Molecular imprinting

Synthesis of molecular imprinting polymers for extraction of gallic acid from urine
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A microfluidic chip integrated with molecular imprinting polymer for surface plasmon resonance detection Abstract: This paper reports a microfluidic chip integrated with molecular imprinting polymers MIP for surface plasmon resonance SPR detection of specific label-free bio-samples. With the help of SPR sensing techniques, the microfluidic biochips have the potential to be widely used for bio-sensing applications.

While compared to other sensing techniques, the developed system has several advantages, including labeling-free, high sensitivity, capability of quantitative analysis of nano-scale bio-molecules in real-time fashion. They also have shown that the anion in the copper salt participates in the recognition process and in the complex formation [ 27 ]. Even though Cu II forms the most stable coordination compounds with ligands bearing N-donor atoms, the best imprinting efficiency is achieved in the case of Co II , as evidenced in multiple studies that compared the imprinting performances of multiple metal ions [ 15 , 18 , 21 ].

The Co II -mediated MIPs emerge also in other two studies [ 21 , 22 ] in which ketoprofen and ketoprofen with naproxen, respectively were used as templates. The binding affinity of Ni II to the N containing ligands especially aminoacids containing compounds was employed in creating imprinted polyacrylamides as artificial receptors for different peptides cholecystokinin C-terminal pentapeptide CCK-5 [ 35 ] and His-Alac [ 36 ]. The functional monomer nitrilotriacetic acid occupies four positions in the octahedral coordination sphere of Ni II , leaving the remaining two for selective interactions with the template.

The same mole ratio , methacryloyl-l-cysteine methyl ester functional monomer :Fe III :template uric acid was found in the coordination compound used for the surface plasmon resonance SPR detection of uric acid [ 39 ]. Metal—template binding should be stable under polymerization conditions yet labile enough to allow removal of substrates-templates.

With few exceptions, [ 41 ] the design of MIPs for the selective recognition of amino acids and peptides has been limited to the traditional imprinting strategy, which employs polyacrylates with MAA as the functional monomer in organic solvents. Bulkier templates, such as macromolecules especially proteins are not compatible with the organic media because of their low solubility and tendency toward denaturation, thus using water as solvent is essential.

However, polar solvents will interfere in template-monomer hydrogen bonding, therefore metal-coordination interactions represent an effective alternative in imprinting biological-relevant compounds. The affinity of N-terminal histidine for Ni II allowed the creation of MIP receptors for peptides with exposed histidine residues [ 36 ].

It was shown that the metal ion works not just as a link between the monomer and template, it also influences the steric environment around the metal ion during polymerization step. The superior performance of metal-ion mediated imprinting compared with the metal-free approach, was demonstrated for CCK-5 [ 35 ]. Using Cu II chelation strategy, the cytochrome c was successfully imprinted into a supermacroporous cryogel, which was employed for template separation from a mixture of proteins cytochrome c, lysozyme, and BSA. Protein imprinting is still a challenging task mainly because of their huge molecular size and conformational flexibility and complexity, which makes template removal and the subsequent protein rebinding onto imprinted sites very difficult.

One alternative to the protein bulk imprinting is the metal-ion mediated surface imprinting in which the specific recognition sites are located at the surface of MIP. Porcine serum albumin was imprinted on the surface of silica microparticles via a metal chelating strategy in phosphate buffer [ 32 ]. Satisfactory selectivity was obtained using three competitive proteins: cytochrome c, ribonuclease B and myoglobin.

Another metal-ion imprinted thin polymeric film was synthesized on the surface of cellulose nanofibers for the selective recognition and purification of hemoglobin from hemolysate [ 33 ]. Metal chelating approach was employed for the chiral discrimination of different amino acids, like phenylalanine, tyrosine, alanine, valine, leucine, isoleucine [ 29 ], and Boc-L-Phe-OH [ 25 ] and other compounds mandelic acid [ 15 ].

The MIPs prepared with aliphatic amino acids showed no or little enantioselectivity. Amino acids containing aromatic or heterocyclic groups yielded MIPs with good chiral discriminative properties. According to the three-point interaction model, these bulky groups are responsible for the third necessary interaction with the polymer matrix, sterically hindering the opposite enantiomer. Regarding the smaller and simpler no multiple functional groups molecules, non-covalent imprinting is more difficult because of the smaller number of possible interactions between the template and functional monomer, especially in aqueous media.

It is the case of formate, acetate and propionate anions, which showed no imprinting effect using 4-VPy as functional monomer. However, if these anions are part of a ternary complex with picolinamide as ligand and Cu II ion as mediator during the polymerization process as well as during the rebinding step , their indirect analysis is possible [ 28 ]. Metal ion mediated approach may be an alternative for compounds with strong intramolecular hydrogen bonds that can interfere in the formation of template-monomer intermolecular hydrogen bonds, thus inhibiting the MI effect. For example, picolinamide cannot be imprinted through the noncovalent approach, but if it is included in a ternary Cu II complex with 4-VPy both as ligand and monomer , the imprinted polymer showed a high molecular recognition ability [ 27 ]. Metal ion-mediated imprinting was also used to prepare different MIPs for the specific recognition of multiple drugs with high metal chelating capability: tetracyclines [ 37 , 38 ], quinolones [ 37 ], ketoprofen [ 21 ], furosemide [ 40 ], and naproxen [ 26 ]. Two pharmaceutical compounds, naproxen, and ketoprofen were simultaneously imprinted using metal chelating strategy without loss of selectivity and it was found to give better results versus traditional MIPs [ 22 ].

Because of the stronger coordination binding compared with noncovalent imprinting, metal ion mediated imprinted polymers can be successfully used as selective sorbents for the concentration and the clean-up of different pollutants and toxic compounds methylmercury from human hair and soil [ 42 ], organohalide pesticide 4- 2,4-dichlorophenoxy butyric acid 2,4-DB [ 16 ], thiabendazole fungicide in citrus and soil samples [ 31 ]. MIPs were also used as extraction media of active compounds from complicated natural products, using metal coordination interactions.

Quercetin was shown to form coordination compounds with Zn II through 3-hydroxylketone electron donor functionality from its structure [ 43 ].

Molecularly Imprinted Polymers (MIPs)

Epigallocatechin gallate was separated from natural plant extracts employing gallic acid as a dummy template in order to reduce the MIPs manufacturing costs [ 18 ]. The combination of using ionic liquid [Bmim]BF 4 and metal pivoting was employed in imprinting a polar compound, methyl gallate, exhibiting superior recognition abilities than the ion-free polymer [ 24 ]. It is assumed that the ionic liquid improves the imprinting process by limiting the polymer swelling and shrinkage [ 44 ].

A successful metal ion-imprinting process is achieved if the formation of the template-metal ion-functional monomer ternary complex involves strong coordination interactions. Therefore, the choice of the functional monomer is very important. It must interact with the metal ion and template in a particular geometry offering the anchor point for the coordination compound on the polymer backbone.

One approach is to synthesize the metal ion-functional monomer complex before the addition of template, complex that will be incorporated into the polymer matrix and will be preserved after template removal [ 16 , 17 , 29 , 35 , 36 ]. Thus, in the rebinding step, the MIP should be exposed only to the free-form of the template.

However, in the metal-mediated imprinting, the most widely used functional monomer is by far 4-VPy, because of its ability to form strong coordination bonds with a large spectrum of divalent metals. Different metal ionVPy molar ratios have been used, ranging from [ 43 ], [ 19 , 20 , 27 , 28 ], [ 22 ] up to [ 15 , 18 , 23 ]. It appears that with the increasing molar ratio of functional monomer, the IFs are also increasing up to a ratio of An excess of functional monomer is needed in order to stabilize the ternary complex and to achieve good fidelity of the binding sites.

Surprisingly, when 4-VPy was investigated as functional monomer versus acrylamide, and MAA, the best performances were exhibited by acrylamide-imprinted polymer, even though among the three monomers, acrylamide generates the lowest binding energy. Commonly used monomers in MI often possess the ability to universally bond a multitude of metal ions, with variable selectivity.

The series of reviews published throughout the years offer general guidelines and concepts on the development of ion imprinted polymers IIPs synthesis, characterization, types of imprinting, and assessment of analytical performance and various applications selective detection, sample enrichment, recovery, and decontamination of metal ions in the biomedical and environmental fields [ 46 , 47 , 48 , 49 , 50 ].

1. Introduction

In chemistry, molecular imprinting is a technique to create template-shaped cavities in polymer matrices with memory of the template molecules to be used in . Molecular imprinting is the process of generating an impression within a solid.

Herein, several aspects on different materials, natural and synthetic, used in the design of IIPs and the particular features that allow these materials to selectively bind distinct metal ions will be pointed out. The choice of the chelating agent, the complexation mode, the particular geometry of the coordination compound, the charge, and the size of the imprinted metal ions are key factors in determining the selectivity of the resultant imprinted polymer [ 34 , 51 , 52 ].

The inclusion of the metal binding entity in the polymerization matrix can be achieved through four distinct approaches: a crosslinking of linear chain polymers carrying metal-binding groups, b chemical immobilization, c surface imprinting, and d trapping of ligand in the polymeric matrix [ 47 ]. This approach is currently used mainly with natural linear polymers, such as chitosan CTS and cellulose. The uptake of metal occurs mainly by chelation and is most likely to occur inter- or intra-CTS chains via one to four amino groups, with the nitrogen atoms in the amino and N-acetyl amino groups acting as electron donors.

Upon deprotonation, hydroxyl groups may also be involved in metal ion coordination [ 54 ]. The poor selectivity, low stability in acidic solutions, and weak mechanical strength of nonimprinted raw CTS renders it inappropriate as selective metal ion sequestrant; these drawbacks, however, may be addressed by crosslinking and functionalization [ 53 , 54 , 55 ].

Nevertheless, crosslinking may decrease the metal uptake efficiency as, often, the functional groups of CTS involved in metal binding are also involved in the crosslinking reaction. The reactive amine and hydroxyl groups most likely to be involved in metal chelation are protected by ion imprinting prior to crosslinking [ 56 , 57 ]. The commonly used crosslinkers include, but are not limited to, aldehydes formaldehyde, glutaraldehyde, and glyoxal , heterocyclic compounds [epichlorohydrin ECH ], and ethers [crown ethers, ethylene glycol diglycidyl ether EGDE ].

Chemical immobilization, trapping, and crosslinking of linear chain polymers, prepared mainly by traditional polymerization methods bulk, precipitation, and suspension , present several drawbacks i. Surface imprinting addresses these issues by generating binding cavities at the surface of the imprinted polymer. A thin imprinted layer is immobilized on the surface of fibers or small sized particles of organic or inorganic nature [ 48 ].

A polypropylene membrane was used as support for a Pb II imprinted composite material in a process that implied grafting polymerization of AA on the polypropylene membrane and subsequent covalent immobilization of CTS [ 68 ]. Surface-imprinting modification of magnetic particles such as TiO 2 and Fe 2 O 3 is particularly appealing since the post processing of solid-phase extraction is reduced to a simple magnetic separation. Modified silica gel particles are extensively used as support for the imprinted layer because of their mechanical and chemical stability, low cost, and ease of preparation and functionalization through the silanol groups.

Pb II imprinted silica sorbents were designed using a tetradentate chelating silylating agent derived from 3-[2- 2-aminoethylamino ethylamino]propyltrimethoxysilane and 2-pyridinecarboxaldehyde [ 70 ] or a N,N-bidentate group in the structure of the functional monomer 4- di 1H—pyrazolyl methyl phenol [ 71 ]. The chemical immobilization technique employs bifunctional ligands that possess both polymerizable functional group i. Currently, the technique is a one-step process that implies mixing together the metal ion, the bifunctional monomer and the crosslinker prior to co-polymerization.

Common monomers such as 4-VPy, 1-vinylimidazole, AA or acrylamide may serve for chemical immobilization, but they show low binding capacities and low selectivity. Considering however that the use of simple, commercially available monomers results in materials with generally low binding capacity and selectivity, new tailored bifunctional ligands, bearing both chelating functionalities and polymerizable groups, have been proposed. Benzocrownacrylamide, 4-vinylbenzocrown-6, and 2- allyoxy methylcrown-4 have been successfully employed for the imprinting of K I , [ 78 ] Pb II [ 79 ] and Li I ions [ 80 , 81 ].

Amino acids or amino acid derivatives bearing vinylated groups, e. N-methacryloyl- L -histidine , [ 83 , 84 ] vinylated SALEN, [ 85 ] [N- 4-vinybenzyl imino]diacetic acid, [ 34 ] are other examples of bifunctional ligands that have been reported for the chelation of various metal ions and subsequent copolymerization with a suitable crosslinking agent.

The Emerging Technique of Molecular Imprinting and Its Future Impact on Biotechnology

Chemical immobilization shows the advantage of ligands not being leached out during the elution of the template. The magnitude of the imprinting effect is however rather low; this adds up to the difficulty of the vinylation procedure [ 47 ]. The stability of the binding sites depends upon the correct immobilization of the ligand in the polymeric matrix and the presence and the integrity of the ligand during and after the template removal [ 47 , 48 ].

The imprinted polymer was synthesized by co-polymerization of a coordination compound between Dy III , 5,7-dichloroquinolineol and 4-VPy, in the presence of divinylbenzene DVB as crosslinker [ 87 ]. The entrapped species may be a metal ion:ligand binary complex, as in the case of Zn II hydroxyquinoline 1,2 and Alhydroxyquinoline 1,3 coordination compounds embedded in the polymeric matrix formed by MAA and DVB [ 88 ]. In most cases, however, a ternary metal complex is formed, the metal ion being coordinated by both the ligand ensuring selectivity and the functional monomer e.

The ternary complex can be prepared in situ, just before the polymerization step or synthesized, isolated and characterized before being introduced in the polymerization. Comparative studies on the efficiency of polymers prepared with such ternary complexes vs. Alizadeh used 4-VPy as functional monomer and quinaldic acid as complexing agent to imprint Cd II and employed experimental design to study various binary and ternary mixtures [ 89 ].

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IPs prepared from binary complexes were found to be less efficient than those prepared with ternary complexes. Crown ethers and derivatives with cavities of appropriate size were trapped in the polymer network by using suitable functional monomers and crosslinking agents and the polymer imprinted with alkali metals ions. Dicyclohexylcrown-6, [ 90 ] dibenzocrown-7, [ 91 ] dibenzocrown-8 ether [ 92 ] and the aza-thioether crown containing a 1,phennathroline subunit 5-azamethyl-2,8-dithia [ 9 ], 2,9 -1,phenanthrolinophane , [ 93 ] were used by Shamsipur and coll.

As compared to chemical immobilization, the trapping approach is easier to implement. The stability of the binding sites created via the trapping approach, however, depends upon the correct immobilization of the ligand in the polymeric matrix and the presence and the integrity of the ligand during and after the removal of template [ 48 ]. Polymers have played an integral role in the advancement of drug delivery systems DDS through the last three decades, improving safety, efficacy, and patient compliance during long-term medication therapy by providing sustained release of both hydrophilic and hydrophobic therapeutic agents [ 98 ].

MIPs used as excipients of solid pharmaceutical dosage forms have been tested for tuning drug release profiles and eventually protect their load from enzymatic degradation while being freight through the body, nevertheless the inherent feature of these polymers, their selectivity, has not been put to a proper use. Therefore, efforts have been made to integrate MIPs in therapeutic systems for intelligent drug release or as targeting drug vectors [ 99 ]. These tailor-made IPs would be therapeutically advantageous for several reasons as they can act as molecular trap sequestrant systems, [ ] as reservoir for prolonged release of a particular drug, they can enable an increased loading capacity of the therapeutic formulation, facilitate environmentally or physiologically responsive intelligent release of the therapeutic agent [ ] and if required, they can confer an enantioselective load or release [ , ].

Using conventional drug formulations, repeated administration would help in building up the required therapeutic levels of the drug in various biological compartments blood, tissues, urine, etc. In the initial and most simple approaches the payload of biologically active molecule was non-covalently bound hydrogen bonding, hydrophobic interactions, charge transfer, or van der Waals forces to the imprinted polymer network [ ]. Nevertheless, the overall controllability and reliability of DDS based on noncovalent binding might not be ideal in a living organism.

Therefore, as an alternative, metal ion-mediated coordinate bonds between the functional monomer and the targeted drug molecule template has been investigated offering higher specificity and strength, as well as spatial directionality in comparison with noncovalent bonding.

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Additionally, metal coordination bonds are more compatible with the polar environment of living tissues and they can be easily manipulated through changes of the local hydrogen ion concentration, a feature extremely helpful in the development of pH-responsive delivery systems. Furthermore, MIPs prepared by noncovalent imprinting methods usually require using organic solvents, which eventually leave toxic traces, incompatible with biomedical applications.

Some of the imprinted polymers employed nowadays in intelligent DD [i. Various aspects about the encountered recognition and drug release mechanisms, optimization of the drug loading capacity, latest trends in various routes of DD, as well as limitations and future prospects of such molecularly imprinted DDS may be found in different reviews [ 99 , , , ].

A wide range of biocompatible semi-synthetic and synthetic polymers have been tested as suitable imprinted frameworks for DD. PHEMA and its derivatives or nanocomposites continues to be one of the most widely used biomaterials due to their low toxicity, excellent and long-term biocompatibility including hemocompatibility and high resistance to degradation [ , ].