Application of Molecularly Imprinted Polymers in Plant Natural Products: Current Progress and Future Perspectives

Plants, as a large and complex system, are rich in a variety of natural bioactive constituents. It is crucial to enrich, isolate, purify and detect these natural products. Molecularly imprinted polymers (MIPs) are a class of polymers prepared by molecularly imprinted technology (MIT) that have specific recognition sites and are complementary to templates in shape, size, and binding groups. The synthesis and polymerization mechanism of MIPs are introduced. A variety of preparation methods for MIPs have been developed. MIPs can be classified into three types: non-covalent molecularly imprinted, covalent molecularly imprinted, and semi-covalent molecularly imprinted. MIPs usually consists of five parts: template, functional monomer, cross-linker, initiator, and solvent/reagent. With the advantages of high-specificity binding ability, MIPs have shown excellent efficacy in the separation, enrichment, and purification of plant active products, such as flavonoids, polyphenols, terpenoids, and other components, especially as specific adsorbent materials. Due to the high selectivity to target the analytes, MIPs have also been used as sensors to detect the bioactive constituents in plants. Undeniably, MIPs still face undeniable limitations in the application of plant natural products. The development of MIPs with high selectivity, strong affinity, cost-effectiveness, sensitivity, and environmental friendliness are valuable and promising.     

二氯喹啉酸分子印迹聚合物微球的制备

采用改进的分散聚合方法制得的纳米级聚苯乙烯微球(PS)为种球,以二氯喹啉酸(quinclorac)为模板分子,通过单步溶胀聚合法在水相中制备了单分散分子印迹聚合物微球(MIPs)。通过红外光谱分析MIPs的结合位点;利用紫外光谱研究了MIPs的结合机理和识别特性;用扫描电镜观察了微球的形貌。结果表明,PS微球的粒径分布100～150nm,MIPs的粒径分布为200～300nm;Scatchard分析表明,MIPs在识别二氯喹啉酸过程中存在两类结合位点:高亲和性位点的解离常数KD1=0.0488mmol/L;低亲和性位点的解离常数KD2=0.423mmol/L。     

Molecularly imprinted polymers: present and future prospective

Molecular Imprinting Technology (MIT) is a technique to design artificial receptors with a predetermined selectivity and specificity for a given analyte, which can be used as ideal materials in various application fields. Molecularly Imprinted Polymers (MIPs), the polymeric matrices obtained using the imprinting technology, are robust molecular recognition elements able to mimic natural recognition entities, such as antibodies and biological receptors, useful to separate and analyze complicated samples such as biological fluids and environmental samples. The scope of this review is to provide a general overview on MIPs field discussing first general aspects in MIP preparation and then dealing with various application aspects. This review aims to outline the molecularly imprinted process and present a summary of principal application fields of molecularly imprinted polymers, focusing on chemical sensing, separation science, drug delivery and catalysis. Some significant aspects about preparation and application of the molecular imprinting polymers with examples taken from the recent literature will be discussed. Theoretical and experimental parameters for MIPs design in terms of the interaction between template and polymer functionalities will be considered and synthesis methods for the improvement of MIP recognition properties will also be presented.     

有机-无机分子印迹杂化材料的研究进展

分子印迹技术是制备选择性识别特定分子的聚合物的方法,因其制备简单、稳定性好且具有特异分子识别功能使其在色谱分离、固相萃取、化学传感和模拟酶催化等方面都有广泛的应用。有机-无机杂化分子印迹聚合物集有机和无机聚合物的优点,不仅机械强度高,而且耐溶剂性好,是分子印迹技术的一个崭新领域。在介绍有机-无机杂化分子印迹聚合物基本概况的基础上,综述了有机-无机杂化分子印迹聚合物制备的原理、方法和特点,并对未来的发展提出了展望。     

Imprinted microspheres doped with carbon nanotubes as novel electroresponsive drug‐delivery systems

Novel molecularly imprinted polymers (MIPs) suitable for the electroresponsive release of diclofenac were synthesized by precipitation polymerization in the presence of carbon nanotubes (CNTs). Both conventional and electroresponsive imprinted polymers were synthesized with methacrylic acid as the functional monomer and ethylene glycol dimethacrylate as the crosslinker. Preliminary experiments were performed to fully characterize the conventional MIPs and composite materials in terms of their morphological properties, recognition behavior, and electric resistivity. In vitro release experiments were performed in aqueous media to elucidate the ability of the MIPs and spherical imprinted polymers doped with CNTs to release the loaded template in a sustained manner over time in comparison to the that of the corresponding nonimprinted materials. Furthermore, a 20‐V direct‐current voltage was applied through the releasing media to evaluate how the electric field influenced the drug release to demonstrate the suitability of the proposed macromolecular system as an electroresponsive drug‐delivery device. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 829‐834, 2013     

Engineering molecularly imprinted polymer (MIP) materials: Developments and challenges for sensing and separation technologies

Molecular imprinting, artificial receptors, plastic antibodies are terms associated with synthetic materials capable of chemical and biological sensing. Through the years, these sensors have advanced greatly not only in analytical chemistry; they have high utility for environmental, health, security, military, etc. monitoring and separations applications. New transduction methods and miniaturization have enabled in-situ and real-time sensing capabilities. On the other hand, they have high utility as matrices for chemical and biological separations. The challenge of employing molecularly imprinted polymers or MIPs as receptors lie in demonstrating high selectivity and sensitivity. Robustness and cost are also important considerations. Traditional methods of monolith polymerization employing free radical polymerization mechanisms have yielded good performance but lack the ability to demonstrate repeatable selectivity and sensitivity. Thin films have been deemed to be more useful in sensing applications, but may not offer the right throughput for separations applications. Engineering optimized materials require not only adapting to new chemistries but also knowing their structure-property relationships.     

Surface molecularly imprinted polymer prepared by reverse atom transfer radical polymerization for selective adsorption indole

The preparation of indole molecularly imprinted polymers (indole‐MIPs) using 4‐vinylpyridine as functional monomer, silica gel as matrix were used to adsorb indole from fuel oil specifically. The reverse atom transfer radical polymerization (RATRP) technology was introduced to prepare the surface molecularly imprinted polymers, and the precipitation polymerization was adopted in the preparation process. The obtained indole‐MIPs were characterized by nitrogen adsorption, Fourier transform infrared spectrometry and scanning electron microscopy. The results show that indole‐MIPs were provided with the larger surface areas and more pores. The adsorption capacity of indole‐MIPs was 31.80 mg g^?1 at 298 K, and the adsorption equilibrium was reached in a short time. The adsorption process was spontaneous by thermodynamic analysis, and an appropriate decrease in temperature could enhance the adsorption capacity. The adsorption process obeyed pseudo‐second‐order kinetic model by kinetics analysis. The isotherm analysis results show that both Langmuir and Sips equations were suitable to experimental data. The selective adsorption and reusable performance of indole‐MIPs were favorable. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40473.     

Molecularly imprinted polymers via living radical polymerization: Relating increased structural homogeneity to improved template binding parameters

This work examined imprinted polymer networks prepared via controlled/living radical polymerization (LRP) and conventional radical polymerization (CRP) on chain growth, network formation, and efficiency of producing molecularly imprinted, macromolecular memory sites for the template molecule, diclofenac sodium. LRP extended the reaction-controlled regime of the polymerization reaction and formed more homogeneous polymer chains and networks with smaller mesh sizes. In addition, LRP negated the effect of the template on polymer chain growth resulting in polymers with a more consistent PDI independent of template concentration in the pre-polymerization solution. Improved network homogeneity within imprinted poly(HEMA-co-DEAEM-co-PEG200DMA) networks prepared via LRP resulted in a 38% increase in template binding affinity and 43% increase in the template binding over imprinted networks prepared via CRP and a 97% increase in affinity and 130% increase in capacity over non-imprinted networks prepared by LRP. By varying certain parameters, it was possible to create imprinted networks with even higher template binding affinities (155% over non-imprinted) and capacities (261% over non-imprinted). This work is the first to conclusively demonstrate that the observed improvement in binding parameters in weakly crosslinked, imprinted polymer networks could be explained by the more uniform molecular weight evolution associated with the LRP mechanism and the longer lifetime of an active polymer chain relative to the total polymerization time, which allowed for the formation of a more homogenous imprinted polymer network.     

可逆加成-断裂链转移沉淀聚合法制备噻菌灵分子印迹聚合物

采用可逆加成-断裂链转移（RAFT）聚合技术与沉淀聚合技术相结合的方法合成了噻菌灵分子印迹聚合物。该聚合物微粒具有更好的分散性,其印迹效果比传统沉淀聚合法得到的分子印迹聚合物更好。为从复杂的农药残留中富集和分离噻菌灵提供了可能。     

五种黄酮类分子印迹分离技术研究及应用进展

分子印迹技术用于从复杂的结构类似物混合物中选择性提取黄酮类化合物已经引起近年来的广泛关注。采用传统方法所制备的分子印迹聚合物（MIP）存在诸多缺点,限制了其应用发展。本文主要对5种典型黄酮类化合物（槲皮素、芦丁、异槲皮苷、葛根素、山奈酚）在分子印迹分离方面的研究及应用情况进行综述;对MIP的模拟、合成、表征、应用及优化进行了讨论;采用可逆加成-断裂链转移自由基聚合（RAFT）技术、磁功能化、计算机模拟、优化固相萃取性能参数等措施可以增强MIP印迹结合容量、选择性、传质和分离的程度;指出了开发新单体,引入新聚合方法,提高MIP制备效率,开发大分子检测MIP,使用MIP作为微流体工具,提出合成MIP的新配置,优化MIP的合理设计,探索MIP的大规模合成方法等发展趋势,可为黄酮类化合物及其类似物的分子印迹分离研究提供参考。     

丙烯酰胺为功能单体制水杨酸分子印迹聚合物

1HNMR实验表明,在弱极性溶剂中,水杨酸与丙烯酰胺之间的氢键作用大于水杨酸与α-甲基丙烯酸之间的氢键作用。据此以丙烯酰胺为功能单体、二甲基丙烯酸乙二醇酯为交联剂,合成了水杨酸分子印迹聚合物。电镜和静态吸附实验表明,选用乙腈做溶剂合成的印迹聚合物疏松多孔、吸附性能较好,而用氯仿做溶剂合成的印迹聚合物致密、吸附性能较差。以丙烯酰胺为功能单体合成的水杨酸分子印迹聚合物分离因子α=7.2,印迹效率因子β=5.1;而以α-甲基丙烯酸为功能单体合成的水杨酸分子印迹聚合物分离因子α=1.7,印迹效率因子β=2.1。     

Molecularly imprinted polymer microspheres with nanopore cavities prepared by precipitation polymerization as new carriers for the sustained release of dipyridamole

Imprinted polymers are now being increasingly considered for active biomedical uses such as drug delivery. In this work, the use of molecularly imprinted polymers (MIPs) in designing new drug delivery devices was studied. Imprinted polymers were prepared from methacrylic acid (MAA) (functional monomer), ethylene glycol dimethacrylate (cross‐linker), and dipyridamole (DIP) (as a drug template) using precipitation polymerization method. The influence of the template/functional monomer proportion and pH on the achievement of MIPs with nanopore cavities with a high enough affinity for the drug was investigated. The small pores (average 3.9 nm) in the imprinted microspheres show excellent retention properties for the target analyte. The polymeric devices were further characterized by FT‐IR, thermogravimetric analysis, scanning electron microscopy, photon correlation spectroscopy, Brunauer‐Emmett‐Teller analysis, and binding experiments. The imprinted polymers showed a higher affinity for DIP and a slower release rate than the nonimprinted polymers. The controlled releases of DIP from the prepared imprinted polymers were investigated by an in vitro dissolution test by measuring the absorbance at 284 nm by means of a UV–Visible spectrophotometer. Loaded imprinted microsphers showed very slow release in various solutions such as phosphate buffer solution (pH 6.8), HCl (pH 1.0) and mixture of HCl and MeOH at 37.0 ± 0.5°C and were able to prolong DIP release for more than two days. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Comparison of molecular adsorption ability of the molecularly imprinted polymers prepared by ethylene glycol dimethacrylate and trimethylolpropane trimethacrylate as cross linkers

The target of this study was to synthesize the molecularly imprinted polymers (MIPs) of L ‐phenylalanine as the solid phases for characterization of molecular adsorption by molecularly imprinted solid phase extraction (MISPE). These MIPs, in microscale, were synthesized using thermal (40°C)‐compared with thermal (65°C)‐initiated polymerization process. Itaconic acid was chosen as the functional monomers, and either ethylene glycol dimethacrylate or trimethylolpropane trimethacrylate (TRIM) was used as the cross linker and was compared together. The influences of several parameters on the properties of the MIPs were investigated, especially physical robustness from the percentage yields and molecular adsorption from the percentage recovery by MISPE. The best yields were obtained from polymers made using TRIM and thermal (65°C)‐initiated polymerization. However, there were no significant differences in molecular adsorption. It was concluded that these parameters can be considered to synthesize MIPs for chiral separation in advance steps such as other related chromatographic techniques. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2325–2330, 2007     

Recent advances on ion-imprinted polymers

Selective recognition of metal ions is a real challenge for a large range of applications in the analytical field (from extraction to detection and quantification). For that purpose, ion-imprinted polymers (IIPs) have been increasingly developed during the last 15 years on the principle of molecularly imprinted polymers (MIPs). Those imprinted materials are designed to mimic the binding sites of biological entities and assure an improved recognition of the template species. The aim of this review is to give the current state of the art in the conception of IIPs from the components to the polymerization process. Some applications of those materials will be also discussed.     

三硝基甲苯分子印迹电化学传感器的制备和应用

以三硝基甲苯（TNT）为模板分子,甲基丙烯酸（MAA）为功能单体,采用乳液聚合法制备TNT的分子印迹聚合物（MIPs）。将制备的MIPs分散在溶剂中,通过表面涂覆法制备出检测TNT的分子印迹电化学传感器。紫外光谱表明TNT与MAA之间存在相互作用力,有助于形成结构稳定、亲和性强的MIPs。利用扫描电镜观测不同制备条件下印迹聚合物的表观形貌,发现溶剂用量为30mL、乳化剂用量为12mg时制备的聚合物形貌较优异。吸附实验表明MIPs对TNT的吸附量随着TNT初始浓度的增加而增加,140min后达到最大吸附量的95%。MIPs对TNT的分离常数远大于RDX和DNT,对RDX和DNT的选择性系数均达到4.4以上,说明MIPs对TNT有较好的选择性吸附能力。铁氰化钾探针实验和对TNT的响应曲线验证了电化学传感器的成功制备,该传感器富集3min就达到了最大电流值的94%,5min内达到吸附平衡。TNT浓度在0.1~5mg/mL的范围内与峰电流有良好的线性关系,检出限为0.06mg/mL。MIPs传感器对TNT的电流响应分别为DNT和RDX的3.13倍、3.27倍,说明其对TNT分子具有很强的特异性识别能力。     

Effect of the synthesis initiation mode on the structure and properties of sulfadiazine molecularly imprinted polymers

In the presence of imprinting molecules of sulfadiazine, two kinds of molecularly imprinted polymers (MIPs) were synthesized by photoinitiated and thermally initiated polymerizations, respectively. The combination of sulfadiazine and α‐methyl acrylic acid and their composite ratio were studied by differential UV absorption spectrometry. The results show that a combined effect between the functional monomer and the imprinting molecule occurred in the solution. The structure and properties of these synthetic polymers were researched and compared with IR spectroscopy, transmission electron microscopy, and a balanced combination of static experiments. The polymer materials synthesized in these two ways had the same molecular structure, but their morphology was different. Furthermore, through the adsorption isotherm, Scatchard analysis, and evaluation of the imprinting efficiency, we determined that the lower temperature was a more suitable synthesis condition for the polymerization of the MIPs. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Optimal design of an imprinted preassembled system by quantum chemical calculations and preparation of a surface‐imprinted material for the selective removal of quinoline

In this study, we examined the rational preparation of molecularly imprinted polymers (MIPs) for the selective removal of quinoline from octane. Before the preparation, density functional theory, as one of the methods of quantum chemical calculation, was used for the simulation of a quinoline‐imprinted preassembly system. Methacrylic acid turned out to be the more suitable monomer for quinoline compared with acrylamide, and different template–monomer ratios, including 1:1, 1:2, and 1:3, were studied and are discussed. On the basis of the result of molecular simulation, quinoline‐imprinted polymers were prepared with a combination of surface imprinting and living polymerization. The prepared quinoline–MIPs were characterized and used as selective adsorbents for batch‐mode binding experiments. The fitting result of the adsorption data indicates that the adsorption kinetics and adsorption isotherms of the quinoline‐imprinted polymers fit well a pseudo‐second‐order kinetics model and the Freundlich model, respectively. A selective recognition ability was demonstrated by equilibrium binding analysis. This study will provide needful guidance and a theoretical basis for the preparation of imprinted materials in the field of industrial denitrification. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41730.     

Uniformly sized molecularly imprinted polymers for on‐line concentration,purification, and measurement of nimodipine in plasma

Uniformly sized molecularly imprinted polymers (MIPs) for nimodipine have been prepared in an aqueous system by multi‐step swelling and polymerization method, utilizing 4‐vinylpyridine (4‐VPY) or methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EDMA) as a cross‐linking agent. Scanning electron microscopy was used to identify the structure features of the obtained polymers. Further, the influences of some chromatographic conditions were examined to explore the possible recognition mechanism. The results reveal that stable molecularly imprinted polymeric microspheres with good size monodispersity were obtained, and the polymer beads showed specific recognition for the template molecule and some other dihydropyridine calcium antagonists (DHPs). Besides hydrophobic interaction, the molecular shape complementation of DHPs and the MIPs seems to play an important role in the retention and recognition of DHPs. The Scatchard analysis showed that two kinds of binding sites existed in the MIPs. The MIPs was then used as a high‐performance liquid chromatography (HPLC) separation medium to simultaneously concentrate and purify nimodipine in plasma. The results reveal that the obtained MIPs could be used for on‐line concentration, purification, and measurement of nimodipine in biological samples. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Preparation,characterization and adsorption performance of molecularly imprinted microspheres for erythromycin using suspension polymerization

BACKGROUND: There are few reports on erythromycin molecularly imprinted polymers (MIPs) used as HPLC stationary phase and solid phase extraction matrices. These imprinted polymers are prepared by bulk polymerization, which is tedious and time‐consuming, and they are irregular and possess poor reproducibility and low binding capacity. In this study, molecularly imprinted microspheres for erythromycin were prepared by aqueous suspension polymerization for the first time. RESULTS: Imprinted microspheres for erythromycin were prepared using suspension polymerization in which 1.5% PVA‐water solution is used as continuous phase, and chloroform solution containing erythromycin, methacrylic acid and crosslinker is used as disperse phase. The composition of disperse phase is optimized, and the optimum molar ratio of erythromycin to methacrylic acid was 1:5. Selectivity analysis revealed that the imprinted microspheres can specifically recognize erythromycin from its structure analogues. The binding mechanism between erythromycin and methacrylic acid was investigated by UV‐Vis spectrophotometry. Adsorption kinetics and the adsorption isotherm of the imprinted microspheres indicate that erythromycin can be adsorbed rapidly by the imprinted microspheres and the maximum theoretical static binding capacity is 128.6110 mg g^?1. The imprinted microspheres were used to extract erythromycin from a milk sample and a high recovery rate was obtained. CONCLUSION: Molecularly imprinted microspheres for erythromycin were uniform and possess high adsorption capacity and excellent selectivity. They are therefore a promising extraction and chromatographic media. Copyright © 2011 Society of Chemical Industry     

以混旋的头孢拉定为模板的分子印迹聚合物的制备及拆分性能研究

以混旋的头孢拉定为模板分子与合成的（S）-（1-苯乙基）-甲基丙烯酰胺作为功能单体制备分子印迹聚合物,并用高效液相色谱法对印迹聚合物的选择性进行了考察。实现了对混旋的头孢拉定的拆分。同样的方法分别制备了3种混旋的氨基酸衍生物的分子印迹聚合物,未能实现对其混旋物质的分离。对比得出结论：对混旋物质的直接印迹需要模板分子应具有4个以上的作用位点。