Research article

Synthesis and computational investigation of molecularly imprinted nanospheres for selective recognition of alpha-tocopherol succinate

Theeraphon Piacham1[*], Chanin Nantasenamat1,2, Chartchalerm Isarankura-Na-Ayudhya1, Virapong Prachayasittikul1

1Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

2Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

EXCLI J 2013;12:Doc701



Molecularly imprinted polymers (MIPs) are macromolecular matrices that can mimic the functional properties of antibodies, receptors and enzymes while possessing higher durability. As such, these polymers are interesting materials for applications in biomimetic sensor, drug synthesis, drug delivery and separation. In this study, we prepared MIPs and molecularly imprinted nanospheres (MINs) as receptors with specific recognition properties toward tocopherol succinate (TPS) in comparison to tocopherol (TP) and tocopherol nicotinate (TPN). MIPs were synthesized using methacrylic acid (MAA) as functional monomer, ethylene glycol dimethacrylate (EGDMA) as crosslinking agent and dichloromethane or acetronitrile as porogenic solvent under thermal-induced polymerization condition. Results indicated that imprinted polymers of TPS-MIP, TP-MIP and TPN-MIP all bound specifically to their template molecules at 2 folds greater than the non-imprinted polymers. The calculated binding capacity of all MIP was approximately 2 mg per gram of polymer when using the optimal rebinding solvent EtOH:H2O (3:2, v/v). Furthermore, the MINs toward TPS and TP were prepared by precipitation polymerization that yielded particles that are 200-400 nm in size. The binding capacities of MINs to their templates were greater than that of the non-imprinted nanospheres when using the optimal rebinding solvent EtOH:H2O (4:1, v/v). Computer simulation was performed to provide mechanistic insights on the binding modalities of template-monomer complexes. In conclusion, we had successful prepared MIPs and MINs for binding specifically to TP and TPS. Such MIPs and MINs have great potential for industrial and medical applications, particularly for the selective separation of TP and TPS.

Keywords: molecular imprinting, molecularly imprinted polymer, anti-cancer, tocopherol succinate, computational chemistry


Significant changes to the environment and climate as a result of global warming had increased the exposure to toxic substances that may culminate in the development of pathogenic diseases (Dapul-Hidalgo and Bielory, 2012[15]; Hunter, 2003[24]; Thomas et al., 2012[68]). Among these, cancer has been found to increase incidentally owing to increases of UV exposure and toxicant-induced gene mutation. The development of therapeutic agent toward cancer has predominantly focused on addressing issues pertaining to its toxicity, drug delivery properties and multidrug resistance (Abraham et al., 2000[1]; Dubikovskaya et al., 2008[17]). Furthermore, intense efforts have been invested in improving therapeutic approaches as to increase patient survival (Bechet et al., 2008[4]; Campbell et al., 2009[7]).

Tocopherol succinate (TPS), a vitamin E analogue, is a promising and attractive compound with known anti-cancer activity toward several types of human cancer cell lines. Particularly, TPS can selectively induce apoptosis in malignant cells (Constantinou et al., 2008[13]; Neuzil, 2003[43]; Shanker et al., 2007[61]; Zhao et al., 2009[79]) while being non-toxic to normal cells and tissues. Structure-function relationship study of the terminal dicarboxylic moiety of tocopherol (TP) analogues have been previously investigated (Kogure et al., 2004[26]) and it was concluded that the apoptogenic activity depended on the length and charge of the ester moiety. Birringer et al. (2003[6]) provided further insights into the structure-function relationship of vitamin E by dividing the structure into three distinct domains. The pharmacokinetic property of TPS is similar to that of TP in which after infusion it is circulated in the blood stream by docking to lipoproteins where it subsequently targets the micro-capillary of tumor cells. In regards to its physicochemical properties, the hydrophobic nature of the molecule is responsible for the propensity of TP to bind lipoprotein and travel through the peripheral tissues followed by its sequential transfer to tumor cells. As compare to the normal tissue that exerts neutral state membrane, malignant cells possess acidic membranes in the protonated state. The inherent physicochemical property of TPS enables it to counteract this by being freely diffusible into malignant cells owing to its weak acidic nature that comprises of charged and deprotonated moieties. TPS undergoes hydrolysis and is converted to TP by nonspecific esterases from hepatocytes (Neuzil and Massa, 2005[44]; Wu and Croft, 2007[74]).

Molecular imprinting is a technique that affords the production of synthetic receptors or so-called plastic antibodies. Such molecularly imprinted polymers (MIPs) are recognition matrices that have the ability to recognize and bind specifically to compounds of interest. MIPs are known to possess higher durability than biological receptors as it is known to possess excellent thermostability, reusable and is easy to store (Bagheri et al., 2012[3]). As such, MIP has been successfully utilized for various applications such as substitutes for biological antibodies and receptors (Ye and Mosbach, 2008[76]), separation matrices for chromatography (Wei et al., 2005[71]) and solid phase extraction (Pichon and Haupt, 2006[52]), analytical sensors (Piacham et al., 2005[50]; Ton et al., 2012[69]), immuno assays (Moreno-Bondi et al., 2012[33]), drug delivery (Cunliffe et al., 2005[14]; Puoci et al., 2011[59]), enzyme inhibitor synthesis (Yu et al., 2002[77]; Zhang et al., 2006[78]) and enzyme mimetics (Piacham et al., 2003[48], 2006[49]). In recent years, molecular imprinting have been employed in the synthesis of polymers affording robust recognition properties toward several compounds of interests and several recent reviews have been published describing their potential utilizations for selective separation of compounds (Chen and Li, 2012[9]; Cheong et al., 2013[10][11]; Hu et al., 2013[23]; Murray and Örmeci, 2012[34]; Sharma et al., 2012[62]; Vasapollo et al., 2011[70]). Of particular note, is its utilization as specific drug delivery agents such as for metal-based anti-inflammatory drug (Sumi et al., 2008[66]), glycyrrhizic acid (Cirillo et al., 2010[12]), hyaluronic acid (Ali and Byrne, 2009[2]) and 5-fluorouracil (Puoci et al., 2007[60]) among others.

Molecularly imprinted polymers are prepared in essentially three major steps:

(i) Formation of template-monomer complexes, cross-linking and polymerization (Komiyama et al., 2003[27]). The first step involving the self-association of template-monomer complexes in which functional monomers affording the strongest binding are typically deemed as the optimal one to use in molecular imprinting experiments. Several approaches exist for calculating the interaction energy of template-monomer complexes:

(ii) Computational chemistry approach (i.e. involving the computation of the molecular energy of template, monomer and their complexes followed by calculating their energetic difference) (Piletsky et al., 2001[53]; Subrahmanyam et al., 2001[63]),

(iii) Data mining approach (i.e. involving the use of multivariate analysis methods such as neural network for correlating molecular descriptors with their experimental imprinting factor) (Nantasenamat et al., 2007[37], 2005[41]), molecular dynamics approach (i.e. involving the construction of atomistic model of molecularly imprinted polymer in which the cross-linked polymer contained template cavities to mimic experimental settings) (Dong et al., 2009[16]; Herdes and Sarkisov, 2009[22]; Lv et al., 2008[31]). Previously, we had successfully employed the computational chemistry approach for calculating the interaction energy of sulfonamides (Isarankura-Na-Ayudhya et al., 2008[25]) and tocopherols (Piacham et al., 2009[51]). The data mining approach was first introduced by us as a facile method that allows simultaneous modeling of molecular and solvent descriptors by means of quantitative structure-property relationship (QSPR) to make predictions of the imprinting factor values for template-monomer complexes of interests (Nantasenamat et al., 2007[37], 2005[41]). A more extensive account on computational approaches for the rational design of molecularly imprinted polymers has previously been reviewed (Levi et al., 2011[29]; Nicholls et al., 2009[45], 2011[46]). Further information on QSPR is provided in our previous review articles (Nantasenamat et al., 2009[35], 2010[38]) and the utilization of such modeling approach had successfully been demonstrated on a wide range of biological activities (Mandi et al., 2012[32]; Pingaew et al., 2012[54]; Thippakorn et al., 2009[67]; Worachartcheewan et al., 2011[72], 2009[73]) and chemical properties (Nantasenamat et al., 2007[37][39], 2008[36], 2005[41], 2013[42]).

A wide range of MIPs with specific binding properties towards TP and its derivatives has been synthesized by various polymerization techniques. Faizal and Kikuchi, (2010[19]) utilized molecular imprinting membranes synthesized via phase inversion technique bearing calix[4]resorcarenes moieties that engages in multiple non-covalent interactions with TP. The imprinted membrane was reported to bind TP over 2-folds higher than the non-imprinted membranes in methanol/water (2:1, v/v). Furthermore, Faizal et al. (2008[18]) had also employed the phase inversion imprinting technique for preparing copolymers of acrylonitrile with α-tocopherol methacrylate (TPM) monomer by means of the covalent imprinting method. Moreover, Faizal and Kobayashi (2008[20]) had also synthesized a hybrid molecular imprinting polymer for TP using pre-polymerization powders of TPM cross-linked by divinylbenzene onto a scaffold matrix of polysulfone, cellulose acetate, and nylon. Puoci et al. (2007[58]) demonstrated the use of α-TP imprinted polymer as solid phase extraction sorbents of α-TP from bay leaves extract. In our previous investigation we had successfully prepared bulk monoliths and nanospheres for selective recognition of TP and TP acetate (TPA). The study also provided mechanistic insights into the binding modes of TP-MAA and TPA-MAA complexes (Piacham et al., 2009[51]). Liu et al. (2012[30]) prepared MIP-based nano-sensing material towards TP by anchoring the MIP layer onto 1-vinyl-3-octylimidazolium ionic liquid-modified CdSe/ZnS quantum dots. Such smart material exhibited florescence quenching signal upon TP binding without the need for inducers and derivatization. TP-MIP as drug delivery devices has been investigated for their recognition characteristics in organic and aqueous media including their release property in gastrointestinal simulated fluids (Puoci et al., 2008[57]).

Molecularly imprinted polymers with binding specificity towards the apoptogenic TPS have not yet been reported. Therefore, this study aims to synthesize bulk monoliths and nanospheres via precipitation polymerization for further application as TPS delivery matrices. Computer simulation was also employed to provide pertinent insights on the binding modalities of the investigated template-monomer complexes in order to understand the origins of the observed binding performance.

Materials and Methods


Tocopherol (TP), tocopherol nicotinate (TPN), tocopherol succinate (TPS), methacrylic acid (MAA), ethyleneglycol dimethylacrylate (EDMA) and azobis-isobutyronitrile (AIBN) were purchased from Sigma-Aldrich. All solvents were of analytical or HPLC grade.

Preparation of molecularly imprinted polymer

Molecularly imprinted polymers were synthesized using TP, TPN and TPS as template molecules (Figure 1(Fig. 1)). To 10 ml of DCM, 0.5 mmol of template, 8 mmol of MAA as functional monomer, 50 mmol of EDMA as cross-linking monomer and 202 mg of AIBN were added. The pre-polymerization mixture was purged with argon for 10 min and screw-capped in a 20 ml borosilicate tube. Thermal-induced polymerization was performed in a pre-heated water bath at 60 °C for 18 h. The obtained monolithic polymer was ground by a mechanical mortar to produce particles of varying sizes. Sedimentation in acetone was performed to separate and collect particles with diameters around 10-25 μm. Templates were eluted from the polymer by using acetic acid: methanol (15 %, v/v). Spectrophotometric examinations were performed in order to determine the amount of remaining templates. Non-imprinted polymers (NIPs) were prepared in the same manner with the omission of templates.

Preparation of molecularly imprinted polymers nanospheres

Molecularly imprinted polymers nanospheres (MINs) toward TP and TPS were prepared according to Ye et al. (1999[75]). Briefly, 80 ml of pre-polymerization mixture in acetonitrile contained 0.5 mmol of template, 8 mmol of MAA, 50 mmol EDMA and AIBN. The pre-polymerization mixture was purged with argon for 15 min prior to subjecting it to thermal-induced polymerization at 60 °C for 24 h. Templates were then eluted from the obtained nanospheres using acetic acid:methanol (15 %, v/v) via Soxhlet extraction. The non-imprinted polymers nanospheres (NINs) were prepared in the absence of template molecules.

Scanning electron microscopy

Particle sizes of imprinted and non-imprinted nanospheres were determined from scanning electron microscope (HITACHI S-3400). Briefly, the nanospheres were mounted on metallic studs via double-sided conductive tape and subsequently applying gold ion coating using sputter coater (Bal-tec SCD 050) for 90 s under vacuum at current intensity of 60 mA and scanning accelerating voltage of 15 kV.

Binding analysis

Binding analysis was performed by incubating a fixed amount of template (0.1 mg/mL) against various amounts of polymers in a 1 ml microfuge tube on a rocking table at room temperature for 12 h. Supernatants were taken after centrifugation at 12,000 rpm for 5 min prior to determining the amount of template bound via spectrophotometry.

Computer simulation

Chemical structures of template molecules (i.e. TP, TPN and TPS) and functional monomer MAA were drawn into Marvin Sketch (ChemAxon Ltd.) and were subsequently converted to the Gaussian input file format using Babel (OpenEye Scientific Software). Full geometry optimizations with no symmetry constrains were then performed initially at the semi-empirical AM1 level in order to afford good starting structures for subsequent refinement at the density functional theory level using Becke's three-parameter Lee-Yang-Parr (B3LYP) (Becke, 1993[5]; Lee et al., 1988[28]) and the 6-31G(d) basis set. Single point energy calculation was then performed on these optimized structures using the B3LYP functional and 6-311++G(d,p) basis set. All computational chemistry calculations were performed using Gaussian 09 (Frisch et al., 2009[21]).

Template-monomer complexes were then constructed by using the optimized structures of template and monomer. The functional monomer MAA was placed near each of the oxygen and nitrogen atoms of the template molecule to give rise to several possible template-monomer complexes. These structures were then subjected to full geometry optimizations. Finally, the total energy of the template molecules, functional monomers and complexes were parsed from the Gaussian output files using in-house developed scripts. The interaction energy was then computed using the following equation:

represents the interaction energy, energy of template-monomer complexes, energy of template molecule and energy of functional monomer, respectively.


Molecular imprinting of tocopherols

Molecularly imprinted polymers toward TP, TPN and TPS have been successfully prepared. Results indicated that TP-MIP, TPN-MIP and TPS-MIP in DCM displayed very low binding capacity toward their respective template analytes. Such findings were in accordance with the results from our previous investigations (Piacham et al., 2009[51]). In order to resolve this situation, appropriate solvents for template rebinding were investigated using various amounts of aqueous-ethanol mixtures. It was found that the optimum ratio for the ethanol-aqueous mixture was 3:2, v/v. Such aqueous mixtures ratio displayed good rebinding and selective recognition for TP and its analogs as compared to the control non-imprinting polymer (NIP) as shown in Figure 2(Fig. 2). It should be noted that these MIPs were synthesized via thermal-induced polymerization. TP-MIP displayed recognition property greater than the MIP prepared from the previous report (Piacham et al., 2009[51]), which was also synthesized by thermal-induced polymerization. binding properties may be attributed to differences in the template and monomer content ratio and the porogenic solvent used (Puoci et al., 2007[58]). Particularly, results revealed that TP-MIP, TPS-MIP and TPN-MIP all bound its respective template molecules with 2-fold greater binding than the NIP at 10 mg polymer. The binding capacity for all MIPs was approximately 2 mg/g of polymer.

It was observed that NIP could bind TP and TPN rather non-specifically even when the polymer concentration was increased. On the other hand, NIP was shown to have low binding capacity towards TPS. It can be seen from Figure 2(Fig. 2) that 80 mg of TPS-MIP exhibited high affinity towards TPS as deduced from a binding capacity of greater than 92 % in comparison to 13 % binding by NIP at template concentration of 0.1 mg/mL while TPN-MIP, TPS-NIP, TP-MIP and TP-NIP provided binding performances of 78.2 %, 55.2 %, 92 % and 55 %, respectively. It can be seen that TPS-MIP provided over 7 folds higher % binding when compared to their control NIP while TPN-MIP and TP-MIP afforded roughly 1.5-folds higher % binding than the NIP. Such specific binding of TPS may be attributed to their inherent physicochemical properties in which the succinic moiety of TPS possesses both hydrogen bond donating and accepting properties. This may consequently lead to strong binding of TPS to MAA, which also contain hydrogen bond donating and accepting capacities. Such strong template-monomer interaction of TPS and MAA may potentially give rise to a rather defined binding cavity. On the other hand, the rather non-specific binding of MIP and NIP to their respective templates TP and TPN may be attributed to the long chain aliphatic moiety as well as the one-point monomer interactions at hydroxyl group of TP and pyridine nitrogen of TPN.

In light of the non-specific binding properties as afforded by TP-MIP and TPN-MIP, a second round of polymer synthesis was performed to produce molecularly imprinted nanospheres toward TP and TPS using the precipitation polymerization technique. Sizes and morphology of the obtained nanospheres were determined by SEM (Figure 3(Fig. 3)) to have uniform shape and size in the range of 200-400 nm, which may be suitable for future drug delivery applications. The binding capacities of TP-MIN, TPS-MIN and NIN were investigated by means of batch analysis in acetonitrile.

It was observed that 80 mg of TPS-MIN and NIN afforded binding capacities of 47 % and 19 %, respectively, while TP-MIN and NIN had binding performances of 35 % and 22 %, respectively (Figure 4(Fig. 4)). Such results indicated that TPS-MIN could bind to its template more specific than that of TP-MIN. To further enhance the binding performance of TPS-MIN, the binding solvents were subjected to optimization studies in which the aqueous content in organic solvent was varied. As shown in Figure 5(Fig. 5), 40 mg of TPS-MIN were incubated with 0.1 mg/mL of TPS in different solvent mixtures including EtOH:H2O (4:1, v/v), EtOH:H2O (3:2, v/v) and MeCN:H2O (1:1, v/v), which afforded % binding of 43 %, 22 % and 17 %, respectively for TPS-MIN while % binding of 10 %, 7 % and 8 %, respectively, for TPS-NIN. The results indicated that EtOH:H2O using a ratio of 4:1, v/v augmented the binding specificity of TPS-MIN by 4-folds higher than the control NIN.

Computer simulation of tocopherol-imprinted polymers

Mechanistic insights into the origin of the observed binding specificities for the tocopherol-imprinted polymers were deduced from computational chemistry calculations. Computational chemistry had been demonstrated to be useful in elucidating the physicochemical properties of chemical entities that is pertinent for understanding the origins of the investigated biological activities and chemical properties (Nantasenamat et al., 2012[40]; Piacham et al., 2006[49]; Prachayasittikul et al., 2007[56], 2010[55]; Suksrichavalit et al., 2008[65], 2009[64]).

First, the template and functional monomer were subjected to an initial geometry optimization at AM1 level followed by a refined optimization at DFT level using B3LYP/6-31G(d) and finally subjected to a single point energy calculation at B3LYP/6-311++G(d,p) level. Second, the optimized structures of template and functional monomer were used for subsequent geometry optimizations of template-monomer complexes by iteratively placing the functional monomer at each of the possible functional moiety of the template molecule. This resulted in several possible complexes and their corresponding interaction energy, which were obtained by calculating the energetic difference of the template, functional monomer and their complexes.

It can be seen from Table 1(Tab. 1) that TP-MAA complexes revealed interaction energies (in order of increasing values) of -46.462, -31.612, -30.683, -28.122 and -16.199 kJ mol-1 for TP-MAA complexes 1, 3, 2, 4 and 5, respectively, where its binding modalities are correspondingly shown in Figures 6a(Fig. 6), 6c(Fig. 6), 6b(Fig. 6), 6d(Fig. 6) and 6e(Fig. 6), respectively. It was observed from TP-MAA complex 1 that the hydroxyl group emanating from the benzopyran core structure acted as both hydrogen bond donor and acceptor by interacting with the two complementary functional moieties (i.e. hydroxyl and carbonyl groups) of MAA. Such two-point interaction with MAA accounted for the high interaction energy of TP-MAA complex 1. The remaining complexes essentially provided one-point interaction and consequently had lower interaction energy than that of TP-MAA complex 1.

The interaction energies for TPN-MAA complexes were -54.083, -41.588 and -23.627 kJ mol-1 for TPN-MAA complexes 2, 1 and 3, respectively, and its structures are correspondingly depicted in Figures 7b(Fig. 7), 7a(Fig. 7) and 7c(Fig. 7), respectively. As TPN could only provide hydrogen bond accepting capacity, its interaction with MAA were essentially one-point interactions. It was observed from TPN-MAA complex 2 that the nitrogen atom from the pyridine ring afforded the highest interaction energy while one-point interaction with oxygen atoms at various positions of TPN provided lower interaction energy.

Interaction energies of -76.378, -42.562, -41.882, -37.031 and -32.917 kJ mol-1 were observed for TPS-MAA complexes 1, 4, 2, 3 and 5, respectively, and its structures are correspondingly shown in Figures 8a(Fig. 8), 8d(Fig. 8), 8b(Fig. 8), 8c(Fig. 8) and 8e(Fig. 8), respectively. TPS-MAA complex 1 was found to afford the highest interaction energy of -76.378 and this could be attributed to the two-point interaction of MAA with the succinate moiety of TPS in which the carboxylic group provided both hydrogen bond donating and accepting capacities. The bond distances of interacting atoms at the site of this two-point interaction were 1.67 and 1.68 Å. Such distances were found to be the least of the investigated conformers thereby corroborating the observed high interaction energy.

The computer simulation suggested that template-monomer complexes providing the strongest binding were TPS-MAA > TPN-MAA > TP-MAA where the highest interaction energy were -76.378, -54.083 and -46.462, respectively. The high interaction energy afforded by TPS-MAA complex is in good agreement with the experimental finding that TPS-MIP also provided the best binding performance of up to 7-folds higher than the control NIP for bulk monoliths while 3-folds higher binding than the control NIP were observed for the uniformly-sized TPS-MIN.


Everyday we are constantly bombarded by a wide range of environmental factors that predisposes us to the development of cancer. Tocopherol succinate is a vitamin E derivative that has been shown to possess promising anti-cancer activity. In this work, molecularly imprinted polymers with bind- ing specificity toward tocopherol and derivatives were prepared by bulk polymerization and precipitation polymerization. TPS-imprinted polymers prepared by both methods were found to have higher specificity and selectivity than the other derivatives as deduced from 7- and 3-folds higher % binding for bulk and uniformly-sized particles, respectively. Nanospheres prepared by precipitation polymerization afforded polymers with uniform size (~200-400 nm) and shape, which are suitable for further applications in drug delivery efforts.



1. Abraham A, Sridhar N, Veeranjaneyulu A. Cancer chemotherapy and radiation induced emesis (CRIE): Current and future therapeutic approaches. Indian J Pharmacol. 2000;32:256-68.
2. Ali M, Byrne ME. Controlled release of high molecular weight hyaluronic acid from molecularly imprinted hydrogel contact lenses. Pharm Res. 2009;26:714-26.
3. Bagheri H, Piri-Moghadam H, Naderi M. Towards greater mechanical, thermal and chemical stability in solid-phase microextraction. Trends Anal Chem. 2012;34:126-38.
4. Bechet D, Couleaud P, Frochot C, Viriot ML, Guillemin F, Barberi-Heyob M. Nanoparticles as vehicles for delivery of photodynamic therapy agents. Trends Biotechnol. 2008;26:612-21.
5. Becke AD. A new mixing of Hartree-Fock and local density-functional theories. J Chem Phys. 1993;98:1372-7.
6. Birringer M, EyTina JH, Salvatore BA, Neuzil J. Vitamin E analogues as inducers of apoptosis: Structure-function relation. Brit J Cancer. 2003;88:1948-55.
7. Campbell RB, Ying B, Kuesters GM, Hemphill R. Fighting cancer: From the bench to bedside using second generation cationic liposomal therapeutics. J Pharm Sci. 2009;98:411-29.
8. ChemAxon Ltd. MarvinSketch, Version 5.11.4;Budapest, Hungary.
9. Chen L, Li B. Application of magnetic molecularly imprinted polymers in analytical chemistry. Anal Meth. 2012;4:2613-21.
10. Cheong WJ, Ali F, Choi JH, Lee JO, Yune Sung K. Recent applications of molecular imprinted polymers for enantio-selective recognition. Talanta. 2013;106:45-59.
11. Cheong WJ, Yang SH, Ali F. Molecular imprinted polymers for separation science: A review of reviews. J Sep Sci. 2013;36:609-28.
12. Cirillo G, Parisi OI, Curcio M, Puoci F, Iemma F, Spizzirri UG, et al. Molecularly imprinted polymers as drug delivery systems for the sustained release of glycyrrhizic acid. J Pharm Pharmacol. 2010;62:577-82.
13. Constantinou C, Papas A, Constantinou AI. Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs. Int J Cancer. 2008;123:739-52.
14. Cunliffe D, Kirby A, Alexander C. Molecularly imprinted drug delivery systems. Adv Drug Deliv Rev. 2005;57:1836-53.
15. Dapul-Hidalgo G, Bielory L. Climate change and allergic diseases. Ann Allergy Asthma Immunol. 2012;109:166-72.
16. Dong C, Li X, Guo Z, Qi J. Development of a model for the rational design of molecular imprinted polymer: Computational approach for combined molecular dynamics/ quantum mechanics calculations. Anal Chim Acta. 2009;647:117-24.
17. Dubikovskaya EA, Thorne SH, Pillow TH, Contag CH, Wender PA. Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters. Proc Natl Acad Sci USA. 2008;105:12128-33.
18. Faizal CKM, Hoshina Y, Kobayashi T. Scaffold membranes for selective adsorption of α-tocopherol by phase inversion covalently imprinting technique. J Memb Sci. 2008;322:503-11.
19. Faizal CKM, Kikuchi Y. Molecular imprinting membrane having calix[4]resorcarenes moieties for selective separation of α-tocopherol. In: 2nd International Conference on Chemical, Biological and Environmental Engineering 2010, pp 274-6.
20. Faizal CKM, Kobayashi T. Tocopherol-targeted membrane adsorbents prepared by hybrid molecular imprinting. Polym Eng Sci. 2008;48:1085-93.
21. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 09, revision A.1. Wallingford, Connecticut, 2009.
22. Herdes C, Sarkisov L. Computer simulation of volatile organic compound adsorption in atomistic models of molecularly imprinted polymers. Langmuir. 2009;25:5352-9.
23. Hu Y, Pan J, Zhang K, Lian H, Li G. Novel applications of molecularly-imprinted polymers in sample preparation. Trends Anal Chem. 2013;43:37-52.
24. Hunter PR. Climate change and waterborne and vector-borne disease. J Appl Microbiol. 2003;94:37S-46S.
25. Isarankura-Na-Ayudhya C, Nantasenamat C, Buraparuangsang P, Piacham T, Ye L, Bülow L, et al. Computational insights on sulfonamide imprinted polymers. Molecules. 2008;13:3077-91.
26. Kogure K, Hama S, Kisaki M, Takemasa H, Tokumura A, Suzuki I, et al. Structural characteristic of terminal dicarboxylic moiety required for apoptogenic activity of α-tocopheryl esters. Biochim Biophys Acta. 2004;1672:93-9.
27. Komiyama M, Takeuchi T, Mukawa T, Asanumi H. Molecular imprinting - from fundamentals to applications. Weinheim: Wiley-VCH, 2003.
28. Lee C, Yang W, Parr RG. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B. 1988;37:785-9.
29. Levi L, Raim V, Srebnik S. A brief review of coarse-grained and other computational studies of molecularly imprinted polymers. J Mol Recognit. 2011;24:883-91.
30. Liu H, Fang G, Li C, Pan M, Liu C, Fan C, et al. Molecularly imprinted polymer on ionic liquid-modified CdSe/ZnS quantum dots for the highly selective and sensitive optosensing of tocopherol. J Mat Chem. 2012;22:19882-7.
31. Lv Y, Lin Z, Tan T, Feng W, Qin P, Li C. Application of molecular dynamics modeling for the prediction of selective adsorption properties of dimethoate imprinting polymer. Sens Actuators B. 2008;133:15-23.
32. Mandi P, Nantasenamat C, Srungboonmee K, Isarankura-Na-Ayudhya C, Prachayasittikul V. QSAR study of anti-prion activity of 2-aminothiazoles. EXCLI J. 2012;11:453-67.
33. Moreno-Bondi MC, Benito-Peña ME, Urraca JL, Orellana G. Immuno-like assays and biomimetic microchips. Topics Curr Chem. 2012;325:111-64.
34. Murray A, Örmeci B. Application of molecularly imprinted and non-imprinted polymers for removal of emerging contaminants in water and wastewater treatment: A review. Environ Sci Pollut Res. 2012;19:3820-30.
35. Nantasenamat C, Isarankura-Na-Ayudhya C, Naenna T, Prachayasittikul V. A practical overview of quantitative structure-activity relationship. EXCLI J. 2009;8:74-88.
36. Nantasenamat C, Isarankura-Na-Ayudhya C, Naenna T, Prachayasittikul V. Prediction of bond dissociation enthalpy of antioxidant phenols by support vector machine. J Mol Graph Model. 2008;27:188-96.
37. Nantasenamat C, Isarankura-Na-Ayudhya C, Naenna T, Prachayasittikul V. Quantitative structure-imprinting factor relationship of molecularly imprinted polymers. Biosens Bioelectron. 2007;22:3309-17.
38. Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul V. Advances in computational methods to predict the biological activity of compounds. Exp Opin Drug Discov. 2010;5:633-54.
39. Nantasenamat C, Isarankura-Na-Ayudhya C, Tansila N, Naenna T, Prachayasittikul V. Prediction of GFP spectral properties using artificial neural network. J Comput Chem. 2007;28:1275-89.
40. Nantasenamat C, Li H, Isarankura-Na-Ayudhya C, Prachayasittikul V. Exploring the physicochemical properties of templates from molecular imprinting literature using interactive text mining approach. Chemometr Intell Lab Syst. 2012;116:128-36.
41. Nantasenamat C, Naenna T, Isarankura Na-Ayudhya C, Prachayasittikul V. Quantitative prediction of imprinting factor of molecularly imprinted polymers by artificial neural network. J Comput Aid Mol Des. 2005;19:509-24.
42. Nantasenamat C, Srungboonmee K, Jamsak S, Tansila N, Isarankura-Na-Ayudhya C, Prachayasittikul V. Quantitative structure - property relationship study of spectral properties of green fluorescent protein with support vector machine. Chemometr Intell Lab Syst. 2013;120:42-52.
43. Neuzil J. Vitamin E succinate and cancer treatment: A vitamin E prototype for selective antitumour activity. Brit J Cancer. 2003;89:1822-6.
44. Neuzil J, Massa H. Hepatic processing determines dual activity of α-tocopheryl succinate: A novel paradigm for a shift in biological activity due to pro-vitamin-to-vitamin conversion. Biochem Biophys Res Commun. 2005;327:1024-7.
45. Nicholls IA, Andersson HS, Charlton C, Henschel H, Karlsson BCG, Karlsson J, et al. Theoretical and computational strategies for rational molecularly imprinted polymer design. Biosens Bioelectron. 2009;25:543-52.
46. Nicholls IA, Andersson HS, Golker K, Henschel H, Karlsson BCG, Olsson GD, et al. Rational design of biomimetic molecularly imprinted materials: Theoretical and computational strategies for guiding nanoscale structured polymer development. Anal Bioanal Chem. 2011;400:1771-86.
47. OpenEye Scientific Software Babel, Version 3.3. Santa Fe, NM.
48. Piacham T, Isarankura Na Ayudhya C, Prachayasittikul V, Bulow L, Ye L. A polymer supported manganese catalyst useful as a superoxide dismutase mimic. Chem Commun. 2003:1254-5.
49. Piacham T, Isarankura-Na-Ayudhya C, Nantasenamat C, Yainoy S, Ye L, Bulow L, et al. Metalloantibiotic Mn(II)-bacitracin complex mimicking manganese superoxide dismutase. Biochem Biophys Res Commun. 2006;341:925-30.
50. Piacham T, Josell A, Arwin H, Prachayasittikul V, Ye L. Molecularly imprinted polymer thin films on quartz crystal microbalance using a surface bound photo-radical initiator. Anal Chim Acta. 2005;536:191-6.
51. Piacham T, Nantasenamat C, Suksrichavalit T, Puttipanyalears C, Pissawong T, Maneewas S, et al. Synthesis and theoretical study of molecularly imprinted nanospheres for recognition of tocopherols. Molecules. 2009;14:2985-3002.
52. Pichon V, Haupt K. Affinity separations on molecularly imprinted polymers with special emphasis on solid-phase extraction. J Liq Chromatol Rel Technol. 2006;29:989-1023.
53. Piletsky SA, Karim K, Piletska EV, Day CJ, Freebairn KW, Legge C, et al. Recognition of ephedrine enantiomers by molecularly imprinted polymers designed using a computational approach. Analyst. 2001;126:1826-30.
54. Pingaew R, Tongraung P, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, et al. Cytotoxicity and QSAR study of (thio)ureas derived from phenylalkylamines and pyridylalkylamines. Med Chem Res. 2012:1-14.
55. Prachayasittikul S, Wongsawatkul O, Worachartcheewan A, Nantasenamat C, Ruchirawat S, Prachayasittikul V. Elucidating the structure-activity relationships of the vasorelaxation and antioxidation properties of thionicotinic acid derivatives. Molecules. 2010;15:198-214.
56. Prachayasittikul V, Isarankura-Na-Ayudhya C, Tantimongcolwat T, Nantasenamat C, Galla H.J. EDTA-induced membrane fluidization and destabilization: Biophysical studies on artificial lipid membranes. Acta Biochim Biophys Sin. 2007;39:901-13.
57. Puoci F, Cirillo G, Curcio M, Iemma F, Parisi OI, Castiglione M, et al. Molecularly imprinted polymers for α-tocopherol delivery. Drug Deliv. 2008;15:253-8.
58. Puoci F, Cirillo G, Curcio M, Iemma F, Spizzirri UG, Picci N. Molecularly imprinted solid phase extraction for the selective HPLC determination of α-tocopherol in bay leaves. Anal Chim Acta. 2007;593:164-70.
59. Puoci F, Cirillo G, Curcio M, Parisi O.I, Iemma F, Picci N. Molecularly imprinted polymers in drug delivery:State of art and future perspectives. Exp Opin Drug Discov. 2011;8:1379-93.
60. Puoci F, Iemma F, Cirillo G, Picci N, Matricardi P, Alhaique F. Molecularly imprinted polymers for 5-fluorouracil release in biological fluids. Molecules. 2007;12:805-14.
61. Shanker M, Gopalan B, Patel S, Bocangel D, Chada S, Ramesh R. Vitamin E succinate in combination with mda-7 results in enhanced human ovarian tumor cell killing through modulation of extrinsic and intrinsic apoptotic pathways. Cancer Lett. 2007;254:217-26.
62. Sharma PS, D'Souza F, Kutner W. Molecular imprinting for selective chemical sensing of hazardous compounds and drugs of abuse. Trends Anal Chem. 2012;34:59-76.
63. Subrahmanyam S, Piletsky SA, Piletska EV, Chen B, Karim K, Turner APF. 'Bite-and-Switch' approach using computationally designed molecularly imprinted polymers for sensing of creatinine. Biosens Bioelectron. 2001;16:631-7.
64. Suksrichavalit T, Prachayasittikul S, Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul V. Copper complexes of pyridine derivatives with superoxide scavenging and antimicrobial activities. Eur J Med Chem. 2009;44:3259-65.
65. Suksrichavalit T, Prachayasittikul S, Piacham T, Isarankura-Na-Ayudhya C, Nantasenamat C, Prachayasittikul V. Copper complexes of nicotinic-aromatic carboxylic acids as superoxide dismutase mimetics. Molecules. 2008;13:3040-56.
66. Sumi VS, Kala R, Praveen RS, Prasada Rao T. Imprinted polymers as drug delivery vehicles for metal-based anti-inflammatory drug. Int J Pharm. 2008;349:30-7.
67. Thippakorn C, Suksrichavalit T, Nantasenamat C, Tantimongcolwat T, Isarankura-Na-Ayudhya C, Naenna T, et al. Modeling the LPS neutralization activity of anti-endotoxins. Molecules. 2009;14:1869-88.
68. Thomas P, Swaminathan A, Lucas RM. Climate change and health with an emphasis on interactions with ultraviolet radiation:A review. Global Change Biol. 2012;18:2392-405.
69. Ton XA, Acha V, Haupt K, Tse Sum Bui B. Direct fluorimetric sensing of UV-excited analytes in biological and environmental samples using molecularly imprinted polymer nanoparticles and fluorescence polarization. Biosens Bioelectron. 2012;36:22-8.
70. Vasapollo G, Sole RD, Mergola L, Lazzoi MR, Scardino A, Scorrano S, et al. Molecularly imprinted polymers:Present and future prospective. Int J Mol Sci. 2011;12:5908-45.
71. Wei X, Samadi A, Husson SM. Synthesis and characterization of molecularly imprinted polymers for chromatographic separations. Sep Sci Technol. 2005;40:109-29.
72. Worachartcheewan A, Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul S, Prachayasittikul V. Predicting the free radical scavenging activity of curcumin derivatives. Chemometr Intell Lab Syst. 2011;109:207-16.
73. Worachartcheewan A, Nantasenamat C, Naenna T, Isarankura-Na-Ayudhya C, Prachayasittikul V. Modeling the activity of furin inhibitors using artificial neural network. Eur J Med Chem. 2009;44:1664-73.
74. Wu JH, Croft KD. Vitamin E metabolism. Mol Aspects Med. 2007;28:437-52.
75. Ye L, Cormack PAG, Mosbach K. Molecularly imprinted monodisperse microspheres for competitive radioassay. Anal Commun. 1999;36:35-8.
76. Ye L, Mosbach K. Molecular imprinting:Synthetic materials as substitutes for biological antibodies and receptors. Chem Mat. 2008;20:859-68.
77. Yu Y, Ye L, Haupt K, Mosbach K. Formation of a class of enzyme inhibitors (drugs), including a chiral compound, by using imprinted polymers or biomolecules as molecular-scale reaction vessels. Angew Chem Int Ed. 2002;41:4459-63.
78. Zhang H, Piacham T, Drew M, Patek M, Mosbach K, Ye L. Molecularly imprinted nanoreactors for regioselective huisgen 1,3-dipolar cycloaddition reaction. J Am Chem Soc. 2006;128:4178-9.
79. Zhao Y, Neuzil J, Wu K. Vitamin E analogues as mitochondria-targeting compounds:From the bench to the bedside? Mol Nutr Food Res. 2009;53:129-39.

Figure 1: Chemical structures of tocopherol (TP), tocopherol nicotinate (TPN), tocopherol succinate (TPS) and methacrylic acid (MAA)

Figure 2: Rebinding experiment of tocopherol molecularly imprinted polymers (TP-MIP), tocopherol succinate molecularly imprinted polymer (TPS-MIP) and tocopherol nicotinate molecularly imprinted polymer (TPN-MIP) toward their template as well as their non-imprinted counterparts (TP-NIP, TPS-NIP and TPN-NIP)

Figure 3: Scanning electron micrograph of topherol succinate molecularly imprinted nanospheres (TPS-MIN) (a), tocopherol molecularly imprinted nanospheres (TP-MIN) (b) and non-imprinted nanospheres (NIN) (c)

Figure 4: Rebinding experiment of tocopherol succinate molecularly imprinted nanospheres (TPS-MIN), tocopherol molecularly imprinted nanospheres (TP-MIN) and non-imprinted nanospheres (NIN) toward tocopherol succinate (TPS) and tocopherol (TP)

Figure 5: Optimization of binding solvent of tocopherol succinate molecularly imprinted nanospheres (TPS-MIN)

Figure 6: Possible binding modalities as obtained from computational chemistry calculations for tocopherol-methacrylic acid (TP-MAA) complexes 1-5 (a-e)

Figure 7: Possible binding modalities as obtained from computational chemistry calculations for tocopherol nicotinate-methacrylic acid (TPN-MAA) complexes 1-3 (a-c)

Figure 8: Possible binding modalities as obtained from computational chemistry calculations for tocopherol succinate-methacrylic acid (TPS-MAA) complexes 1-5 (a-e)


Table 1: Summary of the energetic properties of templates, functional monomer and their complexes

[*] Corresponding Author:

Theeraphon Piacham, Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; phone: +66 2 441 4371, fax: +66 2 441 4380, eMail: