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Molecular imprinting: A useful approach for drug delivery
Materials Science for Energy Technologies 3 (2020) 72–77
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Materials Science for Energy Technologies
CHINESE ROOTS GLOBAL IMPACT
journal homepage: www.keaipublishing.com/en/journals/materials-science-for-energy-technologies
Molecular imprinting: A useful approach for drug delivery Shabi Abbas Zaidi Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha 2713, Qatar
a r t i c l e
i n f o
Article history: Received 24 April 2019 Revised 28 October 2019 Accepted 29 October 2019 Available online 1 November 2019 Keywords: Molecular imprinted polymer Synthesis Drug delivery
a b s t r a c t Molecular imprinting polymers (MIPs) is an artificial receptor of target molecules and functions as biomimetic way of natural antibody-antigen systems. Their mechanism can be understood from lock and key mechanism, thus indicating that MIPs selectively bind the molecule with which they were templated during synthesis. Among many beneficial applications of MIPs, drug delivery is considered an excellent and promising method of sustained release of drug to achieve desired therapeutic results. Thus, many scientists devoted their research to learn the potential method of their synthesis and to improve the control release of imprinted drugs in desired environment. In this review, we focus and comprehensively explains about MIPs as drug delivery systems (DDS) and their progress in last 3 years. In the end, the challenges faced during their synthesis and applications are discussed. Ó 2019 The Author. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
1. Introduction The Molecular imprinting technique are a very well-known phenomenon used for the synthesis of Molecular imprinting Polymers (MIPs) [1–5]. In the preparation of MIPs, a complex is formed between a target analyte and a functional monomer followed by polymerization in the presence of excess of cross-linking monomer and appropriate solvent. The polymerization can be carried out via thermal polymerization, electricity, and UV etc. In different cases, other constituent may also be required such as an initiator. Once the polymerization is stopped, the trapped template molecules are extracted from the polymer with the help of organic solvents leaving behind as 3-D polymer. This polymer possess the recognition sites exactly in shape, size and chemical functionality as the template molecule. Usually, non-covalent and covalent bonding drive the molecular recognition phenomena between the template analytes and functional monomer groups. The non-covalent bonding interaction is commonly preferred owing to convenient binding and rebinding phenomenon [6–11] The development of electrochemical sensors and biosensors is one of the most discussed field of research [12–16]. Due to their
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features such as high sensitivity and selectivity, MIPs are extensively employed to obtain robust molecular recognition materials able to mimic natural recognition entities including antibodies and biological receptors [17]. Moreover, they literally have shown their tremendous potential in numerous areas including recognition for biomolecules [18–20], proteins detection [21], proteomic analysis [22], capturing of hazardous radioactive waste [23,24], sensors [25–27], drug delivery [28], and chromatographic separation [29,30]. Apart from many different ways employed for drug delivery [31], one of the fascinating method of drug delivery is the utilization of MIPs as drug delivery systems (DDS) [32]. The management of drug delivery is widely studied branch in which a drug is delivered to its target and its efficacy is controlled. Furthermore, some drugs need to be administered over an extended period of time (controlled release) to achieve the maximum therapeutic effect for drugs that are rapidly metabolized and eliminated from the body after administration [33]. This is also widely known that a lower or higher dose of a drug may cause detrimental effects such as toxicity or no effects at all. Therefore, in order to achieve the control release and maximum therapeutic benefits of drugs, the synergistic effect of various approaches involving pharmaceutical science, polymer chemistry and molecular biology are integrated and utilized. Apart from many biomaterials being employed in Therapeutics and Diagnostic [34–36], polymeric DDS are good candidate for effective drug delivery but sometimes they exhibit burst release of drug due to unfavorable harsh surrounding conditions such as (e.g. thermal, mechanical, and highly acidic and basic pH
https://doi.org/10.1016/j.mset.2019.10.012 2589-2991/Ó 2019 The Author. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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conditions) of environment, or human body. However, the utilization of MIPs based DD vehicles showed better performance in terms of drug release, and hence, their application in DDS is overwhelming. The enhanced affinity of the template to the functional monomer, thereby increasing the residence time of the drug (in vivo/in vitro), high drug loading capacity of an MIP material, their high stability and durability against harsh conditions, easy regulation of cross-linking ability of polymer, and utilization of non-covalent or covalent interactions are few lucrative features. These characteristics make MIP an obvious choice of DDS [37,38]. Some notable and interesting works on MIP based DDS were summarized in previous years [39–41]. However, in this work, we intend to discuss the benefits offered by molecular imprinting technique and the latest progress in MIP based DDS in last 3 years. We discussed the synthesis strategy undertaken in various works for better understanding. In the last, we highlighted the challenges and the future perspectives. 2. Discussion of MIP based DDS Suksuwan et al. prepared an enantioselective drug delivery receptor for thermoresponsive R-thalidomide imprinted nanoparticles using methacrylic acid, a fluorescently active 2,6-bis (acrylamido)pyridine and N,N’ methylene-bis-acrylamide via both a covalent approach and a physical approach. The nanoparticles sizes were as small as 100 nm. The results suggested that the MIP nanoparticles prepared by physical approach exhibited the potential to make the drug effective for attacking multidrugresistant cell under suitable temperature conditions [42]. Rivastigmine is an acetylcholine esterase inhibitor of the carbamate type. It is for the treatment of Alzheimer’s disease. Hemmati et al. prepared a magnetic nanocomposite of MIP and graphene oxide (GO). They obtained the desired imprinted matrix polymer via a cocktail of acrylamido-2-methyl-1-propanesulfonic acid (AMPS) as functional monomer and ethylene glycol diacrylate (EGDA) as cross-linker in the presence of acrylate functionalized Fe3O4 nanoparticles. The adsorption mechanism of rivastigmine by polymer followed the Langmuir model with the maximum capacity of 71.41 mg/g, the kinetic data well fitted to pseudo first-order model, and the selectivity factor (e) was 1.98 comparing to the nonimprinted polymer. The cytotoxicity experiments indicated the high biocompatibility of polymer materials due to the 84.4% cell viability at high concentration (1 mg/mL) [43]. Zhang et al. used pH and glutathione stimulated double responsive surface molecular imprinting polymer (SMIP) with doxorubicin (DOX). The DOX molecules imprinted on the surface of mesoporous silica nanoparticles (MSNs). It was observed that 10.5 ± 0.2 wt% of DOX can be loaded over MNSs with loading efficiency of 70 ± 8%. The authors found that the higher amount of DOX can be released owing to the synergistic decomposition of sulphur-sulphur bonding with an acidic pH and glutathione (GSH) compared to physiological conditions as shown in Fig. 1. Moreover, the released DOX was able to inhibit TCA8113 cells growth with the low cytotoxicity [44]. Wang et al. used frontal polymerization for the synthesis of hydrogel-based MIP using a mixture of gatifloxacin (template), N-isopropylacrylamide, acrylic acid and N,N’-methylenebisacrylamide. Frontal polymerization (FP) allows the conversion of monomer into polymer in a localized reaction zone that propagates in an unstirred medium, able to selfsustain and propagate throughout the monomeric mixture and offers simpler reaction route, shorter time, and lower energy consumption than batch polymerization (BP). The release of gatifloxacin from hydroMIPs could be controlled by pH and temperature. The In vivo pharmacokinetic study showed adsorption and elimination of drug reached equilibrium between 2 and 10 h [45].
Fig. 1. Release curves of DOX from the nanocarrier under different conditions (Reproduced with permission from Ref. [44]).
Neurological disorders are complex and cause major health problems causing high ill effects and disabilities in humans. This may cost escalated burden on economy. L-DOPA is an amino acid precursor to the neurotransmitter dopamine extensively used as a prodrug for the treatment of Parkinson’s disease. However, LDOPA is an unstable compound: when exposed to light or added to aqueous solutions, it may degrade, compromising its therapeutic properties. Thus, MIP can offer a remedy where a large amount of L-DOPA is imprinted and b-cyclodextrin (b-CD) used to prepare nanocarrier for L-DOPA as they make inclusion complex. The MIP-b-CD nanosponges released appropriate amount of L-DOPA in acidic condition. It is shown that L-DOPA is stable in acidic condition, however, it degraded at neutral condition [46]. Bakhshizadeh et al. presented core-shell TiO2-based Mitoxantrone imprinted nanoparticles DDS by using Poly (Methacrylic acid-co-polycaprolctone diacrylate) and other functional monomer (such as 4-vinylpyridine, 4-VP) as well. In this work, TiO2 and MIP were employed as core and shell, respectively. The results indicated that MAA-based MIP offered better binding properties in comparison to its non-imprinted polymer (NIP) and higher imprinting factor value than MIP-4VP [47]. Antibacterial wound dressing is a good method for DDS. Thus, Kurczewska and colleagues prepared a vancomycin drug encapsulated in alginate matrix to obtain a potential antibacterial wound dressing. The incorporation of alginate in the imprinted polymer exhibited lower release of vancomycin as compared to the polymer without the alginate from 87% to 47% in 24 h. The release profile found to be diffusion and swelling controlled mechanism (non-Fickian transport) and demonstrated antibacterial activity towards selected bacteria strains successfully [48]. A well-known group of Suedee showed the preparation of insulin-imprinted polymer nanoparticles as a potential oral DDS. The MIP nanoparticles exhibited a significantly higher release of insulin in solution at pH 7.4 than at pH 1.2 with non-Fickian transport. An in vivo study conducted at diabetic Wistar rats confirmed the glucose reduction in 24 h. Moreover, the change in the ratio of functional monomer and cross-linkers controlled the response of blood glucose level [49]. Pawley et al. studied the drug delivery kinetics of a nanoporous matrix using a MIP. In this work, the release profile of acetylsalicylic acid (aspirin) loaded on Ag nanoporous matrix measured at regular time intervals. The release of aspirin demonstrated that the metalorganic framework releases the drug steadily over the course of the first hour, after which
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the concentration reaches a plateau. This release phenomenon of drug release attributed to substantial number of nano-scale pores, high adsorption capacity, and favorable mechanical properties of metalorganic matrix over other types of nanomaterials [50]. In DDS, targeted drug delivery is a critical issue which focuses to kill diseased cells while leaving healthy cells unharmed. Hence, the overexpressed cells are considered as targets and the corresponding ligands are used as targeting moieties and conjugated onto the surface of drug carriers. Epitope imprinting is used in some targeted DDS. For example, inducible epitope imprinting by Liu et al. where a target flexible peptide chain can go through conformational change from disordered-to-ordered by suitable inducement through a molecular imprinting procedure. The prepared MIP nanoparticles in this way adjust the original peptide and binds specifically to the corresponding protein as needed. The study performed in vivo tests in xenograft mouse model and showed a stronger inhibitory effect on HeLa subcutaneous xenografts as compared to non-imprinted polymer nanoparticles with high bio-compatibility [51]. Li group also presented a hidden epitope imprinting procedure in which Fibroblast growth factor-inducible 14 that is overexpressed in a range of solid tumor types such as breast cancer, brain tumors, and pancreatic cancer and its transmembrane domain were used as target receptor and template. The fabrication and recognizing method is shown in Fig. 2. As shown in the figure, firstly the disordered peptide converted to ordered template before its polymerization in the presence of functional monomer followed by template removal. The construction of these polymeric nanoparticles assisted in improved cellular uptake and permeability in target tissues for tumor-targeted drug delivery without any change in native conformation of template peptide [52]. HER2 is a human epidermal growth factor receptor and is over expressed in 30% of ovarian cancers. Thus, Hashemi-Moghaddam group synthesized an artificial conformational epitope of the HER2 antigen and used as template together with DOX for the synthesis of an MIP using dopamine as a functional monomer on the surface of silica Silica nanoparticles (SiNPs). The size of MIPs NPs were approximately 80 nm in size, suitable for small nanodrugs delivery. It was observed that the MIPs exhibited controlled release of DOX which suppressed the ovarian cancer tumor size effectively to those of only DOX imprinted polymers or only DOX biodistribution [53].
Marcelo et al developed a pH-responsive MIP for oral DDS for metronidazole (MZ) based on itaconic acid and ethylene glycol dimethacrylate (EGDMA) via supercritical fluid technology. Supercritical fluids are considered an alternative to organic solvents due their excellent properties such as nontoxicity, non-flammability and low critical point, leaving the solute without any solvent residues and ready-to-use dry powders, with no need of further drying. Under optimum conditions, MIP showed higher uptake ability with MZ loading of 18–61 wt% in MIPs, compared to 7– 20 wt% in NIPs indicating the drug partition between the supercritical fluid and polymeric phases significantly. Furthermore, MIPs release higher amounts of MZ at the lowest pH than at pH 7.4 as shown in Fig. 3 [54]. Nichols and co-workers prepared prostaglandin derivative, (bimatoprost used in the treatment for glaucoma) imprinted MIP hydrogel for ocular drug delivery with help of various functional monomer including 2-hydroxyethyl methacrylate (HEMA), dimethylaminoethyl methacrylate (DMA), and tetraethylene glycol dimethacrylate (TEGDMA). The results showed that HEMA based backbone structure prove to serve as a viable drug delivery system that can be used multiple times. This type of hydrogel can be easily integrated in contact lenses and is capable of withstanding over 10,000 cycles of the mechanical movement of swelling without affecting the drug delivery ability of the lens [55]. Abdollahi et al. reported about the development of phenytoin imprinted DDS using acrylamide (AAm) and ethylene glycol dimethacrylate (EGDMA) by via reversible addition fragmentation transfer polymerization (RAFT) with different cross-linker content. The results of the MIP-RAFT system showed much extended release profile from 12 h (unloaded drug) to 40–140 h, better imprinting factor, and delayed release profile compared with MIPs prepared with traditional radical polymerization (TRP) [56]. Han and colleagues developed cancer antigen 125 (CA125) imprinted MIPs on the surface of graphene oxide for drug delivery of DOX. As shown in the results, GO-MIP exhibited high loading capacity as compared negligible loading of DOX on MIP. The high DOXloading capacities and encapsulation efficiency of composite based on GO resulted from combination of the P- P stacking interaction between the GO and DOX and the electrostatic interaction between GO and DOX. The P- P stacking interaction between the GO and DOX occurs due the existence of oxygen containing groups and aromatic sp2 hybrid domains of GO which assist in high loading of DOX. It was shown in Fig. 4 that higher amount of drug was released at acidic pH which is beneficial because acidic condition
Fig. 2. Polymeric nanoparticles specifically recognizing the transmembrane helical domain of a membrane receptor (Reproduced with permission from Ref. [52]).
Fig. 3. Release profiles of MZ polymers after immersion in pH 2.2 solution, for 4 h, and pH 7.4 PBS solution, for 4 h (Reproduced with permission from Ref. [54]).
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treat them but high production cost and low stability are the major issues. Canfarotta et al. tackled these problems by synthesizing double-imprinted nanoparticles (nanoMIPs) that were capable of loading of cytotoxic acgen DOX and selectively recognizing EGFRover-expressing cells. The fabrication scheme and TEM images of EGFR nanoMIPs depicted in Fig. 5. This work demonstrated that a DOX loading in nanoMIPs were responsible to more-profound cell death [58]. 3. Challenges
Fig. 4. The release of DOX on GO-MIP-DOX at different pH values (Reproduced with permission from Ref. [57]).
is prevalent in tumor cells. Moreover, GO-MIP-DOX presented much more cytotoxicity to target tumor cells than normal cells with good biocompatibility [57]. A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is a potential marker of breast, colorectal, and lung cancers. Although anti-EGFR antibodies can be effectively used to
The MIP based DDS offers great advantages being cost effective, enhanced stability, better tailoring properties. These systems have shown tremendous development, nevertheless, there are many hurdles that need to be addressed for their application in commercial purposes. Controlling the balance between pharmacokinetics and pharmacodynamics, the selective recognition, release the toxicity and biocompatibility of the employed polymer, the efficacy of drug loading, and the behavior of the MIPs in the surrounding environment are few of them. Despite much strategies opted for adequate drug loading and their effective therapeutic release, either the quick release or an initial burst release of a high percentage of the drug molecules is detrimental for normal cells. In hydrogel MIPs, the deformation of imprinted cavities of MIPs in solvent is another issue due to swelling behavior. More steps needs to be taken for the preparation of surface imprinted DDS in order to high drug release without much complexity. One of the critical issue is the lack of in vivo study is few
Fig. 5. (a) Scheme of the solid-phase synthesis process for double-imprinted nanoMIPs using a peptide epitope of EGFR as primary template attached to the solid phase and doxorubicin as secondary template in solution. (b) The 3D structure of EGFR shown in blue is the sequence of the peptide template used for nanoMIPs fabrication, and the antigenic region for the therapeutic antibody cetuximab, which targets the same receptor, is shown in yellow. (c, d) TEM images of EGFR nanoMIPs at (c) 20,000 magnification and (d) 80,000 magnification. Scale bars are, respectively, 1 lm and 200 nm (Reproduced with permission from Ref. [58]). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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cases. Without this study, how can one see the effect and biocompatibility of drug in real conditions?
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Contents lists available at ScienceDirect
Materials Science for Energy Technologies
CHINESE ROOTS GLOBAL IMPACT
journal homepage: www.keaipublishing.com/en/journals/materials-science-for-energy-technologies
Molecular imprinting: A useful approach for drug delivery Shabi Abbas Zaidi Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha 2713, Qatar
a r t i c l e
i n f o
Article history: Received 24 April 2019 Revised 28 October 2019 Accepted 29 October 2019 Available online 1 November 2019 Keywords: Molecular imprinted polymer Synthesis Drug delivery
a b s t r a c t Molecular imprinting polymers (MIPs) is an artificial receptor of target molecules and functions as biomimetic way of natural antibody-antigen systems. Their mechanism can be understood from lock and key mechanism, thus indicating that MIPs selectively bind the molecule with which they were templated during synthesis. Among many beneficial applications of MIPs, drug delivery is considered an excellent and promising method of sustained release of drug to achieve desired therapeutic results. Thus, many scientists devoted their research to learn the potential method of their synthesis and to improve the control release of imprinted drugs in desired environment. In this review, we focus and comprehensively explains about MIPs as drug delivery systems (DDS) and their progress in last 3 years. In the end, the challenges faced during their synthesis and applications are discussed. Ó 2019 The Author. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
1. Introduction The Molecular imprinting technique are a very well-known phenomenon used for the synthesis of Molecular imprinting Polymers (MIPs) [1–5]. In the preparation of MIPs, a complex is formed between a target analyte and a functional monomer followed by polymerization in the presence of excess of cross-linking monomer and appropriate solvent. The polymerization can be carried out via thermal polymerization, electricity, and UV etc. In different cases, other constituent may also be required such as an initiator. Once the polymerization is stopped, the trapped template molecules are extracted from the polymer with the help of organic solvents leaving behind as 3-D polymer. This polymer possess the recognition sites exactly in shape, size and chemical functionality as the template molecule. Usually, non-covalent and covalent bonding drive the molecular recognition phenomena between the template analytes and functional monomer groups. The non-covalent bonding interaction is commonly preferred owing to convenient binding and rebinding phenomenon [6–11] The development of electrochemical sensors and biosensors is one of the most discussed field of research [12–16]. Due to their
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features such as high sensitivity and selectivity, MIPs are extensively employed to obtain robust molecular recognition materials able to mimic natural recognition entities including antibodies and biological receptors [17]. Moreover, they literally have shown their tremendous potential in numerous areas including recognition for biomolecules [18–20], proteins detection [21], proteomic analysis [22], capturing of hazardous radioactive waste [23,24], sensors [25–27], drug delivery [28], and chromatographic separation [29,30]. Apart from many different ways employed for drug delivery [31], one of the fascinating method of drug delivery is the utilization of MIPs as drug delivery systems (DDS) [32]. The management of drug delivery is widely studied branch in which a drug is delivered to its target and its efficacy is controlled. Furthermore, some drugs need to be administered over an extended period of time (controlled release) to achieve the maximum therapeutic effect for drugs that are rapidly metabolized and eliminated from the body after administration [33]. This is also widely known that a lower or higher dose of a drug may cause detrimental effects such as toxicity or no effects at all. Therefore, in order to achieve the control release and maximum therapeutic benefits of drugs, the synergistic effect of various approaches involving pharmaceutical science, polymer chemistry and molecular biology are integrated and utilized. Apart from many biomaterials being employed in Therapeutics and Diagnostic [34–36], polymeric DDS are good candidate for effective drug delivery but sometimes they exhibit burst release of drug due to unfavorable harsh surrounding conditions such as (e.g. thermal, mechanical, and highly acidic and basic pH
https://doi.org/10.1016/j.mset.2019.10.012 2589-2991/Ó 2019 The Author. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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conditions) of environment, or human body. However, the utilization of MIPs based DD vehicles showed better performance in terms of drug release, and hence, their application in DDS is overwhelming. The enhanced affinity of the template to the functional monomer, thereby increasing the residence time of the drug (in vivo/in vitro), high drug loading capacity of an MIP material, their high stability and durability against harsh conditions, easy regulation of cross-linking ability of polymer, and utilization of non-covalent or covalent interactions are few lucrative features. These characteristics make MIP an obvious choice of DDS [37,38]. Some notable and interesting works on MIP based DDS were summarized in previous years [39–41]. However, in this work, we intend to discuss the benefits offered by molecular imprinting technique and the latest progress in MIP based DDS in last 3 years. We discussed the synthesis strategy undertaken in various works for better understanding. In the last, we highlighted the challenges and the future perspectives. 2. Discussion of MIP based DDS Suksuwan et al. prepared an enantioselective drug delivery receptor for thermoresponsive R-thalidomide imprinted nanoparticles using methacrylic acid, a fluorescently active 2,6-bis (acrylamido)pyridine and N,N’ methylene-bis-acrylamide via both a covalent approach and a physical approach. The nanoparticles sizes were as small as 100 nm. The results suggested that the MIP nanoparticles prepared by physical approach exhibited the potential to make the drug effective for attacking multidrugresistant cell under suitable temperature conditions [42]. Rivastigmine is an acetylcholine esterase inhibitor of the carbamate type. It is for the treatment of Alzheimer’s disease. Hemmati et al. prepared a magnetic nanocomposite of MIP and graphene oxide (GO). They obtained the desired imprinted matrix polymer via a cocktail of acrylamido-2-methyl-1-propanesulfonic acid (AMPS) as functional monomer and ethylene glycol diacrylate (EGDA) as cross-linker in the presence of acrylate functionalized Fe3O4 nanoparticles. The adsorption mechanism of rivastigmine by polymer followed the Langmuir model with the maximum capacity of 71.41 mg/g, the kinetic data well fitted to pseudo first-order model, and the selectivity factor (e) was 1.98 comparing to the nonimprinted polymer. The cytotoxicity experiments indicated the high biocompatibility of polymer materials due to the 84.4% cell viability at high concentration (1 mg/mL) [43]. Zhang et al. used pH and glutathione stimulated double responsive surface molecular imprinting polymer (SMIP) with doxorubicin (DOX). The DOX molecules imprinted on the surface of mesoporous silica nanoparticles (MSNs). It was observed that 10.5 ± 0.2 wt% of DOX can be loaded over MNSs with loading efficiency of 70 ± 8%. The authors found that the higher amount of DOX can be released owing to the synergistic decomposition of sulphur-sulphur bonding with an acidic pH and glutathione (GSH) compared to physiological conditions as shown in Fig. 1. Moreover, the released DOX was able to inhibit TCA8113 cells growth with the low cytotoxicity [44]. Wang et al. used frontal polymerization for the synthesis of hydrogel-based MIP using a mixture of gatifloxacin (template), N-isopropylacrylamide, acrylic acid and N,N’-methylenebisacrylamide. Frontal polymerization (FP) allows the conversion of monomer into polymer in a localized reaction zone that propagates in an unstirred medium, able to selfsustain and propagate throughout the monomeric mixture and offers simpler reaction route, shorter time, and lower energy consumption than batch polymerization (BP). The release of gatifloxacin from hydroMIPs could be controlled by pH and temperature. The In vivo pharmacokinetic study showed adsorption and elimination of drug reached equilibrium between 2 and 10 h [45].
Fig. 1. Release curves of DOX from the nanocarrier under different conditions (Reproduced with permission from Ref. [44]).
Neurological disorders are complex and cause major health problems causing high ill effects and disabilities in humans. This may cost escalated burden on economy. L-DOPA is an amino acid precursor to the neurotransmitter dopamine extensively used as a prodrug for the treatment of Parkinson’s disease. However, LDOPA is an unstable compound: when exposed to light or added to aqueous solutions, it may degrade, compromising its therapeutic properties. Thus, MIP can offer a remedy where a large amount of L-DOPA is imprinted and b-cyclodextrin (b-CD) used to prepare nanocarrier for L-DOPA as they make inclusion complex. The MIP-b-CD nanosponges released appropriate amount of L-DOPA in acidic condition. It is shown that L-DOPA is stable in acidic condition, however, it degraded at neutral condition [46]. Bakhshizadeh et al. presented core-shell TiO2-based Mitoxantrone imprinted nanoparticles DDS by using Poly (Methacrylic acid-co-polycaprolctone diacrylate) and other functional monomer (such as 4-vinylpyridine, 4-VP) as well. In this work, TiO2 and MIP were employed as core and shell, respectively. The results indicated that MAA-based MIP offered better binding properties in comparison to its non-imprinted polymer (NIP) and higher imprinting factor value than MIP-4VP [47]. Antibacterial wound dressing is a good method for DDS. Thus, Kurczewska and colleagues prepared a vancomycin drug encapsulated in alginate matrix to obtain a potential antibacterial wound dressing. The incorporation of alginate in the imprinted polymer exhibited lower release of vancomycin as compared to the polymer without the alginate from 87% to 47% in 24 h. The release profile found to be diffusion and swelling controlled mechanism (non-Fickian transport) and demonstrated antibacterial activity towards selected bacteria strains successfully [48]. A well-known group of Suedee showed the preparation of insulin-imprinted polymer nanoparticles as a potential oral DDS. The MIP nanoparticles exhibited a significantly higher release of insulin in solution at pH 7.4 than at pH 1.2 with non-Fickian transport. An in vivo study conducted at diabetic Wistar rats confirmed the glucose reduction in 24 h. Moreover, the change in the ratio of functional monomer and cross-linkers controlled the response of blood glucose level [49]. Pawley et al. studied the drug delivery kinetics of a nanoporous matrix using a MIP. In this work, the release profile of acetylsalicylic acid (aspirin) loaded on Ag nanoporous matrix measured at regular time intervals. The release of aspirin demonstrated that the metalorganic framework releases the drug steadily over the course of the first hour, after which
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the concentration reaches a plateau. This release phenomenon of drug release attributed to substantial number of nano-scale pores, high adsorption capacity, and favorable mechanical properties of metalorganic matrix over other types of nanomaterials [50]. In DDS, targeted drug delivery is a critical issue which focuses to kill diseased cells while leaving healthy cells unharmed. Hence, the overexpressed cells are considered as targets and the corresponding ligands are used as targeting moieties and conjugated onto the surface of drug carriers. Epitope imprinting is used in some targeted DDS. For example, inducible epitope imprinting by Liu et al. where a target flexible peptide chain can go through conformational change from disordered-to-ordered by suitable inducement through a molecular imprinting procedure. The prepared MIP nanoparticles in this way adjust the original peptide and binds specifically to the corresponding protein as needed. The study performed in vivo tests in xenograft mouse model and showed a stronger inhibitory effect on HeLa subcutaneous xenografts as compared to non-imprinted polymer nanoparticles with high bio-compatibility [51]. Li group also presented a hidden epitope imprinting procedure in which Fibroblast growth factor-inducible 14 that is overexpressed in a range of solid tumor types such as breast cancer, brain tumors, and pancreatic cancer and its transmembrane domain were used as target receptor and template. The fabrication and recognizing method is shown in Fig. 2. As shown in the figure, firstly the disordered peptide converted to ordered template before its polymerization in the presence of functional monomer followed by template removal. The construction of these polymeric nanoparticles assisted in improved cellular uptake and permeability in target tissues for tumor-targeted drug delivery without any change in native conformation of template peptide [52]. HER2 is a human epidermal growth factor receptor and is over expressed in 30% of ovarian cancers. Thus, Hashemi-Moghaddam group synthesized an artificial conformational epitope of the HER2 antigen and used as template together with DOX for the synthesis of an MIP using dopamine as a functional monomer on the surface of silica Silica nanoparticles (SiNPs). The size of MIPs NPs were approximately 80 nm in size, suitable for small nanodrugs delivery. It was observed that the MIPs exhibited controlled release of DOX which suppressed the ovarian cancer tumor size effectively to those of only DOX imprinted polymers or only DOX biodistribution [53].
Marcelo et al developed a pH-responsive MIP for oral DDS for metronidazole (MZ) based on itaconic acid and ethylene glycol dimethacrylate (EGDMA) via supercritical fluid technology. Supercritical fluids are considered an alternative to organic solvents due their excellent properties such as nontoxicity, non-flammability and low critical point, leaving the solute without any solvent residues and ready-to-use dry powders, with no need of further drying. Under optimum conditions, MIP showed higher uptake ability with MZ loading of 18–61 wt% in MIPs, compared to 7– 20 wt% in NIPs indicating the drug partition between the supercritical fluid and polymeric phases significantly. Furthermore, MIPs release higher amounts of MZ at the lowest pH than at pH 7.4 as shown in Fig. 3 [54]. Nichols and co-workers prepared prostaglandin derivative, (bimatoprost used in the treatment for glaucoma) imprinted MIP hydrogel for ocular drug delivery with help of various functional monomer including 2-hydroxyethyl methacrylate (HEMA), dimethylaminoethyl methacrylate (DMA), and tetraethylene glycol dimethacrylate (TEGDMA). The results showed that HEMA based backbone structure prove to serve as a viable drug delivery system that can be used multiple times. This type of hydrogel can be easily integrated in contact lenses and is capable of withstanding over 10,000 cycles of the mechanical movement of swelling without affecting the drug delivery ability of the lens [55]. Abdollahi et al. reported about the development of phenytoin imprinted DDS using acrylamide (AAm) and ethylene glycol dimethacrylate (EGDMA) by via reversible addition fragmentation transfer polymerization (RAFT) with different cross-linker content. The results of the MIP-RAFT system showed much extended release profile from 12 h (unloaded drug) to 40–140 h, better imprinting factor, and delayed release profile compared with MIPs prepared with traditional radical polymerization (TRP) [56]. Han and colleagues developed cancer antigen 125 (CA125) imprinted MIPs on the surface of graphene oxide for drug delivery of DOX. As shown in the results, GO-MIP exhibited high loading capacity as compared negligible loading of DOX on MIP. The high DOXloading capacities and encapsulation efficiency of composite based on GO resulted from combination of the P- P stacking interaction between the GO and DOX and the electrostatic interaction between GO and DOX. The P- P stacking interaction between the GO and DOX occurs due the existence of oxygen containing groups and aromatic sp2 hybrid domains of GO which assist in high loading of DOX. It was shown in Fig. 4 that higher amount of drug was released at acidic pH which is beneficial because acidic condition
Fig. 2. Polymeric nanoparticles specifically recognizing the transmembrane helical domain of a membrane receptor (Reproduced with permission from Ref. [52]).
Fig. 3. Release profiles of MZ polymers after immersion in pH 2.2 solution, for 4 h, and pH 7.4 PBS solution, for 4 h (Reproduced with permission from Ref. [54]).
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treat them but high production cost and low stability are the major issues. Canfarotta et al. tackled these problems by synthesizing double-imprinted nanoparticles (nanoMIPs) that were capable of loading of cytotoxic acgen DOX and selectively recognizing EGFRover-expressing cells. The fabrication scheme and TEM images of EGFR nanoMIPs depicted in Fig. 5. This work demonstrated that a DOX loading in nanoMIPs were responsible to more-profound cell death [58]. 3. Challenges
Fig. 4. The release of DOX on GO-MIP-DOX at different pH values (Reproduced with permission from Ref. [57]).
is prevalent in tumor cells. Moreover, GO-MIP-DOX presented much more cytotoxicity to target tumor cells than normal cells with good biocompatibility [57]. A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is a potential marker of breast, colorectal, and lung cancers. Although anti-EGFR antibodies can be effectively used to
The MIP based DDS offers great advantages being cost effective, enhanced stability, better tailoring properties. These systems have shown tremendous development, nevertheless, there are many hurdles that need to be addressed for their application in commercial purposes. Controlling the balance between pharmacokinetics and pharmacodynamics, the selective recognition, release the toxicity and biocompatibility of the employed polymer, the efficacy of drug loading, and the behavior of the MIPs in the surrounding environment are few of them. Despite much strategies opted for adequate drug loading and their effective therapeutic release, either the quick release or an initial burst release of a high percentage of the drug molecules is detrimental for normal cells. In hydrogel MIPs, the deformation of imprinted cavities of MIPs in solvent is another issue due to swelling behavior. More steps needs to be taken for the preparation of surface imprinted DDS in order to high drug release without much complexity. One of the critical issue is the lack of in vivo study is few
Fig. 5. (a) Scheme of the solid-phase synthesis process for double-imprinted nanoMIPs using a peptide epitope of EGFR as primary template attached to the solid phase and doxorubicin as secondary template in solution. (b) The 3D structure of EGFR shown in blue is the sequence of the peptide template used for nanoMIPs fabrication, and the antigenic region for the therapeutic antibody cetuximab, which targets the same receptor, is shown in yellow. (c, d) TEM images of EGFR nanoMIPs at (c) 20,000 magnification and (d) 80,000 magnification. Scale bars are, respectively, 1 lm and 200 nm (Reproduced with permission from Ref. [58]). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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cases. Without this study, how can one see the effect and biocompatibility of drug in real conditions?
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