http://informahealthcare.com/drd ISSN: 1071-7544 (print), 1521-0464 (electronic) Drug Deliv, Early Online: 1–10 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10717544.2014.970297

REVIEW ARTICLE

Molecular imprinted polymers as drug delivery vehicles Shabi Abbas Zaidi

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Department of Chemistry, Kwangwoon University, Seoul, Korea

Abstract

Keywords

This review is aimed to discuss the molecular imprinted polymer (MIP)-based drug delivery systems (DDS). Molecular imprinted polymers have proved to possess the potential and also as a suitable material in several areas over a long period of time. However, only recently it has been employed for pharmaceuticals and biomedical applications, particularly as drug delivery vehicles due to properties including selective recognition generated from imprinting the desired analyte, favorable in harsh experimental conditions, and feedback-controlled recognitive drug release. Hence, this review will discuss their synthesis, the reason they are selected as drug delivery vehicles and for their applications in several drug administration routes (i.e. transdermal, ocular and gastrointestinal or stimuli-reactive routes).

Drug delivery system, molecular imprinted polymer, therapeutic applications

Introduction Molecular imprinted polymers (MIPs) are cross-linked polymers that exhibit specific binding sites for the template molecule. Briefly, in this procedure, a template (target) molecule is introduced in a mixture of monomer and crosslinker dissolved in a solvent resulting into three-dimensional polymer matrix. After removal of the template from asprepared polymer, the permanent cavities of the original template generated in polymer matrix correspond to shape, size and orientation of template molecules are formed which are capable to rebind selectively to the template molecules as shown in Figure 1. The obtained polymer is referred as molecular imprinted polymer (MIP). The pioneering research works of Wulff & Sarhan (1972) and Arshady & Mosbach (1981) opened up ways to imprint a range of target molecules. For the production of MIP, five different components have to be taken into account: the template, the functional monomer, the cross-linker, the porogen and the initiator. The template and its functionalities usually determine the choice of the functional monomer. The polymer is prepared via standard free radical polymerization initiated either by thermal or UV light. The polymer reaction time, temperature and amount of porogen (i.e. organic solvents or water in aqueous preparations) are responsible to determine the morphology of polymer. Finally, the obtained imprinted cavities are capable of rebinding the target molecule with a high specificity. Molecularly imprinted polymers exhibit high selectivity, and stability and durability against Address for correspondence: Shabi Abbas Zaidi, Department of Chemistry, Kwangwoon University, Wolgye-Dong, Nowon-Gu, Seoul 139-701, Korea. Tel: +82-2-940-8661. Fax: +82-29118584. E-mail: [email protected]

History Received 14 August 2014 Revised 23 September 2014 Accepted 24 September 2014

harsh conditions (e.g. thermal, mechanical, and highly acidic and basic pH conditions). Due to their high selectivity and stability, MIPs have been applied for numerous applications, such as chromatographic separation (Zaidi & Cheong, 2008, 2009; Zaidi et al., 2009, 2011; Jang et al., 2011; Zaidi, 2013a; Zaidi & Shin, 2014), recognition for peptides and biomolecules (Subat et al., 2004), capturing of hazardous radioactive waste (Bhaskarapillai et al., 2009), drug delivery (Sancho & Minguillon, 2009), solid phase extraction (Caro et al., 2005), and recognition element for electrochemical and biosensors (Zaidi, 2013b). Drug delivery is the method or process of administering a pharmaceutical compound to achieve an optimal therapeutic effect in humans or animals. Drug delivery systems (DDS) have been extensively studied and have seen a rapid growth in last few decades. The drug delivery strategy by which a drug is delivered to its target plays a vital and significant role on its efficacy. It has been known that some drugs need to be administered in an optimum concentration (controlled release) for maximum therapeutic effects, on contrary, a higher or lower amount of some drugs may induce toxicity or negligible effects on target. The release of drug at controlled rate and accurate target for required time, biocompatibility or biodegradability such that the delivery system is transformed into non-toxic fragments that are eliminated harmlessly from the body are few trivial problems in DDS. Hence, the ideal delivery vehicles will ensure that the drug is released at the right site, in the right dose and for the required time and show no toxic effects on the host body. In order to minimize the problems, interdisciplinary approaches combining pharmaceutical science, polymer chemistry and molecular biology are continuously employed. Due to their versatile properties and easily

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Figure 1. (A) Solution mixture of template, cross-linking monomer, and functional monomers (triangles, squares, circles), (B) complex formation between functional monomers and template via covalent or non-covalent chemistry, (C) the formation of the polymer network typically via free radical polymerization, and (D) template removal step which leaves binding sites specific to the original template (Reproduced with permission from John Wiley & Sons; Kryscio & Peppas, 2009).

Figure 2. Schematic diagram of four conventional categories of DDS based on mechanism of drug release: diffusion-controlled, swelling-controlled, erosion- controlled and stimuli-controlled systems (Reproduced with permission from John Wiley & Sons; Wang & Von Recum, 2011).

engineered architecture, polymer chemistry has been on the forefront of current controlled DSS. Hence, it has been reported that the majority of current controlled DDS are polymer-based. Four conventional categories of DDS, such as diffusion-controlled, swelling-controlled, erosion-controlled and stimulus-controlled systems for controlled drug release have been suggested as displayed in Figure 2. This figure also shows the properties related to all four mechanisms. Furthermore, with the rapid development of material chemistry from macro-scale to micro- and nano-scale systems, the applications of DDS have also shrunk to the nanosize materials and DDS has also extended from small pharmaceutical drugs to large biomolecules, such as proteins and peptides. Therefore, numerous reports aiming to cater the needs of polymeric nano-sized DD materials which could accommodate small and larger drug molecules facilitating easy release of intended drugs have been adapted and employed. (Gaspar & Duncan, 2009; De Souza et al., 2010; Veiseh et al., 2010; Tiwari et al., 2012; Demetzos & Pippa, 2014). Moreover, a review discussing a new type of microelectrochemical system or MEMS-based DDS called microchip (implantable microchip) has been published recently. This report presented an overview of the investigations on the feasibility and application of microchip as an advanced DDS, and their commercial manufacturing materials and methods (Sutradhar & Sumi, 2014).

Rationale for MIPs application in DDS It has been a well-known fact that polymeric materials are one of the very exciting and useful drug delivery vehicles. The drugs are dispersed within the polymer matrix designed to release it over a prolonged period of time or under certain physiological conditions; thus, overcoming the various harmful effects caused by narrow therapeutic window and the concentration below required levels. However, a burst release of drug was found prevalent in these polymeric matrixes leading to potentially serious consequences for the patients. The improved polymeric matrixes were developed, but feedback-controlled release and other problems with many polymeric DDS limited their practical application (Kumari et al., 2010; Mora-Huertas et al., 2010; Vilar et al., 2012; Sood et al., 2014). Due to their unique and outstanding features detailed in preceded section, MIPs are potential and novel alternatives as drug delivery carriers. The MIP matrix usually relies on high degree of cross-linking in order to retain the complimentary cavities and works as a drug reservoir. However, for use in drug delivery, it is usually advantageous to prepare molecularly imprinted polymer gels that are not quite as densely cross-linked, especially when water-soluble monomers are utilized. These types of MIPs show exciting change in their surfaces in response to changes in their external stimuli, including changes in temperature, solvent quality, ionic

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Figure 3. (A) Targeted drug delivery using a molecularly imprinted carrier, (B) targeted drug delivery and facilitated internalization using a MIP (Reproduced with permission from Elsevier Publications; Sellergren & Allender, 2005).

strength, pH, electric fields and irradiation with UV or visible light and presence or absence of chemical species. The imprinted hydrogels modulate (collapse and swell) to suit the conditions where the polymer is going to be used to release its load of therapeutic agent. It has also been reported that the drug release profiles of MIP-based DDS devices were not impressive compared to other controlled polymer systems, which could have been achieved with slight modifications; nevertheless, they behave as smart feedback-controlled DDS sensing the encircling environment and trigger the drug release in overexpressing of biomarker in case of any disease (Cunliffe et al., 2005; Sellergren & Allender, 2005). One of the many fascinating properties of MIPs is that they display high stability and durability against harsh conditions (e.g. thermal, mechanical, and highly acidic and basic pH conditions). MIPs can be stored in the dry state at ambient temperature for several years without losing its recognition features, resistance to crushing and grinding, and withstand in highly acidic and basic conditions. These features make MIPs as suitable candidates for sustained drug delivery formulations as they show high stability in the human body conditions, particularly gastrointestinal conditions, where pH is highly acidic and non-polymeric formulations are shown to be highly unstable leading to burst release. Another advantage of using MIPs as DDS is that the covalent or non-covalent preparations of MIPs may regulate the drug release (i.e. controlled release) actions by increasing and decreasing residence time of drug within the polymer, respectively, to avoid its side effect due to overconcentration of drug within the body at a particular time. Therefore, MIPs can help to achieve sustained release because of the affinity of the template to the functional monomer thereby increasing the residence time of the drug within the body. In the case, where

a particular enantiomer is administered to the patients, MIPs as DDS can selectively release the more effective enantiomer quite easily (Suedee, 2013a,b). In the literature, various concepts for MIP-based DDS have been discussed as described in Figure 3 (Sellergren & Allender, 2005). Besides the concept shown in Figure 3, the concept of intelligent drug delivery which refers to the predictable release of a drug in response to specific stimuli, such as the presence of another molecule has been a well-established drug release way from MIP carrier. Some excellent reviews have been published on the investigation of various aspects of MIPs in drug delivery (Byrne et al., 2002; Hillberg et al., 2005; Kryscio & Peppas, 2009; Rangasamy & Parthiban, 2010; Wang & Von Recum, 2011; Lulinski, 2013). Apart from numerous research reports published on various concepts of MIP-based DDS, some important contributions in the form of book chapters have also been devoted on extensive introduction and applications of MIP-based intelligent drug delivery (Alvarez-Lorenzo & Concheiro, 2013a,b; Alvarez-Lorenzo et al., 2013c–d). In the following sections, we will focus on the use of MIPs as various therapeutic applications. Since the first successful report on a non-covalent MIP-based DDS for sustained release of theophylline by Norell et al. (1998), several research groups used the MIPs for variety of drug delivery applications. Figure 4 shows the release characteristics for theophylline-imprinted polymers loaded with different amounts of theophylline (Norell et al., 1998).

MIP in transdermal therapeutic applications Transdermal or skin has been used extensively for drug introduction as they offer various advantages, including improved bioavailability, longer duration of action resulting

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Figure 4. Release characteristics for theophylline-imprinted polymers. Polymers loaded with: Polymer loaded with: m, 50 mg theophylline/g polymer; g, 10 mg/g; ˙, 2.0 mg/g; , 0.1 mg/g (Reproduced with permission from John Wiley & Sons; Norell et al., 1998).

in less dosing frequency, reduced side effects, more uniform plasma levels and improved therapy due to the maintenance of plasma levels over oral and intravenous routes (Ahad et al., 2014). The capability of MIPs to differentiate between enantiomers led researchers to apply MIP-based DDS for transdermal routes. Suedee group studied intelligent enantio-selective drug delivery behavior system using b-blockers, particularly, propranolol as template. It has been reported that S-isomer of propranolol is 100–130 times as active as its R-isomer, thus, S-propanolol was imprinted with methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDA) as monomer and cross-linker, respectively, and has been investigated for its administration by transdermal route (Suedee et al., 2000, 2002, 2003; Srichana & Suedee, 2001). It is worth noticing that none of the b-blockers (i.e. propranolol) have been marketed as transdermal delivery system; however, numerous research reports concentrating to investigate the skin permeation and to develop transdermal formulations of b-blockers, including propranolol and other related drugs in order to prevent the shortcomings associated with oral route have been appeared. It has been reported that propranolol exhibits longer biological half-life than would be anticipated from its plasma half-life of about 3–6 h. Furthermore, it has a logarithm partition coefficient (log P) of 3.03 and short elimination half-life of about 3 h (Zhao & Singh, 1999), which makes it a suitable candidate to be administrated through transdermal route at a controlled rate (Aqil et al., 2005). In some reports, composites were prepared using bacterially derived cellulose with MIPs for efficient transdermal delivery of S-propanolol (Bodhibukkana et al., 2006; Suedee et al., 2008) as cellulose showed enhanced streoselectivity toward S-propanolol in chromatographic applications (Okamoto et al., 1984; Suedee & Heard, 1997). They applied optimized composite of S-propanolol imprinted polymer and cellulose membrane into transdermal patches, and evaluated them in in vivo studies. It was observed that S-enantiomer was administered in better proportion compared to R-enantiomer of the same drug. These results were encouraging for the possibility of enantio-selective drug delivery devices for chiral mixtures of pharmaceutical compounds where a racemic drug can be delivered.

Furthermore, Suedee and co-workers (Jantarat et al., 2008) synthesized MIP nanoparticle-on-microspheres (NOM) with a multifunctional chiral cinchona anchor synthesized by suspension polymerization using ethylene glycol dimethacrylate as a cross-linker selective for S-propranolol in order to enhance the homogeneity of the porous cellulose-derived composite membrane and utilized their potential to act as transdermal DDS for the S-enantiomers from racemic propranolol, its ester prodrugs (cyclopropanoyl- and valerylpropranolol) or other b-blockers (pindolol and oxprenolol). The as-prepared membrane accomplished greater enentioselectivity and allowed faster rebinding due to nanoparticle nature of MIPs. Figure 5 shows the SEM images of assynthesized membranes and their corresponding drug release profiles have been shown in Figure 6.

MIPs in ocular therapeutic applications Ocular delivery route is widely used method for DDS. However, serious obstacles including high lachrymal turnover and dynamics cause quick precorneal removal of the drug arise, subsequently reducing bioavailability and therapeutic response of the drug. Furthermore, high frequency of drugs or excessive dosage of drugs may pose potential risks to the patients. Due to obstacles including low bioavailability and loading capacity of various ophthalmic solutions, ointments and gels, DDS applications involving the treatment of ocular diseases is the most active research area involving MIPs as they offer solutions for many problems in this area. AlvarezLorenzo et al. (2002) have discussed that timolol maleate, a drug commonly used in glaucoma therapy, has been imprinted as soft contact lenses, which is capable of sustained delivery of timolol. The plasma elimination half-life of timolol is between 1 and 3 h, hence, the usual topical ophthalmic dose of timolol maleate is 1–2 drops of 0.5% solution in the affected eye(s) every 4 h or hourly in the case of primary open angle glaucoma. Therefore, it is necessary to administer timolol for a prolonged period of time. Alvarez-Lorenzo and co-workers have worked extensively to increase the sustained delivery of timolol by employing variety of ways. They synthesized timolol-imprinted contact lenses primarily by cross-linking HEMA or N,N-6 diethylacrylamide (DEAA), materials

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Figure 5. SEM images of membranes: the original bacterial cellulose (A) blank cellulose cast without the addition of PCL-T, (B) blank cellulose cast with the addition of PCL-T, (C) the MIP granule, MIP microsphere and (D–F) surface, (G–I) cross-section, MIP NOM composite cellulose membranes and (J) the enlargement image of MIP-NOM composite membrane (Reproduced with permission from Elsevier Publications; Jantarat et al., 2008).

commonly used in contact lenses, with a small proportion of MAA or methyl methacrylate as a functional monomer and EGDMA as a cross-linker. It was found that varying the amount of constituents of MIP affects the condition of drug release significantly. Hence, various proportions and conditions were optimized in order to acquire the best suited drug delivery device system. In the later study, the groups of Hiratani and Alvarez-Lorenzo investigated the effects of different monomers in order to improve their capacity. They also evaluated the impact of the stoichiometry of reagents and polymerization conditions (Hiratani & Alvarez-Lorenzo, 2002, 2004; Hiratani et al., 2005a,b) and the imprinted soft contact lenses were also investigated for norfloxacin delivery systems by the same group (Alvarez-Lorenzo et al., 2006). After utilizing the super critical fluid technology in MIP-based DDS system, Alvarez-Lorenzo’s group enhanced the drug loading of MIPs and the so-called impregnatedimprinting procedure was introduced to some highly

water-soluble drugs, such as flurbiprofen (Braga et al., 2010; Yanez et al., 2011). Recently, Ketotifen fumarate, an H1-antihistamine drug and mast cell stabilizer which could be administrated via ocular route, is used to prevent allergic reactions. Venkatesh et al. (2007) utilized five different monomers and crosslinkers [Acrylic acid (AA), acrylamide (AAm), 2-hydroxyethylmethacrylate (HEMA), N-vinylpyrrolidinone (NVP), and polyethyleneglycol dimethyacrylate, 200 molecular weight (PEG200DMA)] by employing different formulation to synthesize hydrogels for novel recognitive soft contact lenses. The results demonstrated that one optimized formulation showed six times high drug loading and extended drug release profile over a period of 5 days compared to the control system. The transport and structural analysis of molecular imprinted hydrogels for same drug controlled drug delivery release were investigated extensively by Venkatesh and coworkers (2008).

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Figure 6. The release profiles of propranolol enantiomers from molecularly imprinted and non-imprinted polymers of (A) granule, (B) microsphere and (C) NOM composite bacterial cellulose membranes at the drug:polymer loading ratios of 1:35 for the granule and 1:100 for microsphere and NOM membranes. The experiment was performed by applying pH 7.4 phosphate buffer as medium to the membranes at room temperature (mean ± S.D., n ¼ 3) (Reproduced with permission from Elsevier Publications; Jantarat et al., 2008).

MIPs in oral therapeutic applications Oral drug delivery route has been the most convenient and effective route albeit the physiological effects of gastrointestinal tract, such as irritation, metabolism, variation in delivery rates and interference due to presence of food. Some novel polymeric particles and MIP-based systems were developed for enhanced oral bioavailability of some drugs (Delie & Blanco-Prieto, 2005). 5-fluorouracil (5-FU), an anticancer drug, is used to treat several solid cancers, such as breast, colorectal, brain and liver cancer. Due to its high metabolism in body, continuous administration of 5-FU is required in order to maintain high serum concentrations of this drug to improve its therapeutic activity. It may lead to high dosage of this drug, which produces serious toxic effects (Johnson et al., 1999). It can be avoided by a controlled release of 5-FU as reported in polypeptide- and polysaccharide-based drug delivery devices (Fournier et al., 2004). However, it was believed that the therapeutic importance of 5-FU and the technological significance of molecular imprinting polymers, which acts as base excipients for the controlled release of drugs with narrow therapeutic index to avoid its side effect due to over concentration of drug within the body at a particular time may further enhance the controlled release of 5-FU. It increases bioavailability, and reduces side effects compared to some traditional delivery systems. Puoci et al. (2007) synthesized a 5-FU imprinted polymer using MAA and EDMA to form a copolymer and evaluated its ability for sustained release in in vitro experiments. The studies performed in both gastrointestinal and in plasma simulating fluids demonstrated that MIPs were highly selective toward 5-FU compared to the non-imprinted one, and exhibited sustained release for the period of 30 h. To improve the delivery system of 5-FU over the application of MIP technology, Singh & Chauhan (2008) synthesized imprinted hydrogels containing 2-hydroxyethyl methacrylate, acrylic acid and N,N-methylenebisacrylamide and demonstrated greater loading and controlled release of 5-FU compared to non-imprinted systems. The hydrophilic imprinted nanospheres were also fabricated by one-pot precipitation

Figure 7. Release profile of sulfasalazine from SMIPs and SNIPs at pH 1 from 0 to 2 h, and at pH 6.8 from 2 to 20 h (Reproduced with permission from John Wiley & Sons; Puoci et al., 2004).

method for sustained release of 5-FU. The characterization was carried out and results of imprinted and non-imprinted polymers were compared (Cirillo et al., 2009). Many groups investigated the tunable and versatile characteristics of MIP and their synthesis methods, such as their stimuli-response (i.e. thermo-response, pH response, photoresponse) (Liechty et al., 2010; Puoci et al., 2008a; Suedee et al., 2010) factors, swelling behavior of MIP particles, and hydrophobicity and hydrophilicity to tailor the properties of MIPs for desired materials. For example, Puoci’s group (2004) synthesized spherical MIPs (SMIPs) via novel precipitation polymerization approach using sulfasalazine and studied the effect of pH on drug release profiles of SMIPs and spherical non-imprinted polymers (SNIPs as seen in Figure 7). It is clearly revealed that SMIPs demonstrated a better controlled release of drug compared to that obtained from SNIPs in physiological conditions (pH 6.8). Li et al. (2010) developed a pH-responsive switchable low cross-linked, molecularly imprinted insulin delivery system using pH-dependent interpolymer interactions between poly(methacrylic acid) (PMAA) and poly(ethylene glycol) (PEG). The as-synthesized MIP hydrogel exhibited a relatively slow release at acidic conditions (such as pH 3.5),

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whereas, at neutral or basic conditions (such as pH 7.4), this delivery system was comparable to a non-imprinted hydrogel and caused a rapid release resulting from the dissociation of the PMAA-PEG complexes. Recently, MIP-based DDS was introduced for the controlled release of thiamine hydrochloride (THC), an important member of vitamin B. It controls kidney diseases in type II diabetic patients, whereas, its deficiency which may happen due to an insufficient absorption of vitamin in human body causes conditions, such as beriberi, characterized by accumulation of body fluids (swelling), pain, paralysis and ultimately death. So, a controlled DDS is needed for its release in intestine (Anirudhan et al., 2013). They prepared and characterized novel MIP based on THC-imprinted silylated-montmorillonite with itaconic acid. In the optimizing experimental conditions, the as-synthesized MIP showed excellent diffusion-controlled release of THC up to 8 h. The percentage release of THC at 7.4 (intestinal fluid) was slow but continuous up to 8 h. Within 150 min, 67.8% of THC was released from MIP at pH 7.4 and 9.8% at pH 1.4 (gastric fluid). The release rate at pH 1.4 was observed to be very low owing to the absence of swelling of MIP in less pH. The poor solubility in water and instability in physiological medium restrict the use of oral delivery of quercetin (QC), which is a valuable anti-inflammatory, antioxidant and anticancer agent. Therefore, Curcio et al. (2012) synthesized QC-imprinted nanospheres exploiting the non-covalent imprinting approach using MAA as functional monomer, able to interact with the template by hydrogen bonds, and EGDMA as cross-linking agent. The synthesized MIP exhibited high drug loading and showed excellent in vitro drug release profile for more than 48 h. It was observed that drug release from MIP was about 13% of the loaded drug compared to non-imprinted polymer (NIP) release percentage of 40% in 30 min, suggesting burst release of NIP. Pantoprazole, a proton pump inhibitor, is used in clinical treatment of gastric ulcers, gastro-esophageal reflux and Helicobacter pylori with other drugs. However, it is unstable in acidic conditions, heat and light. Thus, to improve its bioavailability and efficacy in oral delivery route, Mohajeri et al. (2014) prepared a pH-sensitive pantoprazole imprinted polymer and studied drug-binding and releasing properties. It was shown that MIP offered sustained release of pantoprazole at all pH values and also had stronger protective effect in acidic media as compared to the NIP. In addition, several other MIP-based systems have also been used to study the extended release of other pharmaceuticals, such as a-tocopherol (Puoci et al., 2008b), tramadol (Azodi-Deilami et al., 2010), glycyrrhizic acid (Cirillo et al., 2010a), tetracycline (Cai & Gupta, 2004), molsidomine (Lulinski & Maciejewska, 2009), diclofenac (Mohajeri et al., 2012), and phytic acid (Cirillo et al., 2010b). These works led to the fast development of MIP-based DSS. Mashelkar group employed metal-ion coordination and molecular imprinting method for p-aminobenzoic acid pendant chain-linked delivery systems (Kalmarkar et al., 1997). Furthermore, a novel and interesting metal-chelate imprinting DDS has also been developed for a metal-based drug, copper salicylate using metal-chelate embedded polymer (MCEP) material by Sumi et al. (2008). The X-ray

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photoelectron spectroscopy (XPS), flame atomic absorption spectroscopy (FAAS) and high-performance liquid chromatography (HPLC) techniques were performed in order to confirm the successful removal of templates from the polymer and the drug release behavior was examined in vitro with polymer materials having different template to monomer ratio, different cross-linker density and with polymer material loaded with copper salicylate to different extent. Finally, it was concluded that MIP-based material offered better drug loading and higher sustained release over a long period of time. Erythromycin (ERY) is employed to treat upper and lower respiratory tract, skin, soft tissue and genitals. The systematic delivery of ERY faces many challenges, such as poor adsorption, acid degradation in stomach and toxic effects at prolonged treatments. It requires novel therapeutic strategies and dosage regimes. Among many polymer-based nanoparticles, polymer which seeks its targeted and/or sustained release, ERY-MIP-based delivery system has proved to be highly successful. Recently, ERY-imprinted poly(methacrylic acid-co-trimethylolpropane trimethacrylate) nanocarriers and corresponding control nanocarriers were prepared by freeradical precipitation polymerization and erythromycin in vitro release studies were carried out in physiological buffer media. The successful syntheses of MIP nanocarriers were confirmed by TEM dynamic light scattering and nitrogen sorption analysis. It was found that erythromycin loading capacity was 76 mg/g with a loading efficiency of 87%, while the release studies depicted an initial burst release of a quarter of loaded erythromycin during the first day and an 82% release after a week (Kempe et al., 2014). In another recent report, an innovative delivery system for carbazole derivatives (1,4-dimethyl-6-hydroxy-9H-carbazole, CAB1 as template and its analogue 6-bromo-1,4-dimethyl9H-carbazole, CAB2 for comparison) in targeted cancer therapy combining drug controlled release ability of MIP with magnetic properties of magnetite was studied. The authors describe that the carbazole derivatives imprinted materials were highly selective and exhibited controlled release properties with an excellent magnetic responding capacity. The as-synthesized polymeric materials were employed on different cancer cell lines, such as HeLa and MCF-7, successfully (Parisi et al., 2014).

Challenges in MIPs as DD systems Reviewing numerous reports and review articles, it is worth noticing that MIPs-based DDS systems exhibit greater potential and a burgeoning field representing one of the major research and development focus areas in drug delivery today. However, it also faces obvious obstacles, such as controlling balance pharmacokinetics and pharmacodynamics, toxicity and biocompatibility of employed polymer, selective recognition, efficacy of drug loading and release, behavior of MIPs in surrounding environment. For example, the demand of biocompatibility of MIPs significantly reduced the choice of effective functional monomers and crosslinker for the imprinting process, because many of them are highly toxic. Second, most of the polymerization reactions are carried out in organic solvent contrary to the aqueous

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environment required for in-vitro mimicking. Thus, a careful optimization of experimental parameters is essential. In order to improve drug efficacy, distribution of the binding sites and morphological uniformity are required, hence, better polymerization procedure need to be utilized. Furthermore, synthesis reproducibility is also a very important factor for ensuring the robustness and practicability of MIPs. Hence, it can be deduced that MIPs as the drug delivery devices have yet not found any commercial applications. There is still a lot of research that should to be carried out to overcome some of the problems stated above. However, interesting investigations are in progress to apply MIPs as the drug dosage forms.

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Conclusion and future perspective Molecular imprinted polymers are now well established and have a potential approach for electrochemical sensors, molecular recognition, chromatographic separation and analytical sample enrichment but their use as active biomedical devices, such as in drug delivery vehicles is still in the early stages of development as discussed in this work. Although, MIP-based drug carriers have been employed in a variety of drug delivery routes, but, their biocompatibility, and efficacy of drug release have posed greater challenges among the scientists. However, it can be expected that on the basis of current trends and procedures it is most probable that some of the more exciting future developments in drug delivery and therapeutic monitoring will rely on some form of real-time analysis in order to affect an intelligent, feedback responsive outcome of MIP-based DDS systems. It has to be shown in the near future that MIP-based DDS systems may be the real contender for existing drug delivery vehicle materials in biomedical device areas. Furthermore, some elegant studies have established the potential of implantable microchip-based controlled drug delivery. The hybrid of MIPs and microchipbased DDS may prove to be promising biomedical devices in the near future.

Acknowledgements Author thanks Dr Akbar Nawab (College of Medicine, University of Florida, USA) for his helpful comments and discussion.

Declaration of interest The author reports no conflict of interest. The financial support of the Kwangwoon University fund in 2014 is greatly acknowledged.

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