Their frameworks are not restricted to proteins, and a variety of skeletons (e.g., carbon chains and fused aromatic rings) can be used. Thus, the stability, flexibility, and other properties are freely modulated according to need. Even functional groups that are not found in nature can be employed in these synthetic compounds. Furthermore, when necessary, the activity in response towards outer stimuli (photo-irradiation, pH change, electric or magnetic field, and others) can be provided by using appropriate functional groups.

In a molecular imprinting processes, one needs a 1) template, 2) functional monomer(s) 3) cross-linker, 4) radical or other polymerization initiator, 5) porogenic solvent and 6) extraction solvent. According to polymerization method and final polymer format one or some of the reagent can be avoided. [1]

Preparation of molecularly imprinted material Molecular imprinting.png
Preparation of molecularly imprinted material

There are two main methods for creating these specialized polymers. The first is known as self-assembly, which involves the formation of polymer by combining all elements of the MIP and allowing the molecular interactions to form the cross-linked polymer with the template molecule bound. The second method of formation of MIPs involves covalently linking the imprint molecule to the monomer. After polymerization, the monomer is cleaved from the template molecule. [2] The selectivity is greatly influenced by the kind and amount of cross-linking agent used in the synthesis of the imprinted polymer. The selectivity is also determined by the covalent and non-covalent interactions between the target molecule and monomer functional groups. The careful choice of functional monomer is another important choice to provide complementary interactions with the template and substrates. [3] In an imprinted polymer, the cross-linker fulfills three major functions: First of all, the cross-linker is important in controlling the morphology of the polymer matrix, whether it is gel-type, macroporous or a microgel powder. Secondly, it serves to stabilize the imprinted binding site. Finally, it imparts mechanical stability to the polymer matrix. From a polymerization point of view, high cross-link ratios are generally preferred in order to access permanently porous materials and in order to be able to generate materials with adequate mechanical stability.

The self-assembly method has advantages in the fact that it forms a more natural binding site, and also offers additional flexibility in the types of monomers that can be polymerized. The covalent method has its advantages in generally offering a high yield of homogeneous binding sites, but first requires the synthesis of a derivatized imprint molecule and may not imitate the "natural" conditions that could be present elsewhere. [4] Over the recent years, interest in the technique of molecular imprinting has increased rapidly, both in the academic community and in the industry. Consequently, significant progress has been made in developing polymerization methods that produce adequate MIP formats with rather good binding properties expecting an enhancement in the performance or in order to suit the desirable final application, such as beads, films or nanoparticles. One of the key issues that have limited the performance of MIPs in practical applications so far is the lack of simple and robust methods to synthesize MIPs in the optimum formats required by the application. Chronologically, the first polymerization method encountered for MIP was based on "bulk" or solution polymerization. This method is the most common technique used by groups working on imprinting especially due to its simplicity and versatility. It is used exclusively with organic solvents mainly with low dielectric constant and consists basically of mixing all the components (template, monomer, solvent and initiator) and subsequently polymerizing them. The resultant polymeric block is then pulverized, freed from the template, crushed and sieved to obtain particles of irregular shape and size between 20 and 50 µm. Depending on the target (template) type and the final application of the MIP, MIPs are appeared in different formats such as nano/micro spherical particles, nanowires and thin film or membranes. They are produced with different polymerization techniques like bulk, precipitation, emulsion, suspension, dispersion, gelation, and multi-step swelling polymerization. Most of investigators in the field of MIP are making MIP with heuristic techniques such as hierarchical imprinting method. The technique for the first time was used for making MIP by Sellergren et al. [5] for imprinting small target molecules. With the same concept, Nematollahzadeh et al. [6] developed a general technique, so-called polymerization packed bed, to obtain hierarchically-structured, high capacity protein imprinted porous polymer beads by using silica porous particles for protein recognition and capture.

Solid-phase synthesis

Solid-phase molecular imprinting has been recently developed as an alternative to traditional bulk imprinting, generating water-soluble nanoparticles. [7] [8] As the name implies, this technique requires the immobilisation of the target molecule on a solid support prior to performing polymerisation. This is analogous to solid-phase synthesis of peptides. The solid phase doubles as an affinity separation matrix, allowing the removal of low-affinity MIPs and overcoming many of the previously described limitations of MIPs:

MIP nanoparticles synthesised via this approach have found applications in various diagnostic assay and sensors. [9] [10] [11]

Molecular modelling

Molecular modelling has become a convenient choice in MIP design and analysis, allowing rapid selection of monomers and optimization of polymer composition, with a range of different techniques being applied. [12] [13] The application of molecular modelling in this capacity is commonly attributed to Sergey Pletsky and his visiting diploma student Sreenath Subrahmanyam, who developed a method of automated screening of a large database of monomers against a given target or template with a molecular mechanics approach [14] [15] . [16] In recent years technological advances have permitted more efficient analysis of monomer-template interactions by quantum mechanical molecular modelling, providing more precise calculations of binding energies. [17] Molecular dynamics has also been applied for more detailed analysis of systems before polymerisation, [18] [19] and of the resulting polymer, [20] which by including more system components (initiator, cross-linkers, solvents) provides greater accuracy in predicting successful MIP synthesis than monomer-template interactions alone. [21] [22] Molecular modelling, particular molecular dynamics and the less common coarse-grained techniques, [23] can often also be integrated into greater theoretical models permitting thermodynamic analysis and kinetic data for mesoscopic analysis of imprinted polymer bulk monoliths and MIP nanoparticles. [24] [25]

Applications

Niche areas for application of MIPs are in sensors and separation. Despite the current good health of molecular imprinting in general, one difficulty which appears to remain to this day is the commercialization of molecularly imprinted polymers. Despite this, many patents (1035 patents, up to October 2018, according to the Scifinder data base) on molecular imprinting were held by different groups.

Fast and cost-effective molecularly imprinted polymer technique has applications in many fields of chemistry, biology and engineering, particularly as an affinity material for sensors, [26] detection of chemical, antimicrobial, and dye, residues in food, adsorbents for solid phase extraction, binding assays, artificial antibodies, chromatographic stationary phase, catalysis, drug development and screening, and byproduct removal in chemical reaction. [27] Molecular imprinted polymers pose this wide range of capabilities in extraction through highly specific micro-cavity binding sites. [28] [29] Due to the specific binding site created in a MIP this technique is showing promise in analytical chemistry as a useful method for solid phase extraction. [30] The capability for MIPs to be a cheaper easier production of antibody/enzyme like binding sites doubles the use of this technique as a valuable breakthrough in medical research and application. [31] Such possible medical applications include "controlled release drugs, drug monitoring devices, and biological receptor mimetics". [32] Beyond this MIPs show a promising future in the developing knowledge and application in food sciences. [33] [34]

The binding activity of MIPs can be lower compared than that of specific antibodies, even though examples have been reported of MIPs with comparable or better performance to commercially produced antibodies. [35] [36] This yields a wide variety of applications for MIPs from efficient extraction to pharmaceutical/medical uses. [30] [32] MIPs offer many advantages over protein binding sites. Proteins are difficult and expensive to purify, denature (pH, heat, proteolysis), and are difficult to immobilize for reuse. Synthetic polymers are cheap, easy to synthesize, and allow for elaborate, synthetic side chains to be incorporated. Unique side chains allow for higher affinity, selectivity, and specificity.

Molecularly imprinted assays Molecularly imprinted polymers arguably demonstrate their greatest potential as alternative affinity reagents for use in diagnostic applications, due to their comparable (and in some regards superior) performance to antibodies. Many studies have therefore focused on the development of molecularly imprinted assays (MIAs) since the seminal work by Vlatakis et al. in 1993, where the term “molecularly imprinted [sorbet] assay” was first introduced. Initial work on ligand binding assays utilising MIPs in place of antibodies consisted of radio-labelled MIAs, however the field has now evolved to include numerous assay formats such as fluorescence MIAs, enzyme-linked MIAs, and molecularly imprinted nanoparticle assay (MINA). [37]

Molecularly imprinted polymers have also been used to enrich low abundant phosphopeptides from a cell lysate, [38] outperforming titanium dioxide (TiO2) enrichment- a gold standard to enrich phosphopeptides.

History

In a paper published in 1931, [39] Polyakov reported the effects of presence of different solvents (benzene, toluene and xylene) on the silica pore structure during drying a newly prepared silica. When H2SO4 was used as the polymerization initiator (acidifying agent), a positive correlation was found between surface areas, e.g. load capacities, and the molecular weights of the respective solvents. Later on, in 1949 Dickey reported the polymerization of sodium silicate in the presence of four different dyes (namely methyl, ethyl, n-propyl and n-butyl orange). The dyes were subsequently removed, and in rebinding experiments it was found that silica prepared in the presence of any of these "pattern molecules" would bind the pattern molecule in preference to the other three dyes. Shortly after this work had appeared, several research groups pursued the preparation of specific adsorbents using Dickey's method. Some commercial interest was also shown by the fact that Merck patented a nicotine filter, [40] consisting of nicotine imprinted silica, able to adsorb 10.7% more nicotine than non-imprinted silica. The material was intended for use in cigarettes, cigars and pipes filters. Shortly after this work appeared, molecular imprinting attracted wide interest from the scientific community as reflected in the 4000 original papers published in the field during for the period 1931–2009 (from Scifinder). However, although interest in the technique is new, commonly the molecularly imprinted technique has been shown to be effective when targeting small molecules of molecular weight <1000. [41] Therefore, in following subsection molecularly imprinted polymers are reviewed into two categories, for small and big templates.

Production limitations

Production of novel MIPs has implicit challenges unique to this field. These challenges arise chiefly from the fact that all substrates are different and thus require different monomer and cross-linker combinations to adequately form imprinted polymers for that substrate. The first, and lesser, challenge arises from choosing those monomers which will yield adequate binding sites complementary to the functional groups of the substrate molecule. For example, it would be unwise to choose completely hydrophobic monomers to be imprinted with a highly hydrophilic substrate. These considerations need to be taken into account before any new MIP is created. Molecular modelling can be used to predict favourable interactions between templates and monomers, allowing intelligent monomer selection.

Secondly, and more troublesome, the yield of properly created MIPs is limited by the capacity to effectively wash the substrate from the MIP once the polymer has been formed around it. [42] In creating new MIPs, a compromise must be created between full removal of the original template and damaging of the substrate binding cavity. Such damage is generally caused by strong removal methods and includes collapsing of the cavity, distorting the binding points, incomplete removal of the template and rupture of the cavity.

Challenges of Template Removal for Molecular Imprinted Polymers Challenges of Template Removal for Molecular Imprinted Polymers.png
Challenges of Template Removal for Molecular Imprinted Polymers

Template removal

Most of the developments in MIP production during the last decade have come in the form of new polymerization techniques in an attempt to control the arrangement of monomers and therefore the polymers structure. However, there have been very few advances in the efficient removal of the template from the MIP once it has been polymerized. Due to this neglect, the process of template removal is now the least cost efficient and most time-consuming process in MIP production. [43] Furthermore, in order of MIPs to reach their full potential in analytical and biotechnological applications, an efficient removal process must be demonstrated.

There are several different methods of extraction which are currently being used for template removal. These have been grouped into 3 main categories: Solvent extraction, physically assisted extraction, and subcritical or supercritical solvent extraction.

Solvent extraction

Physically-assisted extraction

Subcritical or supercritical solvent extraction

See also

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent called the mobile phase, which carries it through a system on which a material called the stationary phase is fixed. Because the different constituents of the mixture tend to have different affinities for the stationary phase and are retained for different lengths of time depending on their interactions with its surface sites, the constituents travel at different apparent velocities in the mobile fluid, causing them to separate. The separation is based on the differential partitioning between the mobile and the stationary phases. Subtle differences in a compound's partition coefficient result in differential retention on the stationary phase and thus affect the separation.

<span class="mw-page-title-main">ELISA</span> Method to detect an antigen using an antibody and enzyme

The enzyme-linked immunosorbent assay (ELISA) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence of a ligand in a liquid sample using antibodies directed against the protein to be measured. ELISA has been used as a diagnostic tool in medicine, plant pathology, and biotechnology, as well as a quality control check in various industries.

A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physicochemical detector. The sensitive biological element, e.g. tissue, microorganisms, organelles, cell receptors, enzymes, antibodies, nucleic acids, etc., is a biologically derived material or biomimetic component that interacts with, binds with, or recognizes the analyte under study. The biologically sensitive elements can also be created by biological engineering. The transducer or the detector element, which transforms one signal into another one, works in a physicochemical way: optical, piezoelectric, electrochemical, electrochemiluminescence etc., resulting from the interaction of the analyte with the biological element, to easily measure and quantify. The biosensor reader device connects with the associated electronics or signal processors that are primarily responsible for the display of the results in a user-friendly way. This sometimes accounts for the most expensive part of the sensor device, however it is possible to generate a user friendly display that includes transducer and sensitive element. The readers are usually custom-designed and manufactured to suit the different working principles of biosensors.

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<span class="mw-page-title-main">Copolymer</span> Polymer derived from more than one species of monomer

In polymer chemistry, a copolymer is a polymer derived from more than one species of monomer. The polymerization of monomers into copolymers is called copolymerization. Copolymers obtained from the copolymerization of two monomer species are sometimes called bipolymers. Those obtained from three and four monomers are called terpolymers and quaterpolymers, respectively. Copolymers can be characterized by a variety of techniques such as NMR spectroscopy and size-exclusion chromatography to determine the molecular size, weight, properties, and composition of the material.

Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, electrostatic charge, or hydrogen bonding to strong covalent bonding, provided that the electronic coupling strength remains small relative to the energy parameters of the component. While traditional chemistry concentrates on the covalent bond, supramolecular chemistry examines the weaker and reversible non-covalent interactions between molecules. These forces include hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi–pi interactions and electrostatic effects.

<span class="mw-page-title-main">Molecular recognition</span> Type of non-covalent bonding

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A protein microarray is a high-throughput method used to track the interactions and activities of proteins, and to determine their function, and determining function on a large scale. Its main advantage lies in the fact that large numbers of proteins can be tracked in parallel. The chip consists of a support surface such as a glass slide, nitrocellulose membrane, bead, or microtitre plate, to which an array of capture proteins is bound. Probe molecules, typically labeled with a fluorescent dye, are added to the array. Any reaction between the probe and the immobilised protein emits a fluorescent signal that is read by a laser scanner. Protein microarrays are rapid, automated, economical, and highly sensitive, consuming small quantities of samples and reagents. The concept and methodology of protein microarrays was first introduced and illustrated in antibody microarrays in 1983 in a scientific publication and a series of patents. The high-throughput technology behind the protein microarray was relatively easy to develop since it is based on the technology developed for DNA microarrays, which have become the most widely used microarrays.

<span class="mw-page-title-main">End group</span> Functional group at the extremity of an oligomer or other macromolecule

End groups are an important aspect of polymer synthesis and characterization. In polymer chemistry, they are functional groups that are at the very ends of a macromolecule or oligomer (IUPAC). In polymer synthesis, like condensation polymerization and free-radical types of polymerization, end-groups are commonly used and can be analyzed by nuclear magnetic resonance (NMR) to determine the average length of the polymer. Other methods for characterization of polymers where end-groups are used are mass spectrometry and vibrational spectrometry, like infrared and raman spectroscopy. These groups are important for the analysis of polymers and for grafting to and from a polymer chain to create a new copolymer. One example of an end group is in the polymer poly(ethylene glycol) diacrylate where the end-groups are circled.

<span class="mw-page-title-main">Molecular imprinting</span> Technique in polymer chemistry

Molecular imprinting is a technique to create template-shaped cavities in polymer matrices with predetermined selectivity and high affinity. This technique is based on the system used by enzymes for substrate recognition, which is called the "lock and key" model. The active binding site of an enzyme has a shape specific to a substrate. Substrates with a complementary shape to the binding site selectively bind to the enzyme; alternative shapes that do not fit the binding site are not recognized.

<span class="mw-page-title-main">Aptamer</span> Oligonucleotide or peptide molecules that bind specific targets

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<span class="mw-page-title-main">Acrydite</span>

Acrydite is a phosphoramidite that allows the synthesis of oligonucleotides with a methacryl group at the 5' end. Acryl oligonucleotides have been tested, but the acryl group is not stable to storage. Acrydite-modified oligonucleotides can react with nucleophiles such as thiols, this forms the basis of the ez-rays chemistry which was used for microarrays. More importantly, Acrydite-modified oligonucleotides can be incorporated, stoichiometrically, into hydrogels such as polyacrylamide, using standard free radical polymerization chemistry, where the double bond in the Acrydite group reacts with other activated double bond containing compounds such as acrylamide.

<span class="mw-page-title-main">Meir Wilchek</span> Israeli biochemist (born 1935)

Meir Wilchek is an Israeli biochemist. He is a professor at the Weizmann Institute of Science.

<span class="mw-page-title-main">Janus particles</span> Type of nanoparticle or microparticle

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<span class="mw-page-title-main">Affinity electrophoresis</span>

Affinity electrophoresis is a general name for many analytical methods used in biochemistry and biotechnology. Both qualitative and quantitative information may be obtained through affinity electrophoresis. Cross electrophoresis, the first affinity electrophoresis method, was created by Nakamura et al. Enzyme-substrate complexes have been detected using cross electrophoresis. The methods include the so-called electrophoretic mobility shift assay, charge shift electrophoresis and affinity capillary electrophoresis. The methods are based on changes in the electrophoretic pattern of molecules through biospecific interaction or complex formation. The interaction or binding of a molecule, charged or uncharged, will normally change the electrophoretic properties of a molecule. Membrane proteins may be identified by a shift in mobility induced by a charged detergent. Nucleic acids or nucleic acid fragments may be characterized by their affinity to other molecules. The methods have been used for estimation of binding constants, as for instance in lectin affinity electrophoresis or characterization of molecules with specific features like glycan content or ligand binding. For enzymes and other ligand-binding proteins, one-dimensional electrophoresis similar to counter electrophoresis or to "rocket immunoelectrophoresis", affinity electrophoresis may be used as an alternative quantification of the protein. Some of the methods are similar to affinity chromatography by use of immobilized ligands.

Mass spectrometric immunoassay (MSIA) is a rapid method is used to detect and/ or quantify antigens and or antibody analytes. This method uses an analyte affinity isolation to extract targeted molecules and internal standards from biological fluid in preparation for matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). This method allows for "top down" and "bottom up" analysis. This sensitive method allows for a new and improved process for detecting multiple antigens and antibodies in a single assay. This assay is also capable of distinguishing mass shifted forms of the same molecule via a panantibody, as well as distinguish point mutations in proteins. Each specific form is detected uniquely based on their characteristic molecular mass. MSIA has dual specificity because of the antibody-antigen reaction coupled with the power of a mass spectrometer.

A ligand binding assay (LBA) is an assay, or an analytic procedure, which relies on the binding of ligand molecules to receptors, antibodies or other macromolecules. A detection method is used to determine the presence and extent of the ligand-receptor complexes formed, and this is usually determined electrochemically or through a fluorescence detection method. This type of analytic test can be used to test for the presence of target molecules in a sample that are known to bind to the receptor.

<span class="mw-page-title-main">Sergey Piletsky</span> Professor of bio analytical chemistry

Sergey Piletsky is a professor of Bioanalytical Chemistry and the Research Director for School of Chemistry, University of Leicester, United Kingdom.

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