TY - JOUR
AU - Halquist, Matthew S
AB - Abstract In the world of forensic and clinical toxicology, proper sample preparation is one of the key steps in identification and quantification of drugs of abuse. Traditional extraction methods such as solid-phase extraction and liquid−liquid extraction are often laborious and nonselective for the target analytes being measured. Molecularly imprinted polymers (MIPs) can be synthesized for sample extraction and their versatility allows the polymer to be employed in off-line, benchtop extractions or on/in-line instrument extractions, offering a faster and more selective sample preparation without the risk of interfering matrix effects. This review details the synthesis and applications of MIP materials for the extraction of drug compounds from biological matrices in publications from 1994 to today. Introduction The role of a toxicology laboratory is to identify and quantify drugs and toxic compounds in biological matrices. Such matrices include blood, plasma, urine and tissue, which may contain high concentrations of fats, carbohydrates, proteins and salts. The presence of these extraneous compounds often affects the accurate detection and quantitation of the target analyte through interfering and suppressing the ability to detect the drug compounds in analytical instruments (1). To combat this, extensive sample preparation is often required to isolate the analytes of interest from the biological matrix prior to instrumental analysis (2). Common methods to isolate the analyte are liquid−liquid extraction (LLE) and solid-phase extraction (SPE). LLE is often viewed as labor intensive and difficult to automate while consuming large volumes of hazardous solvents with limited selectivity for target compounds. Further, LLE is frequently complicated by the presence of emulsions (3). SPE is typically the preferred method for extraction due to (i) facilitates cleaner, more selective sample extracts, (ii) can be applied to a wide array of compounds and (iii) is capable of being automated. Further, it requires less amount of sample and solvent to be used for extraction compared to LLE (4). SPE has the advantage of LLE through the wide range of sorbent beds that are available for extraction. Depending on the chemical properties of the target compound, SPE sorbent beds can allow for extraction of the target from the biological matrix through either normal or reverse phase interactions, weak cation or anion exchange or a mixed mode of interactions to optimize the extraction of the target compound(s) (3). However, the interactions between the analyte and the SPE sorbent beds are still considered to be nonspecific, which can lead to co-extraction of interfering matrix compounds (1, 5). Further, the increased potency of drugs such as novel psychoactive substances and synthetic fentanyl analogs leads to lower concentrations of drug in biological matrices. This requires toxicology laboratories to have efficient extraction and preconcentration of samples prior to analysis. Molecularly imprinted polymers (MIPs) are synthetic polymers that are capable of selectively extracting a target analyte or class of analytes. The polymer is imprinted with an analyte of choice that is polymerized in the presence of functional and cross-linking monomers. The target analyte is extracted post polymerization and the 3D cavity left behind allows the same analyte, or compounds of a similar structure, to selectively rebind to the cavity through chemical interactions with the functional monomers (1, 6). MIPs are often compared to antibodies for immunoassays because their ability to selectively recognize a compound is similar to the antibody−compound interaction (7, 8). However, unlike antibodies, MIPs are synthetic, requiring no animal component for synthesis, which reduces the cost and time of production. Further, compared to immunoassays, MIPs are considered more robust due to the ability to withstand extreme pH and temperature ranges (9). The concept of MIPs has been present in the literature since the 1970s, when Wulff et al. (10) created a covalently bonded MIP for the separation of racemic compounds. Mosbach et al. (11, 12) created the first noncovalently bonded MIP for L-phenylamine derivatives in 1988. Today, MIPs are used in a wide array of applications, including as sorbent materials for SPE cartridges, solid-phase microextraction (SPME) fibers and high-performance liquid chromatography (HPLC) columns. The use of MIPs as extraction columns dates back to 1994 when Sellergen (13) created an MIP-SPE extraction of pentamidine in urine. Unlike SPE columns, which are one-time use, studies have shown that MIP materials can be reused for multiple extractions. To reuse the MIP materials, a washing or conditioning step is performed after the final elution step to ensure that no analyte is retained and that the column is ready for reuse. Some papers have reported repeat extractions with a single MIP cartridge/column for upwards of 70–100 extractions with no significant changes in extraction efficiency (14–16). Mullett and Lai (17) reported that their molecularly imprinted solid-phase extraction (MISPE) column for theophylline still had molecular recognition capabilities for >1 year. In the last 14 years, numerous papers have been published detailing the synthesis and application of MIPs for the extraction of organic compounds from biological matrices. There are numerous reviews available for the wide array of applications of MIP materials for the extraction of organic compounds from matrices such as environmental and food samples, but none exclusively for the extraction of drugs from biological matrices. This review aims to create a comprehensive review of MIP synthesis and their application in the areas of forensic and clinical toxicology to highlight their potential use for sample preparation. MIP Synthesis Chemical interactions The MIP requires the use of a template molecule, which is typically the analyte of interest or an analyte of a similar structure. The template is mixed with a functional monomer and a cross-linking monomer in a solvent, also known as the porogen, where the polymerization process will take place. The polymerization process is aided by an initiator that is activated by either a controlled temperature bath or an ultraviolent (UV) light. Increased polymer stability and binding capacity is best achieved when the prepolymerization complex has a low kinetic energy. This is often achieved by light initiated polymerization at a low temperature, but the literature reports the use of both mechanisms equally (6). The template interacts with the functional monomer, creating chemical binding sites with functional groups on the template molecule. The cross-linking monomer creates the hard backbone around the template and functional monomer. Once polymerization is complete, the template is removed either via chemical cleavage or a washing extraction. The final result is a hardened polymer with 3D cavities in the shape of the template molecule (Figure 1). Upon reintroduction to the resulting MIP, the analyte of interest will fill the 3D cavity and rebind to the functional monomers bound in the cross-linking monomer. The type of interaction between the functional monomer and the template/analyte depends on whether the polymer was created through covalent or noncovalent interactions. Figure 1 Open in new tabDownload slide Schematic for the polymerization of a noncovalent MIP. Figure 1 Open in new tabDownload slide Schematic for the polymerization of a noncovalent MIP. Covalent imprinting Covalent imprinting was the first interaction created for MIP synthesis by Wulf et al. (10). The template/analyte molecule binds to the functional monomer through covalently binding interactions. After the polymerization process is complete, the template is removed by disrupting the covalent interactions through chemical cleavage of the covalent bond. The advantage of covalent imprinting is that the required ratio of monomer to template is 1:1. This homogenous interaction promotes specific binding sites within the MIP and greatly reduces the chance of nonspecific binding from occurring (1, 6, 18). The major disadvantage to covalent imprinting is that there are a limited number of reliable template/analyte and monomer interactions that can also be reversed so that the template/analyte can later be extracted from the polymer. Further, with those that do have reversible interactions, the binding kinetics to reestablish the covalent interactions between the template and monomer are slow when compared to noncovalent MIPs. Depending on the application, the slow binding kinetics of covalent imprinting may be undesirable (1). Semicovalent imprinting can overcome the disadvantages of covalent imprinting. In semicovalent imprinting, the MIP is synthesized by covalent interactions, but the rebinding kinetics are established through noncovalent interactions. The advantage of this method is the homogenous binding sites through covalent imprinting with the faster rebinding kinetics of the noncovalent imprinting (13, 18). However, the use of semicovalent imprinting is still limited because of the limited number of template/analyte to functional monomer complexes that are capable of forming reversible noncovalent bonds (18). Noncovalent imprinting Noncovalent imprinting was first described by Mosbach et al. (11, 12) in 1988 and is currently the popular choice for synthesis of MIPs. The use of noncovalent interactions significantly broadens the choice of functional monomers that can be used to interact with the template molecule (11, 12). Noncovalent MIPs also have faster binding kinetics, which is more advantageous over covalent MIPs if high-throughput extraction is required to carry out a large number of extractions within a relatively short time period. Noncovalent interactions between the template and monomer are primarily from hydrogen bonding, electrostatic and Van der Waal forces, and hydrophobic interactions. After polymerization, the noncovalent interactions are disrupted through a simple chemical extraction and the template is removed. The wider range of chemical interactions involved in the binding process also allows for molecules of similar shape/structure to the template molecule to interact with the MIP. This is a favorable interaction if the goal of the MIP is to extract a class of compounds that are of a similar shape. Amphetamines, benzodiazepines and cannabinoids are among the class of compounds that have been assessed in their ability for an MIP to extract numerous analogs from a biological matrix (Table I) (14, 15, 19–28). Table I MIPs Synthesized for the Extraction of Drug Compounds from Various Biological Matrices for Off-Line, On-Line or In-Line Extraction Protocols Since 1994* Template . Polymerization strategy . MISPE mode . Analytical platform . Matrix . Analyte . Reference . Pentamidine Bulk In-line HPLC–UV Urine Pentamadine (13) Sameridine Bulk Off-line GC–FID–NPD Plasma Sameridine (45) Theophylline Bulk On-line HPLC Serum Theophylline (17) Pentycaine Bulk Off-line GC Plasma Bupivacaine (32) Ibuprofen + Naproxen Mult-Step Swelling On-line HPLC–UV Plasma Ibuprofen + Naproxen (53) Amobarbital Suspension Off-line HPLC–PDA Urine Barbiturates (4) Hyoscyamine Bulk Off-line HPLC–UV Serum and urine Scopolamine (30) Naproxen Bulk Off-line HPLC–UV Urine Naproxen (54) Ciprofloxacin Bulk Off-line HPLC–MS Urine Ciprofloxacin (55) Propranolol Bulk Off-line HPLC–UV Plasma Clenbuterol (33) Verapamil Bulk On-line HPLC–MS Plasma and Urine Verapamil + metabolites (56) Cephalexin Bulk In-line HPLC–UV Serum Cephalexin (51) NNAL Bulk Off-line LC–API-MS-MS Urine NNAL (57) Enrofloxacin Bulk Off-line HPLC–UV Urine Enrofloxacin (58) Cotinine Bulk Off-line HPLC–PDA Urine Cotinine (59) Diazepam Bulk Off-line LC–MS-MS Hair Diazepam (21) Carbamazepine Bulk Off-line HPLC–UV Urine Carbamazepine (60) Nicotine Bulk Off-line GC x GC–MS Hair Nicotine (41) Diazepam Bulk Off-line LC–MS-MS Hair Benzodiazepines (22) Amoxicillin Bulk Off-line HPLC–UV Urine Amoxicillin + Cephalexin (61) Clomiphene Bulk Off-line HPLC–UV Urine Tamoxifen (34) Carbamazepine Precipitation Off-line HPLC–DAD Urine Carbamazepine & Oxcarbazepine (42) Ergonovine Maleate Bulk Off-line LC–MS-MS Hair and urine LSD (35) Ephedrine Bulk Off-line HPLC–PDA Plasma Ephedrine (62) Tramadol Bulk Off-line HPLC–UV Plasma and Urine Tramadol (63) ATCA Other Off-line ESI–MS-MS Urine ATCA (64) Diazepam Bulk In-Line LC–ESI–MS Plasma Benzodiazepines (14) SupelMIP for Amphetamines LC–MS-MS Urine Amphetamines (23) Methamphetamine Precipitation Off-line GC–MS Urine Amphetamines (15) Methamphetamine Precipitation Off-line GC–FID Urine Amphetamines (25) SupelMIP for Amphetamines GC–MS Whole Blood Amphetamines (24) Cocaine Bulk Off-line LC–UV and LC–MS Hair Cocaine (40) THC-OH Bulk Off-line GC–MS Urine Cannabinoids (26) Testosterone Bulk Off-line GC x GC–MS Synthetic Urine Testosterone (65) Indapamide Bulk Off-line Spectrophotometer Urine Indapamide (66) Catechin Other Off-line LC–MS-MS Oral Fluid and Urine Cannabinoids (67) Cocaine Precipitation Off-line LC–MS-MS Plasma Cocaine (68) Cocaine Other Off-line LC–MS-MS Urine Cocaine + Metabolites (69) THC-COOH Precipitation Off-line LC–MS-MS Plasma and Urine Cannabinoids (28) Amitriptyline Bulk In-line LC–MS-MS Plasma Tricyclic Antidepressants (52) 6-Mercaptopurine Precipitation Off-line LC–MS-MS Plasma 6-Mercaptopurine (70) Affinilute MIP for Amphetamines LC–MS-MS Blood and urine Synthetic Cathinones (19) Morphine Precipitation Off-line HPLC Plasma and urine Morphine (49) Diazepam Other Off-line HPLC–DAD Plasma Benzodiazepines (71) Cocaine Bulk Off-line UHPLC–MS-MS Oral Fluid Amphetamines + Synthetic Cathinones (20) Cocaine Bulk In-line Nano LC–UV Plasma, urine, and saliva Cocaine (47) Template . Polymerization strategy . MISPE mode . Analytical platform . Matrix . Analyte . Reference . Pentamidine Bulk In-line HPLC–UV Urine Pentamadine (13) Sameridine Bulk Off-line GC–FID–NPD Plasma Sameridine (45) Theophylline Bulk On-line HPLC Serum Theophylline (17) Pentycaine Bulk Off-line GC Plasma Bupivacaine (32) Ibuprofen + Naproxen Mult-Step Swelling On-line HPLC–UV Plasma Ibuprofen + Naproxen (53) Amobarbital Suspension Off-line HPLC–PDA Urine Barbiturates (4) Hyoscyamine Bulk Off-line HPLC–UV Serum and urine Scopolamine (30) Naproxen Bulk Off-line HPLC–UV Urine Naproxen (54) Ciprofloxacin Bulk Off-line HPLC–MS Urine Ciprofloxacin (55) Propranolol Bulk Off-line HPLC–UV Plasma Clenbuterol (33) Verapamil Bulk On-line HPLC–MS Plasma and Urine Verapamil + metabolites (56) Cephalexin Bulk In-line HPLC–UV Serum Cephalexin (51) NNAL Bulk Off-line LC–API-MS-MS Urine NNAL (57) Enrofloxacin Bulk Off-line HPLC–UV Urine Enrofloxacin (58) Cotinine Bulk Off-line HPLC–PDA Urine Cotinine (59) Diazepam Bulk Off-line LC–MS-MS Hair Diazepam (21) Carbamazepine Bulk Off-line HPLC–UV Urine Carbamazepine (60) Nicotine Bulk Off-line GC x GC–MS Hair Nicotine (41) Diazepam Bulk Off-line LC–MS-MS Hair Benzodiazepines (22) Amoxicillin Bulk Off-line HPLC–UV Urine Amoxicillin + Cephalexin (61) Clomiphene Bulk Off-line HPLC–UV Urine Tamoxifen (34) Carbamazepine Precipitation Off-line HPLC–DAD Urine Carbamazepine & Oxcarbazepine (42) Ergonovine Maleate Bulk Off-line LC–MS-MS Hair and urine LSD (35) Ephedrine Bulk Off-line HPLC–PDA Plasma Ephedrine (62) Tramadol Bulk Off-line HPLC–UV Plasma and Urine Tramadol (63) ATCA Other Off-line ESI–MS-MS Urine ATCA (64) Diazepam Bulk In-Line LC–ESI–MS Plasma Benzodiazepines (14) SupelMIP for Amphetamines LC–MS-MS Urine Amphetamines (23) Methamphetamine Precipitation Off-line GC–MS Urine Amphetamines (15) Methamphetamine Precipitation Off-line GC–FID Urine Amphetamines (25) SupelMIP for Amphetamines GC–MS Whole Blood Amphetamines (24) Cocaine Bulk Off-line LC–UV and LC–MS Hair Cocaine (40) THC-OH Bulk Off-line GC–MS Urine Cannabinoids (26) Testosterone Bulk Off-line GC x GC–MS Synthetic Urine Testosterone (65) Indapamide Bulk Off-line Spectrophotometer Urine Indapamide (66) Catechin Other Off-line LC–MS-MS Oral Fluid and Urine Cannabinoids (67) Cocaine Precipitation Off-line LC–MS-MS Plasma Cocaine (68) Cocaine Other Off-line LC–MS-MS Urine Cocaine + Metabolites (69) THC-COOH Precipitation Off-line LC–MS-MS Plasma and Urine Cannabinoids (28) Amitriptyline Bulk In-line LC–MS-MS Plasma Tricyclic Antidepressants (52) 6-Mercaptopurine Precipitation Off-line LC–MS-MS Plasma 6-Mercaptopurine (70) Affinilute MIP for Amphetamines LC–MS-MS Blood and urine Synthetic Cathinones (19) Morphine Precipitation Off-line HPLC Plasma and urine Morphine (49) Diazepam Other Off-line HPLC–DAD Plasma Benzodiazepines (71) Cocaine Bulk Off-line UHPLC–MS-MS Oral Fluid Amphetamines + Synthetic Cathinones (20) Cocaine Bulk In-line Nano LC–UV Plasma, urine, and saliva Cocaine (47) * Abbreviations: HPLC-UV, high-performance liquid chromatography–ultraviolet detector; GC–FID–NPD, gas chromatography–flame ionization detector–nitrogen and phosphorous detector; HPLC–PDA, high-performance liquid chromatography–photo diode array; HPLC–MS, higher performance liquid chromatography–mass spectrometry; NNAL, tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; LC–API-MS-MS, liquid chromatography–atmospheric pressure ionization tandem mass spectrometry; LC–MS-MS, liquid chromatography–tandem mass spectrometry; GC x GC–MS, two degree gas chromatography–mass spectrometry; HPLC–DAD, high-performance liquid chromatography–diode array detector; ATCA, 2-aminothiazoline-4-carboxylic acid; EI–MS-MS, electrospray ionization–tandem mass spectrometry; LC–EI–MS, liquid chromatography–electrospray ionization–mass spectrometry; GC–MS, gas chromatography–mass spectrometry; GC–FID, gas chromatography–flame ionization detection; THC-OH, 11-hydroxy-∆9-tetrahydrocannabinol; THC-COOH, 11-Carboxy-∆9-tetrahydrocannbinol; UHPL–MS-MS, ultra high-performance liquid chromatography–tandem mass spectrometry. Open in new tab Table I MIPs Synthesized for the Extraction of Drug Compounds from Various Biological Matrices for Off-Line, On-Line or In-Line Extraction Protocols Since 1994* Template . Polymerization strategy . MISPE mode . Analytical platform . Matrix . Analyte . Reference . Pentamidine Bulk In-line HPLC–UV Urine Pentamadine (13) Sameridine Bulk Off-line GC–FID–NPD Plasma Sameridine (45) Theophylline Bulk On-line HPLC Serum Theophylline (17) Pentycaine Bulk Off-line GC Plasma Bupivacaine (32) Ibuprofen + Naproxen Mult-Step Swelling On-line HPLC–UV Plasma Ibuprofen + Naproxen (53) Amobarbital Suspension Off-line HPLC–PDA Urine Barbiturates (4) Hyoscyamine Bulk Off-line HPLC–UV Serum and urine Scopolamine (30) Naproxen Bulk Off-line HPLC–UV Urine Naproxen (54) Ciprofloxacin Bulk Off-line HPLC–MS Urine Ciprofloxacin (55) Propranolol Bulk Off-line HPLC–UV Plasma Clenbuterol (33) Verapamil Bulk On-line HPLC–MS Plasma and Urine Verapamil + metabolites (56) Cephalexin Bulk In-line HPLC–UV Serum Cephalexin (51) NNAL Bulk Off-line LC–API-MS-MS Urine NNAL (57) Enrofloxacin Bulk Off-line HPLC–UV Urine Enrofloxacin (58) Cotinine Bulk Off-line HPLC–PDA Urine Cotinine (59) Diazepam Bulk Off-line LC–MS-MS Hair Diazepam (21) Carbamazepine Bulk Off-line HPLC–UV Urine Carbamazepine (60) Nicotine Bulk Off-line GC x GC–MS Hair Nicotine (41) Diazepam Bulk Off-line LC–MS-MS Hair Benzodiazepines (22) Amoxicillin Bulk Off-line HPLC–UV Urine Amoxicillin + Cephalexin (61) Clomiphene Bulk Off-line HPLC–UV Urine Tamoxifen (34) Carbamazepine Precipitation Off-line HPLC–DAD Urine Carbamazepine & Oxcarbazepine (42) Ergonovine Maleate Bulk Off-line LC–MS-MS Hair and urine LSD (35) Ephedrine Bulk Off-line HPLC–PDA Plasma Ephedrine (62) Tramadol Bulk Off-line HPLC–UV Plasma and Urine Tramadol (63) ATCA Other Off-line ESI–MS-MS Urine ATCA (64) Diazepam Bulk In-Line LC–ESI–MS Plasma Benzodiazepines (14) SupelMIP for Amphetamines LC–MS-MS Urine Amphetamines (23) Methamphetamine Precipitation Off-line GC–MS Urine Amphetamines (15) Methamphetamine Precipitation Off-line GC–FID Urine Amphetamines (25) SupelMIP for Amphetamines GC–MS Whole Blood Amphetamines (24) Cocaine Bulk Off-line LC–UV and LC–MS Hair Cocaine (40) THC-OH Bulk Off-line GC–MS Urine Cannabinoids (26) Testosterone Bulk Off-line GC x GC–MS Synthetic Urine Testosterone (65) Indapamide Bulk Off-line Spectrophotometer Urine Indapamide (66) Catechin Other Off-line LC–MS-MS Oral Fluid and Urine Cannabinoids (67) Cocaine Precipitation Off-line LC–MS-MS Plasma Cocaine (68) Cocaine Other Off-line LC–MS-MS Urine Cocaine + Metabolites (69) THC-COOH Precipitation Off-line LC–MS-MS Plasma and Urine Cannabinoids (28) Amitriptyline Bulk In-line LC–MS-MS Plasma Tricyclic Antidepressants (52) 6-Mercaptopurine Precipitation Off-line LC–MS-MS Plasma 6-Mercaptopurine (70) Affinilute MIP for Amphetamines LC–MS-MS Blood and urine Synthetic Cathinones (19) Morphine Precipitation Off-line HPLC Plasma and urine Morphine (49) Diazepam Other Off-line HPLC–DAD Plasma Benzodiazepines (71) Cocaine Bulk Off-line UHPLC–MS-MS Oral Fluid Amphetamines + Synthetic Cathinones (20) Cocaine Bulk In-line Nano LC–UV Plasma, urine, and saliva Cocaine (47) Template . Polymerization strategy . MISPE mode . Analytical platform . Matrix . Analyte . Reference . Pentamidine Bulk In-line HPLC–UV Urine Pentamadine (13) Sameridine Bulk Off-line GC–FID–NPD Plasma Sameridine (45) Theophylline Bulk On-line HPLC Serum Theophylline (17) Pentycaine Bulk Off-line GC Plasma Bupivacaine (32) Ibuprofen + Naproxen Mult-Step Swelling On-line HPLC–UV Plasma Ibuprofen + Naproxen (53) Amobarbital Suspension Off-line HPLC–PDA Urine Barbiturates (4) Hyoscyamine Bulk Off-line HPLC–UV Serum and urine Scopolamine (30) Naproxen Bulk Off-line HPLC–UV Urine Naproxen (54) Ciprofloxacin Bulk Off-line HPLC–MS Urine Ciprofloxacin (55) Propranolol Bulk Off-line HPLC–UV Plasma Clenbuterol (33) Verapamil Bulk On-line HPLC–MS Plasma and Urine Verapamil + metabolites (56) Cephalexin Bulk In-line HPLC–UV Serum Cephalexin (51) NNAL Bulk Off-line LC–API-MS-MS Urine NNAL (57) Enrofloxacin Bulk Off-line HPLC–UV Urine Enrofloxacin (58) Cotinine Bulk Off-line HPLC–PDA Urine Cotinine (59) Diazepam Bulk Off-line LC–MS-MS Hair Diazepam (21) Carbamazepine Bulk Off-line HPLC–UV Urine Carbamazepine (60) Nicotine Bulk Off-line GC x GC–MS Hair Nicotine (41) Diazepam Bulk Off-line LC–MS-MS Hair Benzodiazepines (22) Amoxicillin Bulk Off-line HPLC–UV Urine Amoxicillin + Cephalexin (61) Clomiphene Bulk Off-line HPLC–UV Urine Tamoxifen (34) Carbamazepine Precipitation Off-line HPLC–DAD Urine Carbamazepine & Oxcarbazepine (42) Ergonovine Maleate Bulk Off-line LC–MS-MS Hair and urine LSD (35) Ephedrine Bulk Off-line HPLC–PDA Plasma Ephedrine (62) Tramadol Bulk Off-line HPLC–UV Plasma and Urine Tramadol (63) ATCA Other Off-line ESI–MS-MS Urine ATCA (64) Diazepam Bulk In-Line LC–ESI–MS Plasma Benzodiazepines (14) SupelMIP for Amphetamines LC–MS-MS Urine Amphetamines (23) Methamphetamine Precipitation Off-line GC–MS Urine Amphetamines (15) Methamphetamine Precipitation Off-line GC–FID Urine Amphetamines (25) SupelMIP for Amphetamines GC–MS Whole Blood Amphetamines (24) Cocaine Bulk Off-line LC–UV and LC–MS Hair Cocaine (40) THC-OH Bulk Off-line GC–MS Urine Cannabinoids (26) Testosterone Bulk Off-line GC x GC–MS Synthetic Urine Testosterone (65) Indapamide Bulk Off-line Spectrophotometer Urine Indapamide (66) Catechin Other Off-line LC–MS-MS Oral Fluid and Urine Cannabinoids (67) Cocaine Precipitation Off-line LC–MS-MS Plasma Cocaine (68) Cocaine Other Off-line LC–MS-MS Urine Cocaine + Metabolites (69) THC-COOH Precipitation Off-line LC–MS-MS Plasma and Urine Cannabinoids (28) Amitriptyline Bulk In-line LC–MS-MS Plasma Tricyclic Antidepressants (52) 6-Mercaptopurine Precipitation Off-line LC–MS-MS Plasma 6-Mercaptopurine (70) Affinilute MIP for Amphetamines LC–MS-MS Blood and urine Synthetic Cathinones (19) Morphine Precipitation Off-line HPLC Plasma and urine Morphine (49) Diazepam Other Off-line HPLC–DAD Plasma Benzodiazepines (71) Cocaine Bulk Off-line UHPLC–MS-MS Oral Fluid Amphetamines + Synthetic Cathinones (20) Cocaine Bulk In-line Nano LC–UV Plasma, urine, and saliva Cocaine (47) * Abbreviations: HPLC-UV, high-performance liquid chromatography–ultraviolet detector; GC–FID–NPD, gas chromatography–flame ionization detector–nitrogen and phosphorous detector; HPLC–PDA, high-performance liquid chromatography–photo diode array; HPLC–MS, higher performance liquid chromatography–mass spectrometry; NNAL, tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; LC–API-MS-MS, liquid chromatography–atmospheric pressure ionization tandem mass spectrometry; LC–MS-MS, liquid chromatography–tandem mass spectrometry; GC x GC–MS, two degree gas chromatography–mass spectrometry; HPLC–DAD, high-performance liquid chromatography–diode array detector; ATCA, 2-aminothiazoline-4-carboxylic acid; EI–MS-MS, electrospray ionization–tandem mass spectrometry; LC–EI–MS, liquid chromatography–electrospray ionization–mass spectrometry; GC–MS, gas chromatography–mass spectrometry; GC–FID, gas chromatography–flame ionization detection; THC-OH, 11-hydroxy-∆9-tetrahydrocannabinol; THC-COOH, 11-Carboxy-∆9-tetrahydrocannbinol; UHPL–MS-MS, ultra high-performance liquid chromatography–tandem mass spectrometry. Open in new tab Because the imprinting process is carried out through noncovalent interactions, an excess amount of monomer must be employed with the template. Unlike the covalent imprinting, where the 1:1 monomer to template/analyte ratio can create homogenous binding sites, noncovalent imprinting requires a 4:1 monomer to template/analyte ratio to ensure noncovalent interactions will occur (5, 6). With an excess in functional monomers, not all will interact with the template/analyte monomer. This allows for the chance that nonspecific binding sites can be formed on the MIP (6). The nonspecific binding can potentially allow other analytes to interfere with the binding of the target analyte, but a washing step employed during extraction process can help remove the unwanted analytes prior to elution (29). Polymerization process Ingredients for an MIP The template molecule is typically the target analyte that is attempted to be extracted from the matrix. However, a common issue faced with MIPs is that, despite extensive extraction, ~1% of template molecule is retained within the MIP. Overtime, the remaining template molecule may be leached out of the polymer complex (9, 30). Despite this risk, few papers report template bleeding that interferes with accurate concentrations (31). A strategy to circumvent this potential issue is to create a noncovalent MIP with a compound that is of a similar chemical structure to the main target analyte, which is sometimes referred to as a “dummy” template. So long as the “dummy” template has a similar chemical structure to the analyte of interest, the target analyte should be able to fit into the 3D cavity in the resulting MIP. Regardless of whether the target analyte or a “dummy” template is used, the template molecule should have functional groups that are capable of interacting with the functional monomer (9, 18). Despite the knowledge that the template compound can risk bleeding during analysis, only five papers in this review used a “dummy” template for the extraction of another compound (30, 32–35). The functional monomer forms the binding sites with the template monomer in the prepolymerization complex of the MIP. The functional monomer interacts with the template by forming donor−receptor interactions with the functional groups of the template (18, 36). Functional monomers are required to have two factors that will make them desirable for MIP synthesis; first, the recognition unit that can interact with the template molecule and second, the polymerization unit (9). With noncovalent imprinting, there is a wide range of functional monomers that can be used for synthesis, the most popular being methacrylic acid (MAA), because of its ability to act as a reliable hydrogen bond donor−acceptor (9, 36). Further, Zhang et al. (37) demonstrated that because of MAA’s dimerization complex, there was a reduction of nonspecific binding sites being formed within the MIP despite the 4:1 ratio of the monomer and template. The cross-linking monomer creates a cross-linked, hardened polymer that sets the template molecule and functional monomer inside the polymer. The cross-linking monomer also ensures the cavity created by the extracted template remains intact post extraction (9). The amount of cross-linker added to the polymerization matrix is important. Too little cross-linker will not create a stable enough polymer shell and lead to breakdown of the polymer (9, 36). Too much cross-linker will reduce the number of binding sites that can be created in the MIP. Today, the most popular proportion of template to functional monomer to cross-linking monomer complex is typically a ratio of 1:4:20. This ratio, with only a small amount of adjustment depending on the MIP being synthesized, has been demonstrated to create the greatest number of reliable binding sites (38, 39). There are a limited number of cross-linking monomers available to create the needed polymer complex, but the cross-linker most widely used is ethylene glycol dimethacrylate (EGDMA) (9). The porogen is the solvent medium where the polymerization process takes place. The porogen must be chosen carefully as it will influence the strength of interaction between the template and functional monomer (9). In noncovalently imprinted polymers, aprotic, low polarity organic solvents are most desirable for MIP synthesis. A porogen should have low hydrogen bond donor–acceptor interactions. Polar solvents, which have very strong interactions, can promote the creation of nonspecific binding sites outside the template and monomer interactions (6). This is most problematic when aqueous samples containing the target analyte are introduced to the MIP material. The more polar water molecules will compete with the target analyte for binding sites along the surface of the polymer, reducing the binding capacity of the polymer for the target analyte (3). Popular porogens used for noncovalently imprinted MIPs are acetonitrile, chloroform, dichloromethane and toluene (18). Bulk polymerization Bulk polymerization was the first polymerization strategy to be employed and is still one of the most popular polymerization techniques today (1, 18). The template, functional monomer and cross-linking monomer are combined in the ratio described previously in a small volume of porogen. The mixture is then polymerized either through UV light or heat initiation for 24 h, which results in a hardened polymer complex. Once the polymerization process is complete, the hardened material is grounded using a mortar and pestle and sieved for a desired particle size range, which is typically 25–38 μm in size (21, 22, 35, 40, 41). After sieving, the polymer is left to dry overnight either in open air or an oven before the template is extracted. A common caveat to bulk polymerization is the grinding and sieving step. Grinding can destroy the binding sites, reducing the number available when the entire process is complete. In cases of noncovalent imprinting, where the excess of functional monomers can potentially reduce the number of binding sites compared to covalent imprinting, the grinding and sieving of the compound can further reduce the number of specific binding sites (5, 8). Further, the grinding and sieving process creates irregular polymer particle sizes and shapes (5, 18) (Figure 2). This can affect performance in SPE and HPLC columns where a small, uniform polymer is needed for reliable extractions (1). Despite these limitations, bulk polymerization remains to be one of the most popular methods employed because it requires a small amount of materials and is simple to execute. Figure 2 Open in new tabDownload slide Scanning electron microscopy images for molecularly imprinted using two polymerization techniques. Bulk polymerization (A) resulted in irregularly shaped particles, >100 μm in size. The irregular shapes come as a result of grinding the monolithic resin that is created during bulk polymerization. Precipitation polymerization (B), as shown by the arrow, creates small, uniformly shaped spherical particles upon precipitation of the particles in solution. Particles for precipitation polymerization are <20 μm in size. Figure 2 Open in new tabDownload slide Scanning electron microscopy images for molecularly imprinted using two polymerization techniques. Bulk polymerization (A) resulted in irregularly shaped particles, >100 μm in size. The irregular shapes come as a result of grinding the monolithic resin that is created during bulk polymerization. Precipitation polymerization (B), as shown by the arrow, creates small, uniformly shaped spherical particles upon precipitation of the particles in solution. Particles for precipitation polymerization are <20 μm in size. Precipitation polymerization Precipitation polymerization is a favorable method that avoids the caveats of bulk polymerization. In precipitation polymerization, the same ratio of template: monomer: cross-linker in bulk polymerization can be used, but the major difference is the amount of porogen used. In this polymerization process, it has been found that a functional monomer that is <5% (w/v) in the presence of the porogen is desirable. As the polymer begins to be formed in the presences of excess porogen, the growing polymer will reach a critical mass that will cause it to precipitate out of the solution (1). After polymerization is complete, the polymer is separated from any leftover porogen through centrifugation or vacuum filtration and is dried out. The resulting particles are small and spherical in shape (Figure 2) that can be as large as 10 μm, but can be as small as in the submicron range (42). Further sieving of the polymer can occur to ensure that the particle size is uniform, but unlike bulk polymerization, no grinding step is needed to achieve these small, uniformed particles. The small, uniform sizing of the polymer makes it a favorable method to create MIP material to be used as sorbents for SPE and HPLC columns. When carried out properly, precipitation polymerization can create improved binding site recognition (43). A drawback for precipitation polymerization is that it cannot be universally employed for all MIPs. There are few porogen solvents that are capable of performing the precipitation polymerization, which limits the type of templates that can properly interact within the porogen. If the template is not compatible with the porogen, it will result in a low polymerization yield. This will be most noticeable when a nonmolecularly imprinted polymer (NIP) is created and creates a higher polymerization yield (1). Purification of reagents used in the polymerization is needed to improve the polymerization yield (42). Other types of polymerization methods that can create monodisperse particles include suspension and multistep swelling polymerization. Suspension polymerization requires the MIP components to be suspended in an immiscible solvent that is stirred to induce particle precipitation and multistep swelling utilizes seed particles to create the spherical, uniformly sized particles (42). Although both techniques are able to create small, uniformly sized particles comparable to precipitation polymerization, their reputation for being laborious and time-consuming results in few papers utilizing these methods for polymerization (5, 31, 44). Nonmolecularly imprinted polymers NIPs are polymers that are created in the absence of the template molecule. The NIPs are synthesized using the same amounts of functional and crosslinking monomers, porogen and initiator as MIPs. The purpose of the NIP is that it lacks the 3D cavity that is formed by the template and functional monomer’s interactions, which gives the MIP its specific binding sites. Instead, all potential binding sites formed on the NIP are caused by nonspecific interactions with the functional monomers. The NIP is useful in demonstrating how the 3D cavity formed by the template molecule is crucial in creating a specific binding site with the functional monomer. Further, the NIP can be used as a control during the extraction optimization process. When both the NIP and MIP undergo the same extraction conditions, the amount of analyte present in both the wash and elution steps can determine if the extraction conditions promote specific or nonspecific interactions on the MIP. MIP applications MISPE modes For bioanalysis, MIP technologies are primarily used in the place of sorbent materials for SPE or the stationary phase for liquid chromatographic columns. Depending on the type of analysis desired, the application is denoted as off-line, on-line or in-line. Off-line MISPE mode follows the traditional SPE workflow at the bench prior to introduction to an analytical instrument. The first group to use MIP material for off-line SPE was Andersson et al. (45) in their extraction of sameridine from human plasma. On-line extraction uses the MISPE column as a precolumn for sample extraction and enrichment on the instrument prior to introduction to the analytical chromatographic column. Finally, in-line extraction is where the MIP material is used in place for the sorbent material of an HPLC column. Both sample pretreatment and separation happen simultaneously, which Sellergren (13) achieved in the extraction of pentamidine from urine. Off-line MISPE mode Off-line MISPE is the use of the MIP sorbent material in the place of the traditional sorbent material of an SPE cartridge, and the entire extraction process is performed at the bench. Similar to traditional SPE extraction procedures, the conditioning, loading, washing and elution steps must be optimized. However, unlike traditional SPE, which is a one-time use for each sample, MISPE cartridges can be used for multiple extractions, with some studies reporting the use of one cartridge for 70 samples with no sign of cartridge degradation (14). The conditioning step allows the cartridge to be reused by removing any potential carryover from the previous sample and reactivating the binding sites (5). It is recommended that one of the conditioning solvent be similar to the elution solvent to ensure the removal of any remaining analytes. In the loading step, the MIP will have the greatest selectivity for the target analyte when loaded in the same solvent used for polymerization, which are low polarity, organic solvents (5). This can prove difficult for aqueous biological samples, as the hydrogen bonding of water will actively compete for binding sites along the surface of the MIP. In cases of aqueous loading conditions, the MIP is treated like a reverse phase sorbent and a washing step is included (29). The washing step will remove interfering and competing matrix components and redistribute the target analyte to the binding sites. The optimal washing solvent will be one that is strong enough to disrupt the binding of matrix components, but not strong enough to interfere with the binding of the target analyte to the functional monomer. Finally, the elution step is typically a polar solvent that will be strong enough to displace the analyte−monomer binding interaction. The addition of a weak acid or base to ionize the target analyte and further disrupt the binding interactions can also be used (5). It is during the washing and elutions steps that the NIP is best utilized. The NIP can determine the extent at which nonspecific binding is occurring with the polymer. By monitoring the amount of analyte recovered in the washing and elution steps, the washing step’s capability of disrupting the nonspecific binding can be measured (7). Under optimal extraction conditions, the MIP will have low recoveries of the target analyte in the washing step and high recoveries in the elution step when compared with the recoveries of both steps using the NIP. On-line and in-line MISPE modes Where off-line MISPE is performed at the bench prior to introduction to the analytical instrument, on-line MISPE is performed on the instrument. The traditional on-line MISPE cartridge is used as a precolumn that is placed before the chromatographic column. Similar to off-line MISPE, the on-line MISPE column will use conditioning, loading, washing and elution steps. The challenge in using on-line MISPE comes from the potential difficulty in finding an elution solvent that can disrupt the MIP interactions and act as a suitable mobile phase needed for chromatographic separation (31). Traditionally in off-line protocols, if the elution solvent is not compatible with the mobile phase, the eluent is dried down and the sample is reconstituted in a suitable solvent. For the case of on-line MISPE protocols, the HPLC injection loop of the instrument is key. Through the use of a six-port injection valve, the elution solvent can be mixed with the mobile phase before reaching the chromatographic column (29, 31). The advantages of an on-line MISPE system is that sample pretreatment can be performed directly on the instrument, reducing the risk of sample loss that can happen at the bench (5). During in-line MISPE, the MIP material is packed inside a chromatographic column. During sample analysis, the solvents in the conditioning, loading and washing steps are diverted to waste. In the elution step, the eluant with the extracted analyte of interest is directed to the detector (14). The major advantage of in-line MISPE systems is that the target analyte can simultaneously be enriched, separated and extracted from a complex matrix (29, 31). In-line MISPE columns can be created under two conditions discussed in this review. One method is to create the traditional particle material either through bulk or precipitation polymerization and pack the fine particles into the HPLC column via slurry packing. The other method is to create a monolithic rod, which follows the bulk polymerization process, but the materials are added to the column and polymerized in situ, avoiding the grinding and sieving process. The monolithic rod method has advantages similar to precipitation polymerization, as it does not require grinding and sieving and therefore does not destroy the binding sites or create particles that are irregular and of variable sizes (5–7). Sample analysis The use of MIPs for the analysis of drugs in biological matrices was first demonstrated by Sellergren (13) in 1994. Since then, there have been over a hundred publications detailing the synthesis and application of MIP materials to extract drugs from biological matrices. Table I shows a selection of published papers that describe the synthesis and application of MIP materials for the extraction of drugs from biological matrices. All polymers were synthesized for noncovalent interactions with MAA and EGDMA being the most popular functional and cross-linking monomers used. The polymerization strategy was primarily bulk polymerization, but a handful of papers stated that they used precipitation polymerization. One paper used suspension polymerization (4). Plasma and urine were the most popular biological matrices applied to the MIP materials, but other papers reported successful extractions in other matrices such as hair and oral fluid (20–22, 27, 35, 40, 46, 47). Few papers have reported the use of homogenized liver samples, but the research has been limited to nonhuman liver samples such as bovine and pork. Muldoon et al. (48) reported successful extraction of atrazine from bovine liver samples and showed an improved accuracy and recovery via HPLC when compared to crude extracts that did not undergo MISPE. Atrazine recovery with MISPE extracts had limits of detection in the 0.005 ppm range. Further research into MIP extractions for other solid, human tissues such as kidney, brain, heart and vitreous humor is still needed. Off-line MIP application was the most popular technique with 38 of the papers reviewed in this article reporting the use of MIPs for off-line protocols. The majority were MISPE applications, but seven papers reported other MIP applications for extraction purposes. Magnetic MIP material was synthesized in three papers by applying the polymer to magnetite (Fe3O4), citing that the magnetic application allows for a more selective extraction process than traditional MIP sorbent materials. Rahmani et al. (49) applied magnetic MIP material for SPE extraction of morphine in plasma and urine and reported extraction recoveries of 84.9–105.5% and 94.9–102.8% in plasma and urine, respectively. Abrao and Figueirdo (50) created Restricted Access Molecularly Imprinted (RAMIP) fibers for the SPME of benzodiazepines in plasma. Coupled with a simple HPLC with diode-array detection (DAD) analysis, the authors were able to achieve linear ranges for five benzodiazepines within the reported therapeutic ranges and have comparable results to other traditional methods. Three papers reported the use of commercially prepared MISPE cartridges for off-line sample preparation. Widstrand et al. (23) and Kumazawa et al. (24) used the SupelMIP™ for amphetamines by SupelCo for the extraction of amphetamines. Kumazawa et al. (24) was able to successfully extract amphetamine, methamphetamine and five designer amphetamines from whole blood with the SupelMIP™ cartridges. The use of whole blood was also novel as it has more matrix components than plasma and urine, but the researchers were able to achieve recoveries of 88.5% and greater with the amphetamine-based MISPE and did not have to perform a protein precipitation step prior. Widstrand et al. (23) extracted five amphetamine derivatives from urine and reported lower limits of quantitation (LLOQ) a whole order of magnitude less than the LLOQs achieved with traditional hydrophilic polymer SPE cartridges. Murakami et al. (19) used AFFINILUTE MIP-Amphetamine cartridges from Biotage to extract 11 synthetic cathinone’s from urine and whole blood. The inter-day recoveries for urine was between 79.8% and 81.2% and for whole blood was between 68.5% and 74.8%, demonstrating that the MIP material can be applied to an entire class of compounds, depending on the desired application. Despite these commercial products being shown to be capable of extracting a number of class-related drugs from complex biological matrices, Biotage removed their amphetamine MISPE cartridges from market in 2019 and the SupelMIP™ cartridges for amphetamines are no longer available. As noted in other reviews, publications detailing the use of MIP technology for on-line and in-line extraction protocols were low. Mullett and Lai (17) were among the earliest to use on-line MISPE as a precolumn for the extraction of theophylline in serum, utilizing pulsed elution to create a quick extraction procedure that could flow directly onto the analytical column. A protein precipitation step was performed prior to sample loading, but the rest of the extraction was carried out on the instrument, and the authors were able to achieve a limit of detection of 12 ng/mL and a linear dynamic range of 0.25–1000 μg/mL. The authors also stated that the precolumn used for the method development showed no significant performance deterioration over the course of the experiments. A more recent publication by Bouverel et al. (47) created miniaturized, monolithic columns for the on-line extraction of cocaine and its main urinary metabolite, benzoylecgonine, in plasma, saliva and urine. The authors reported the ability to extract and detect cocaine and benzoylecgonine at trace levels in all three biological matrices. For in-line extraction protocols, the use of traditional bulk polymerization followed by slurry packing of HPLC columns was the most common method reported. Santos et al. (52) used the in-line HPLC method for the extraction of five tricyclic antidepressants in plasma. This method paired the MIP material with restricted access media (RAM), preventing the need for any protein precipitation of the samples prior to their analysis on the instrument. The use of protein precipitation of plasma samples prior to instrument introduction for on-line and in-line MISPE extraction was reported for the majority of the papers reviewed in this article (14, 17, 47, 51). With the addition of the RAM material incorporated with the MIP, the only off-line pretreatment required was a dilution step. The authors were able to report low limits of quantitation (15 μg/L) for all five compounds in plasma without the need for off-line protein precipitation or chromatographic separation. Conclusions MIP technology has a wide range of capabilities that have been published in the literature since its conception in the 1970s. Since 1994, there has been an evolution of using this technology for sample preparation for a wide variety of specimens, including complex biological matrices. The advantages of MIP technology are that they have the same inherent mechanism and selectivity of immuno-technologies, but their ability to withstand fluctuations in temperature and pH changes makes them advantageous and robust in comparison. Further, MIP materials can be employed in a range of different extraction techniques that can both improve the extraction recovery of drug compounds and fit the needs of the laboratory. Trends in MIP synthesis and application are improving to overcome the limitations of traditional extraction protocols, but the use of MIPs to extract solid tissues such as liver, brain, kidney, heart, etc. needs to be explored. Bulk precipitation was one of the first polymerization methods reported and is still among the most popular methods to be employed for MIP synthesis. 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TI - Growing Trends in the Efficient and Selective Extraction of Compounds in Complex Matrices Using Molecularly Imprinted Polymers and Their Relevance to Toxicological Analysis
JF - Journal of Analytical Toxicology
DO - 10.1093/jat/bkaa079
DA - 2021-03-12
UR - https://www.deepdyve.com/lp/oxford-university-press/growing-trends-in-the-efficient-and-selective-extraction-of-compounds-aK5kVOjmvK
SP - 312
EP - 321
VL - 45
IS - 3
DP - DeepDyve
ER -