Molecularly imprinted polymer based enantioselective sensing devices: a review.

Chiral recognition is the fundamental property of many biological molecules and is a quite important field in pharmaceutical analysis because of the pharmacologically different activities of enantiomers in living systems. Enantio-differentiating signal of the sensor requires specific interaction between the chiral compounds (one or a mixture of enantiomers) in question and the selector. This type of interaction is controlled normally by at least three binding centers, whose mutual arrangement and interacting characteristics with one of the enantiomers effectively control the selectivity of recognition. Molecular imprinting technology provides a unique opportunity for the creation of three-dimensional cavities with tailored recognition properties. Over the past decade, this field has expanded considerably across the variety of disciplines, leading to novel transduction approaches and many potential applications. The state-of-art of molecularly imprinted polymer-based chiral recognition might set an exotic trend toward the development of chiral sensors. The objective of this review is to provide comprehensive knowledge and information to all researchers who are interested in exploiting molecular imprinting technology toward the rational design of chiral sensors operating on different transduction principles, ranging from electrochemical to piezoelectric, being used for the detection of chiral compounds as they pose significant impact on the understanding of the origin of life and all processes that occur in living organisms.

Doubly imprinted polymer nanofilm-modified electrochemical sensor for ultra-trace simultaneous analysis of glyphosate and glufosinate.

A rapid, selective, and sensitive double-template imprinted polymer nanofilm-modified pencil graphite electrode was fabricated for the simultaneous analysis of phosphorus-containing amino acid-type herbicides (glyphosate and glufosinate) in soil and human serum samples. Since both herbicides respond overlapped oxidation peaks and only glyphosate is prone to nitrosation, n-nitroso glyphosate and glufosinate were used as templates for obtaining the well-resolved quantitative differential pulse anodic stripping voltammetric peaks on the proposed sensor. Toward sensor fabrication, a nano-structured polymer film was first grown directly on the electrode via initial immobilization of gold nanoparticles at its surface. This was followed by linking of monomeric (N-methacryloyl-l-cysteine) molecules through S-Au bonds. Subsequently, these molecules were subjected to free radical polymerization, in the presence of templates, cross linker, initiator, and multiwalled carbon nanotubes as pre-polymer mixture. The modified sensor observed wide linear ranges (3.98-176.23 ng mL(-1) and 0.54-3.96 ng mL(-1)) of simultaneous analysis with detection limits as low as 0.35 and 0.19 ng mL(-1) (S/N=3) for glyphosate and glufosinate, respectively, in aqueous samples. The respective oxidation peak potentials of both analytes were found to be substantially apart by 265 mV. This enabled the simultaneous determination of one target in the presence of other, without any cross reactivity, interferences, and false-positives, in real samples.

An insulin monitoring device based on hyphenation between molecularly imprinted micro-solid phase extraction and complementary molecularly imprinted polymer-sensor.

Molecularly imprinted micro-solid phase extraction fiber was developed by modifying molecularly imprinted polymer film on the surface of silica fiber exploring "grafting via surface attached monomer" (method I) and "grafting via sol-gel" (method II) approaches. The latter approach was found to be inferior to the former one in terms of the sensitivity of insulin detection [method I, LOD=0.009ngmL(-1); method II, LOD=0.064ngmL(-1), RSD=1.21%]. Notably, either of the techniques, molecularly imprinted micro-solid phase extraction or complementary sensor, was found to be incompetent to monitor the stringent level of insulin in the real samples. However, the combination of these techniques has been found quite suitable for achieving the high detection sensitivity of ultra-trace insulin in human blood serum and Huminsulin injection, without any non-specific (false-positives) contributions. The proposed hyphenated device could serve as a possible marker for risk of developing type 2 diabetes mellitus and diabetic coma due to insulin resistance in human beings.

Molecularly imprinted micro solid-phase extraction technique coupled with complementary molecularly imprinted polymer-sensor for ultra trace analysis of epinephrine in real samples.

A simple hyphenation approach was adopted to obtain a new molecularly imprinted micro solid-phase extraction fiber (as a selective extraction tool) and complementary molecularly imprinted polymer coated pencil graphite electrode (as a detection tool) for the selective and sensitive analysis of epinephrine, which is a disease biomarker prevalent at ultra trace level in biological fluids. In both extraction and detection processes, the functionalized multiwalled carbon nanotubes (CNT-mers) were preferred to multiwalled carbon nanotubes (unmodified) in order to obtain a stable homogeneously dispersed imprinted polymer matrix of better electroconductivity and adsorptive characteristics. The hyphenation of both tools helped dual pre-concentration of epinephrine so as to achieve the stringent limit [limit of detection: 0.002 ng mL(-1), S/N=3] of clinical detection, without any problems of non-specific contributions and cross-reactivity.

Molecularly imprinted polymer-matrix nanocomposite for enantioselective electrochemical sensing of D- and L-aspartic acid.

A new molecularly imprinted polymer-matrix (titanium dioxide nanoparticle/multiwalled carbon nanotubes) nanocomposite was developed for the modification of pencil graphite electrode as an enantioselective sensing probe for aspartic acid isomers, prevalent at ultra trace level in aqueous and real samples. The nanocomposite having many shape complementary cavities was synthesized adopting surface initiated-activators regenerated by electron transfer for atom transfer radical polymerization. The proposed sensor has high stability, nanocomposite uniformity, good reproducibility, and enhanced electrocatalytic activity to respond oxidative peak current of L-aspartic acid quantitatively by differential pulse anodic stripping voltammetry, without any cross-reactivity in real samples. Under the optimized operating conditions, the L-aspartic acid imprinted modified electrode showed a wide linear response for L-aspartic acid within the concentration range 9.98-532.72 ng mL(-1), with the minimum detection limit of 1.73-1.79 ng mL(-1) (S/N=3) in aqueous and real samples. Almost similar stringent limit (1.79 ng mL(-1)) was obtained with cerebrospinal fluid which is typical for the primitive diagnosis of neurological disorders, caused by an acute depletion of L-aspartic acid biomarker, in clinical settings.

A dual-template imprinted polymer-modified carbon ceramic electrode for ultra trace simultaneous analysis of ascorbic acid and dopamine.

A dual-template imprinted polymer film containing dispersed multiwalled carbon nanotubes was exploited in the fabrication of a typical, reproducible, and rugged carbon ceramic electrode, adopting "surface grafting from" approach for the growth of a nanometer thin coating on its surface. For this, chloro groups were first introduced at the exterior surface of silica-carbon composite electrode through sol-gel modification using (3-chloropropyl)-trimethoxysilane, followed by an iniferter (sodium diethyl dithiocarbamate) initiated photopolymerization of functional monomer (2,4,6-trisacrylamido-1,3,5-triazine), mixed templates (ascorbic acid and dopamine), and cross-linker (ethylene glycol dimethacrylate), in the presence of multiwalled carbon nanotubes. The modified sensor was validated for the simultaneous analysis of ascorbic acid and dopamine in aqueous, blood serum, cerebrospinal fluid, and pharmaceutical samples, using differential pulse anodic stripping voltammetric technique. The oxidation peak potentials for both analytes were found to be well apart approximately by 300 mV, which was large enough to allow selective and sensitive analysis of one in the presence of other, without any cross reactivity, interferences and false-positives. The detection limits realized by the proposed sensor, under optimized conditions, were found to be as low as 2.24 ng mL(-1) for ascorbic acid and 0.21 ng mL(-1) for dopamine (S/N=3). Such stringent limits could be considered suitable for the primitive diagnosis of several chronic diseases, in clinical settings.

Quantum dots-multiwalled carbon nanotubes nanoconjugate-modified pencil graphite electrode for ultratrace analysis of hemoglobin in dilute human blood samples.

A novel molecularly imprinted polymer, selective for human hemoglobin, was immobilized on the surface of CdS quantum dots-multiwalled carbon nanotubes nanoconjugate-modified pencil graphite electrode. The fabricated sensor was found to be water-compatible and biologically benign, since the molecular imprinting was exclusively carried out in water, without any protein denaturation and electrode fouling. Notably, the pencil graphite electrode modified with merely a nanoconjugate matrix might involve the onset possibilities of electrode passivation and protein denaturation. However, a polymer coating onto the nanoconjugate obviated such obstacle while evaluating human hemoglobin in an aqueous environment (pH 4.2). The quantification of the hemoglobin in the dilute whole blood samples varied in the linear range 27.8-444.0 ng mL(-1); and the detection limit was obtained as 6.73 ng mL(-1) (S/N=3), without any cross-reactivity and false-positives. The proposed sensor can be used as a cost effective sensor for hemoglobin, in clinical settings.

Multiwalled carbon nanotubes bearing 'terminal monomeric unit' for the fabrication of epinephrine imprinted polymer-based electrochemical sensor.

Carbon-nanotubes play a pivotal role in molecularly imprinted polymer technology for inculcating conducting property, high surface to volume ratio, and maximum porosity in the film texture. Contrary to the non-covalent heterogeneous dispersion of pure (unmodified) multiwalled carbon nanotubes in the imprinted polymer film, the homogeneous distribution of their functionalized derivative was found more effective to augment the sensitivity of the measurement. This could be made feasible using multiwalled carbon nanotubes bearing terminal monomeric unit (termed as "CNT-mer") for the polymerization (one CNT-mer in each repeating unit). In this work, the CNT-mer entails a N-hydroxyphenyl maleimide functionality to be utilized in the chain propagation with simultaneous imprinting of epinephrine in the polymeric network. This system, when casted on the tip of a pencil graphite electrode, responded a highly sensitive and selective response for epinephrine, prevalent in aqueous and real samples at ultratrace level (linear range 0.09-5.90 ng mL(-1), limit of detection 0.02 ng mL(-1), S/N=3), without any cross-reactivity and matrix effects. The proposed sensor is advantageous in obtaining enhanced differential pulse anodic stripping voltammetric current vis-a-vis the corresponding imprinted sensor modified with randomly dispersed flocculated multiwalled carbon nanotubes bundles. While the latter might restrict the interlayer diffusion of analyte in the film, the former sensor facilitated high diffusivity with the channelized electron transport to respond higher current. The CNT-mer dispersed sensor was found to be stable and rugged against mechanical stress and can be used, after regeneration, for more than hundred consecutive experiments in clinical settings.

Highly selective and sensitive analysis of dopamine by molecularly imprinted stir bar sorptive extraction technique coupled with complementary molecularly imprinted polymer sensor.

This paper reports a combination of molecularly imprinted stir bar sorptive extraction and complementary molecularly imprinted polymer-sensor for the analysis of dopamine as a biomarker of several neurodegenerative diseases occurred at ultra trace level. This exploited iniferter initiated polymerization via "surface grafting-from" approach onto magnetic stir bar (for sorptive extraction) and multiwalled carbon nanotubes-ceramic electrode (for detection). Such hyphenation helped dual pre-concentration of dopamine in aqueous, biological and pharmaceutical samples. This enabled high sensitivity to achieve the stringent limit [limit of detection: 4.9ngL(-1), RSD=2.4%, S/N=3, cerebrospinal fluid] of clinical detection, without any problems of non-specific contributions and cross-reactivity.

Highly sensitive and selective hyphenated technique (molecularly imprinted polymer solid-phase microextraction-molecularly imprinted polymer sensor) for ultra trace analysis of aspartic acid enantiomers.

The present work is related to combination of molecularly imprinted solid-phase microextraction and complementary molecularly imprinted polymer-sensor. The molecularly imprinted polymer grafted on titanium dioxide modified silica fiber was used for microextraction, while the same polymer immobilized on multiwalled carbon nanotubes/titanium dioxide modified pencil graphite electrode served as a detection tool. In both cases, the surface initiated polymerization was found to be advantageous to obtain a nanometer thin imprinted film. The modified silica fiber exhibited high adsorption capacity and enantioselective diffusion of aspartic acid isomers into respective molecular cavities. This combination enabled double preconcentrations of d- and l-aspartic acid that helped sensing both isomers in real samples, without any cross-selectivity and matrix complications. Taking into account 6×10(4)-fold dilution of serum and 2×10(3)-fold dilution of cerebrospinal fluid required by the proposed method, the limit of detection for l-aspartic acid is 0.031ngmL(-1). Also, taking into account 50-fold dilution required by the proposed method, the limit of detection for d-aspartic acid is 0.031ngmL(-1) in cerebrospinal fluid.

Electrochemically grown imprinted polybenzidine nanofilm on multiwalled carbon nanotubes anchored pencil graphite fibers for enantioselective micro-solid phase extraction coupled with ultratrace sensing of d- and l-methionine.

An alternative method is presented for the modification of pencil graphite fibers using surface imprinting technology. In this new approach, we have adopted surface initiated electropolymerization of benzidine monomer, with simultaneous imprinting of template (d- and l-methionine), on carboxylated multiwalled carbon nanotubes anchored pencil graphite fiber. This yielded a nanostructured ultrathin imprinted film (58.3nm) uniformly coated all along the perimeter and length of pencil graphite fiber, for micro-solid phase extraction with substantial adsorption capability. The same film is coated over the exposed tip of the pencil graphite fiber to serve as a complementary molecularly imprinted polymer-sensor. Both extraction and sensing devices are not capable to measure the stringent limit (0.016ngmL(-1)) of clinical detection of methylenetetrahydrofolate reductase (MTHFR) gene mutation caused by acute methionine depletion, when used alone. However, on combination of both techniques, a successful enantioselective analysis of d- and l-methionine with excellent analytical figures of merit [limit of quantitation range: 0.03-30.00ngmL(-1), limit of detection: 0.0098ngmL(-1) (RSD=2.04, S/N=3)] could be achieved without any problem of non-specific false-positive contribution and cross-reactivity, in real samples.

Multiwalled carbon nanotubes-ceramic electrode modified with substrate-selective imprinted polymer for ultra-trace detection of bovine serum albumin.

This study describes the synthesis of a new class of substrate-selective molecularly imprinted polymer. This involved tetraethylene glycol 3-morpholin propionate acrylate (functional monomer) and bovine serum albumin (template) for polymerization in aqueous condition, using "surface grafting-from" approach directly on a vinyl exposed multiwalled carbon nanotubes-ceramic electrode. The analyte recapture at pH 6.8 in aqueous environment simultaneously involved hydrophobically driven hydrogen bonds and ionic interactions between negatively charged bovine serum albumin and positively charged imprinted nanofilm. The selectively encapsulated bovine serum albumin first gets reduced at -0.9V and then oxidized within the cavity, without getting stripped off, to respond a differential pulse voltammetry signal. The limit of detection [0.42ng mL(-1) (3σ, RSD≤1.02%)] obtained was free from any cross-reactivity and matrix complications in aqueous, pharmaceutical, serum, and liquid milk samples. The proposed sensor can be used as a practical sensor for ultra-trace analysis of bovine serum albumin in clinical settings.

Metal ion mediated imprinting for electrochemical enantioselective sensing of L-histidine at trace level.

Enantioselective trace level sensing of l-histidine (limit of detection, 1.980 ngm L(-1), S/N=3) was feasible with the use of a typical, reproducible, and rugged complex imprinted polymer-based pencil graphite electrode, in aqueous samples. In the present instance, the Cu(2+) ion-mediated imprinting of l-histidine in an molecularly imprinted polymer motif actually helped upbringing electrocatalytic activity to respond an enhanced differential pulse anodic stripping voltammetric oxidation peak of l-histidine, without any cross-reactivity and false-positive, in real samples. The proposed sensor could be considered suitable for the practical applications in biomarking histedinemia, a disease associated with L-histidine metabolic disorders, in clinical settings.

Enantioselective separation and electrochemical sensing of D- and L-tryptophan at ultratrace level using molecularly imprinted micro-solid phase extraction fiber coupled with complementary molecularly imprinted polymer-fiber sensor.

Highly efficient enantioselective separation and quantitative recoveries of D- and L-tryptophan in aqueous and real samples can be achieved, with a monolithic molecularly imprinted polymeric fiber that serves both for micro-solid phase extraction and ultratrace sensing, without any false-positive (non-specific) contribution and cross-reactivity, in the range of 0.15-30.00 ng mL(-1) with detection limit as low as 0.0261 ng mL(-1) (relative standard deviation=0.64%, signal/noise=3). The proposed method combining molecularly imprinted micro-solid phase extraction fiber and a complementary molecularly imprinted polymer-carbon composite fiber sensor is proven to be useful for clinical diagnosis of stress-related diseases caused by acute tryptophan depletion.

Layer-by-layer assembled molecularly imprinted polymer modified silver electrode for enantioselective detection of D- and L-thyroxine.

The present work describes a new, simple, and easy method for the generation of stable molecularly imprinted sites in polymeric film, combining self-assembled monolayer and Layer-by-layer approaches through thermal cross-linking of the layered structures, onto the surface of silver electrode. Modified silver electrodes demonstrate enantiodifferentiation and sensitive (detection limits 0.0060 ng mL(-1) for L- and 0.0062 for D-thyroxine) determination of d- and l-thyroxine with the help of differential pulse anodic stripping voltammetric technique. The binding kinetics of thyroxine was explored using anodic stripping cyclic voltammetry and chronocoulometry. The sensor was also validated for D- and L-thyroxine determinations in biological and pharmaceutical samples.

Enatioselective quantitative separation of D- and L-thyroxine by molecularly imprinted micro-solid phase extraction silver fiber coupled with complementary molecularly imprinted polymer-sensor.

Thyroxine is a known disease biomarker which demands a highly sensitive and selective technique to measure ultratrace level with enantiodifferentiation of its optical isomers (d- and l-), in real samples. In this work, an approach of hyphenation between molecularly imprinted micro-solid phase extraction and a complementary molecularly imprinted polymer-sensor was adopted for enantioseparation, preconcentration, and analysis of d- and l-thyroxine. In both techniques, the same imprinted polymer, coated on a vinyl functionalized self-assembled monolayer modified silver wire, was used as the respective extraction fiber as well as sensor material. This combination enabled enhanced preconcentration of test analyte substantially so as to achieve the stringent limit [limit of detection: 0.0084 ng mL(-1), RSD=0.81%, S/N=3 (d-thyroxine); 0.0087 ng mL(-1), RSD=0.63%, S/N=3 (l-thyroxine)] of clinical detection of thyroid-related diseases, without any problems of non-specific false-positive contribution and cross-reactivity.

Imprinted polymer-carbon consolidated composite fiber sensor for substrate-selective electrochemical sensing of folic acid.

Molecularly imprinted polymers (MIPs) are often electrically insulating materials. Due to the presence of diffusion barrier(s) in between such MIP coating and electrode surface and the absence of a direct path for the conduction of electrons from the binding sites to the electrode, the development of electrochemical sensor is significantly restricted. The direct use of MIPs those possess intrinsic electron-transport properties, is highly limited. These problems are resolved by the design of an original, substrate-selective MIP-fiber sensor that combines conventional insulating MIP and conducting carbon powder in consolidated phase. A layer of conducting carbon particles, arranged orderly as 'carbon strip', is inducted in the polymer for direct electronic conduction. MIP-carbon composite (monolithic fiber) in this work is prepared via in situ free radical polymerization of a new monomer (2,4,6-trisacrylamido-1,3,5-triazine, TAT) and subsequent cross-linkage with ethylene glycol dimethacrylate, in the presence of carbon powder and template (folic acid), at 55 degrees C in a glass capillary. The detection of folic acid with the MIP-fiber sensor was found to be specific and quantitative (detection limit 0.20 ng mL(-1), RSD=1.3%, S/N=3), in aqueous, blood serum and pharmaceutical samples, without any problem of non-specific false-positive contribution and cross-reactivity.

Enantioselective recognition of D- and L-tryptophan by imprinted polymer-carbon composite fiber sensor.

Electrochemical sensors demonstrating enantioselectivity to tryptophan enantiomers, with high selectivity and sensitivity, were fabricated by the use of a monolithic fiber of molecularly imprinted polymer-carbon composite. The recognition mechanism and performance of these sensors were evaluated by differential pulse anodic stripping voltammetry. The sensor imprinted for l-tryptophan not only discriminated the target from its analogues and other amino acids but also responded specifically in racemic mixture in aqueous, biological, and pharmaceutical samples. The binding kinetics of L-tryptophan was also established with the help of anodic stripping cyclic voltammetry and chronocoulometry. The detection limit for L-tryptophan was as low as 0.24 ng mL(-1) (signal/noise=3) which is appropriate for biomarking diseases, caused by an acute tryptophan-depletion, in clinical setting.

Development of a highly sensitive and selective hyphenated technique (molecularly imprinted micro-solid phase extraction fiber-molecularly imprinted polymer fiber sensor) for ultratrace analysis of folic acid.

A simple polymerization strategy is reported in this work which allows molecularly imprinted polymeric fiber (monolith) fabrication for direct use in sensing devices. This is advantageous for achieving higher degree of enrichment of target analyte (folic acid) from the complex matrices of real samples, without any surface fouling, cross-reactivity, and non-specific (false-positive) contributions. In order to measure serum folic acid at ultratrace level to detect spina bifida, a neural tube defect in mother, and other acute cases of proteomic diseases, the hyphenation between molecularly imprinted micro-solid phase extraction fiber and a complementary molecularly imprinted polymer-carbon composite fiber sensor has been found quite efficient. The primitive diagnosis of many chronic diseases is feasible by estimating folic acid as biomarker, with the detection limit as low as 0.0036 ng mL(-1) (relative standard deviation=0.13%, signal/noise=3) in human blood serum.