Synthesis and characterization of paclitaxel-imprinted nanoparticles for recognition and controlled release of an anticancer drug

Imprinted nanoparticles as drug delivery carriers have been considered because owing to their cross-linked network, they act as the drug reservoir for controlled release. In this study, selective MIPs nanoparticles of paclitaxel (PTX) were successfully developed for application in the biological molecular recognition and in the design of new anticancer drug delivery systems. The MIPs nanoparticles prepared by miniemulsion polymerization technique using methacrylic acid (MAA) and methyl methacrylate as non-covalent functional monomer, ethylene glycol dimethacrylate and trimethylolpropane trimethacrylate (TRIM) as cross-linker agent, azobisisobutyronitrile as initiator, and hexadecane as hydrophobic agent. In order to prepare of MIP nanoparticles, the synthesis conditions and effective parameters, such as: cross-linker agent, different molar ratios of template–functional monomer–cross-linker agent, were investigated. In addition, the effect of different molar ratios of template and monomers on polymers binding and morphology were characterized. Structure and thermal properties of MIPs were confirmed by FT-IR spectroscopy and thermogravimetric analysis. Imprinted nanoparticles showed significant drug loading and encapsulation efficiency, 17.8 and 100 %, respectively. The particle size of MIP nanoparticles varies between 187 and 726 nm, according the SEM images and laser light scattering data. The imprinted nanoparticles showed satisfactory affinity (84 %) to PTX with a binding of 12 times higher than non-imprinted nanoparticles in biological samples when MAA and TRIM were used as functional and cross-linker monomer, respectively. Results from release experiments of MIPs showed a very slow and controlled release of PTX which would be helpful for sustained drug delivery.     

Preparation of superparamagnetic ribonuclease A surface-imprinted submicrometer particles for protein recognition in aqueous media

Superparamagnetic ribonuclease A surface-imprinted polymeric particles that can preferentially bind the template protein in an aqueous environment were prepared in this study. Methyl methacrylate and ethylene glycol dimethacrylate were employed as the functional and cross-linker monomers, respectively. Regularly shaped submicrometer (700-800 nm) particles imprinted with ribonuclease A were successfully prepared using redox-initiated miniemulsion polymerization. Nanosized Fe3O4 magnetite was encapsulated in the imprinted particles with good encapsulation efficiency (17.5 wt %) for the incorporation of the superparamagnetic property. Good selectivity toward the template over the control protein in an aqueous environment was demonstrated by the imprinted particles in the batchwise and competitive rebinding tests with the highest template loading, Qmax, of 127.7 mg/g observed in the batch rebinding test. Given the small sizes of the imprinted particles and the presence of the binding sites on the surface, the rebinding process was kinetically favorable despite the sheer bulk of the macromolecules. In the desorption study, it was found that the more hydrophobic solvent was more effective for ribonuclease A desorption from the imprinted particles. This indicated that the hydrophobic effect was probably the main form of interaction responsible for the template rebinding to the imprinted sites in an aqueous media.     

Dipyridamole recognition and controlled release by uniformly sized molecularly imprinted nanospheres

We used novel synthetic conditions of precipitation polymerization to obtain uniformly sized molecularly imprinted nanospheres of dipyridamole for application in the design of new drug delivery systems. In addition, the morphology, drug release, and binding properties of molecularly imprinted polymers (MIPs) were studied, and the effects of morphology on other properties were investigated. The MIPs prepared by acetonitrile/chloroform (19:1, v/v) were uniformly sized nanospheres with an average mean diameter of approximately 88 nm at a wetted state, 50 nm at a dry state, and a polydispersity index of 0.062. The imprinted nanospheres showed excellent binding properties and had 62.7% of template binding compared with 17.1% of its blank polymer. The imprinted nanospheres with 67.5 (mg template/of polymer) of binding capacity had better imprinting efficiency than the 50.5% of binding capacity shown by irregularly shaped MIP particles that were prepared by chloroform. The molecular binding abilities of imprinted nanospheres in human serum were evaluated by HPLC analysis (binding about 77% of dipyridamole). Results from release experiments of MIPs showed a very slow, controlled, and satisfactory release of dipyridamole. The loaded drug was released up to 99% in 17 days for nanospheres and 22 days for irregularly shaped particles.     

Development and characterization of molecularly imprinted polymers for controlled release of citalopram

In this work, the use of molecularly imprinted polymers (MIPs) for citalolpram as anti-depressant drug was studied. Imprinted polymers were prepared from methacrylic acid (MAA; functional monomer), ethylene glycol dimethacrylate (EGDMA; cross-linker), and citalopram (as a drug template) using bulk polymerization method. The polymeric devices were further characterized by FT-IR, thermogravimetric analysis, scanning electron microscopy, and binding experiments. The dissolution media employed in controlled release studies were hydrochloric acid at the pH level of 4.3 and phosphate buffers, at pH levels of 7.2 and 10.1, maintained at 37.0 and 25.0 ± 0.5°C. Results showed the ability of MIP polymers to control the release of citalopram. In all cases, the imprinted polymers showed a higher affinity for citalopram and a slower release rate than the nonimprinted polymers. At the pH level of 4.3 and at the temperature of 25°C, slower release of citalopram imprinted polymer occurred.     

Controlled fabrication of theophylline imprinted polymers on multiwalled carbon nanotubes via atom transfer radical polymerization

Theophylline imprinted polymers were synthesized on the surface of multiwalled carbon nanotubes via atom transfer radical polymerization using brominated multiwalled carbon nanotubes as an initiator. The nanotube-based initiator was prepared by directly reacting acyl chloride-modified multiwalled carbon nanotubes with 2-hydroxylethyl-2'-bromoisobutyrate. The grafting copolymerization of 2-hydroxyethyl-2-methyl-2-propenoate and ethylene glycol dimethacrylate in the presence of template theophylline led to thin molecularly imprinted polymer films coating multiwalled carbon nanotubes. The thickness of molecularly imprinted polymer films prepared in this study was about 5 nm as determined by transmission electron microscopy. Fourier-transform infrared spectroscopy was utilized to follow the introduction of initiator groups as well as polymers on the carbon nanotube surfaces. Thermogravimetric analysis indicated that the molecularly imprinted polymers were successfully grown from the carbon nanotube surfaces, with the final products having a polymer weight percentage of ca. 50 wt%. The adsorption properties, such as adsorption dynamics, special binding and selective recognition capacity, of the as-prepared molecularly imprinted polymer films were evaluated. The results demonstrated that the composite of molecularly imprinted polymers and multiwalled carbon nanotubes not only possessed a rapid dynamics but also exhibited a good selectivity toward theophylline, compared to caffeine.     

Different approaches to synthesize carnosine selective imprinted polymers

Selective recognition of proteins by synthetic molecularly imprinted polymers is one of the interesting topics in biosciences. Carnosine (β-alanyl-l-histidine) and related histidine containing peptides are distributed in a wide range of tissues in vertebrate organisms. These peptides have been extensively studied because of their important physiological properties besides their metal chelation property. In this study, preparation of carnosine specific imprinted polymers (MIPs) for the recognition of imidazole containing peptides with and without copper ion is reported. Carnosine and copper–carnosine complex were employed as template molecules where 4-vinylpyridine and ethylenglycol dimethacrylate were chosen as monomer and crosslinker, respectively. The selectivity and binding studies of copper–carnosine imprinted polymer showed high selectivity toward both carnosine (template peptide) and the cupric ion. The selectivity of copper–carnosine imprinted polymer was 65% and carnosine imprinted polymer was approximately 40%. These results indicate that specific recognition of carnosine is depending on the basis of metal coordination     

Molecularly imprinted Au nanoparticles composites on Au surfaces for the surface plasmon resonance detection of pentaerythritol tetranitrate, nitroglycerin, and ethylene glycol dinitrate

Molecularly imprinted Au nanoparticles (NPs) composites are generated on Au-coated glass surfaces. The imprinting process involves the electropolymerization of thioaniline-functionalized Au NPs (3.5 nm) on a thioaniline monolayer-modified Au surface in the presence of a carboxylic acid, acting as a template analogue for the respective explosive. The exclusion of the imprinting template from the Au NPs matrix yields the respective imprinted composites. The binding of the analyte explosives to the Au NPs matrixes is probed by surface plasmon resonance spectroscopy, SPR, where the electronic coupling between the localized plasmon of the Au NPs and the surface plasmon wave leads to the amplification of the SPR responses originating from the dielectric changes of the matrixes upon binding of the different explosive materials. The resulting imprinted matrixes reveal high affinities and selectivity toward the imprinted explosives. Using citric acid as an imprinting template, Au NPs matrixes for the specific analysis of pentaerythritol tetranitrate (PETN) or of nitroglycerin (NG) were prepared, leading to detection limits of 200 fM and 20 pM, respectively. Similarly, using maleic acid or fumaric acid as imprinting templates, high-affinity sensing composites for ethylene glycol dinitrate (EGDN) were synthesized, leading to a detection limit of 400 fM for both matrixes.     

Development of a pH-responsive imprinted polymer for diclofenac and study of its binding properties in organic and aqueous media

Three different molecularly imprinted polymers (MIPs) for drug delivery of diclofenac in gastrointestinal tract were synthesized employing bulk polymerization method and their binding and release properties were studied in different pH values. Methacrylic acid (MAA), methacrylamide (MAAM) and 4-vinyl pyridine (4VP) were tested as functional monomers and ethylene glycole dimethacrylate (EDMA) was used as a cross-linker monomer in polymeric feed. Binding properties and imprinting factor (IF) of MIPs were studied in comparison with their non-imprinted ones (Blank) in organic and aqueous media. Diclofenac release in aqueous solvents at pH values of 1.5, 6.0 and 8.0, simulating gastrointestinal fluids, were also studied. The results indicated the specific binding of diclofenac to imprinted polymers. Duo to the stronger non-specific bounds in aqueous solutions, IF values decreased in water compared to acetonitrile as an organic medium. Our results proved that all polymers represented pH-responsive diclofenac delivery at above conditions. The data showed that imprinted polymer, prepared by MAA had superior properties, in comparison with other polymers, for minimum release (14%) of drug in gastric acid and maximum release (90%) in basic condition. The results indicated that diclofenac imprinted polymer could be used as a pH-responsive matrix in preparation of a new drug delivery system for diclofenac.     

Development of a pH-responsive imprinted polymer for diclofenac and study of its binding properties in organic and aqueous media

Three different molecularly imprinted polymers (MIPs) for drug delivery of diclofenac in gastrointestinal tract were synthesized employing bulk polymerization method and their binding and release properties were studied in different pH values. Methacrylic acid (MAA), methacrylamide (MAAM) and 4-vinyl pyridine (4VP) were tested as functional monomers and ethylene glycole dimethacrylate (EDMA) was used as a cross-linker monomer in polymeric feed. Binding properties and imprinting factor (IF) of MIPs were studied in comparison with their non-imprinted ones (Blank) in organic and aqueous media. Diclofenac release in aqueous solvents at pH values of 1.5, 6.0 and 8.0, simulating gastrointestinal fluids, were also studied. The results indicated the specific binding of diclofenac to imprinted polymers. Duo to the stronger non-specific bounds in aqueous solutions, IF values decreased in water compared to acetonitrile as an organic medium. Our results proved that all polymers represented pH-responsive diclofenac delivery at above conditions. The data showed that imprinted polymer, prepared by MAA had superior properties, in comparison with other polymers, for minimum release (14%) of drug in gastric acid and maximum release (90%) in basic condition. The results indicated that diclofenac imprinted polymer could be used as a pH-responsive matrix in preparation of a new drug delivery system for diclofenac.     

Probing the recognition of molecularly imprinted polymer beads

A facile, robust and cost-effective suspension polymerisation methodology for the generation of ibuprofen molecularly imprinted polymers in bead formats was evaluated. Mineral oil was employed as the continuous phase whereby microdroplets of the pre-polymerisation mixture were formed through vigorous agitation, followed by photo-polymerisation resulting in formation of imprinted beads. For comparison purposes, irregular particles were also prepared from monolith polymers. Physical characteristics of the imprinted polymers were investigated using scanning electron microscope, particle size distribution, nitrogen sorption porosimetry and solvent swelling ratios, with subsequent correlation of these parameters to analyte rebinding performance. Overall, an increase in affinity was observed with decreasing the degree of cross-linking, however, specific rebinding was compromised. An inverse relationship between polymer affinity for the template and surface area was identified, while solvent swelling ratios were directly related to polymer affinity. Correlation between pre-polymerisation studies and polymer binding performance highlighted the significance of employing the polymerisation solvent in template rebinding in order to achieve superior recognition capabilities. Additionally, shape selectivity of binding sites was demonstrated by the decreased binding performance of template structural analogues to the imprinted polymer.     

An imprinted organic–inorganic hybrid sorbent for selective separation of copper ion from aqueous solution

A new organic–inorganic hybrid sorbent was prepared by a double-imprinting approach for the selective separation of Cu(II) from aqueous solution. In the prepared hierarchically imprinted sorbent, both Cu(II) and surfactant micelles (cetyltrimethylammonium bromide) were used as templates. The sorbent was prepared through self-hydrolysis, self-condensation, and co-condensation of the crosslinking agent (tetraethoxysilane) and the functional precursor (3-aminopropyltrimethoxysilane) in an alkaline media followed by gelation. The adsorption property and selective recognition ability of the sorbents were studied by equilibrium-adsorption method. Results showed that in the presence of Zn(II) the biggest selectivity coefficient of the imprinted sorbents for Cu(II) was over 500, which is much higher than those of non-imprinted sorbents. The largest relative selectivity coefficient (k′) of the ion-imprinted functionalized sorbent between Cu(II) and Zn(II) was over 500. The uptake capacities and the selectivity coefficients of the hierarchically imprinted sorbent were much higher than those of the sorbent prepared without CTAB template. Furthermore, the new imprinted sorbent possessed a fast kinetics for the removal of Cu(II) from aqueous solution with the saturation time less than 10 min, and could be used repeatedly. This sorbent has been successfully applied to the separation and determination of the trace Cu(II) in real water samples and those spiked with standards. This new sorbent can be used as an effective solid-phase extraction material for the highly selective preconcentration and separation of Cu(II) in environmental samples.     

Protein recognition via surface molecularly imprinted polymer nanowires

In this paper, we present a technique for the preparation of polymer nanowires with the protein molecule imprinted and binding sites at surface. These surface imprinting nanowires exhibit highly selective recognition for a variety of template proteins, including albumin, hemoglobin, and cytochrome c. This recognition may be through a multistep adsorption, with the specificity conferred by hydrogen bonding and shape selectivity. Due to the protein imprinted sites are located at, or close to, the surface; these imprinted nanowires have a good site accessibility toward the target protein molecules. Furthermore, the large surface area of the nanowires results in large protein molecule binding capacity of the imprinted nanowires.     

Biomimetic sensor for cAMP using an ion-sensitive field-effect transistor

A biomimetic sensor for cAMP was fabricated in combination with an ion-sensitive field-effect transistor (ISFET) as a transducer and a cAMP-imprinted polymer as a molecular recognition material. The cAMP-imprinted polymer was prepared using 1-allyl-2-thiourea as a functional monomer, and the binding ability and the selectivity of the polymer were evaluated. In addition, the imprinted polymer membrane was coated on the ISFET electrode, and the response of the sensor was evaluated. The cAMP-imprinted polymer showed high binding ability to and selectivity for cAMP in aqueous media. The linear relationship was obtained from 0.1 to 1.0 mM cAMP from the calibration curve in the cAMP-sensor.     

单一结合位点分子印迹聚合物的合成及性能

采用分子自组装印迹技术在光引发条件下制备了以(S)-布洛芬为模板分子,α-甲基丙烯酸为功能单体的分子印迹聚合物。通过红外对聚合物的结构进行了表征。透射电镜结果表明,交联剂用量对印迹聚合物的形貌特征具有显著的影响。同时结合Scatchard分析研究了印迹聚合物的吸附性能及选择性识别能力,表明印迹聚合物特异性吸附容量为41μmol/g,印迹指数为2.28,对(S)-布洛芬形成单一结合位点,且表现出明显的吸附选择性。     

Exploiting β-cyclodextrin as functional monomer in molecular imprinting for achieving recognition in aqueous media

A series of molecularly imprinted polymers (MIPs) for 4,4′-(1,4-phenylenediisopropylidene)bisphenol (BPP) were prepared by using β-cyclodextrin (β-CD) as functional monomer, toluene 2,4-diisocyanate (TDI) or 4,4′-Diphenylmethane diisocyanate (DDI) as the cross-linker. The results of binding experiments showed that the MIPs can bind the template selectively in aqueous media. The binding specificity mechanism of the polymers was investigated in detail. The template molecule is too large and cannot be included in the cavity of one β-CD molecule. The mutual orientation of β-CD molecules in the imprinted polymers is regulated by molecular imprinting, so that they can cooperatively bind the template molecule. It is suggested that the major contribution to the recognition ability of the imprinted polymer was the stereo-shape effect inherent in the MIPs. The study indicated that hydrophobic effects play an important role in the recognition process.     

阿司匹林表面印迹微球的制备与药物缓释性能评价

采用表面印迹技术,选取γ-氨丙基三甲氧基硅烷(APTS)和甲基丙烯酰氯修饰的硅胶为载体,以阿司匹林(Asp)为模板分子,丙烯酰胺(AM)为功能单体,乙二醇二甲基丙烯酸酯(EDGMA)为交联剂,在乙腈溶液中合成了阿司匹林表面分子印迹聚合物微球(MIPs)和非印迹聚合物微球(NIPs)。通过紫外、红外光谱、扫描电镜、透射电镜、热重分析以及吸附实验进行了表征并进行了药物扩散实验。结果表明,MIPs平衡吸附量可达164.40μmol/g,对苯甲酸(BA)和水杨酸(SA)的分离因子达到3.15和3.32,有很好的热稳定性和选择性吸附能力;MIPs持续释药时间是NIPs的2.6倍,有很好的缓释效果和应用价值。     

Bisphenol A imprinted polymer adsorbents with selective recognition and binding characteristics

Imprinted copolymers, which highly recognized and bound bisphenol A (Bis A), were synthesized by using covalent imprinting technique. Bisphenol A dimethacrylate (BADM) was used as a template monomer in the copolymerization with a crosslinkable monomer of divinyl benzene (DVB), ethylene glycol dimethacrylate (EGDM) or N,N’-methylenebisacrylamide (MBAA). The resultant copolymer was hydrolyzed in acidic or basic condition. It was found that the Bis A imprinted copolymers of EGDM and MBAA had no selectivity to Bis A, because the crosslinker dissociated by the hydrolysis reaction and thus comprehensive imprinted sites were not formed. On the other hand, imprinted copolymer of DVB showed excellent selectivity to differentiate Bis A from bisphenol E and bisphenol F (Bis F). Characterization of the copolymers suggested that the DVB copolymer had resistance to the acid and alkali conditions. Effect of recognition by the Bis F imprinted polymer was also compared with that of the Bis A imprinted polymer, when DVB and bisphenol F dimethacrylate were copolymerized. The Bis F imprinted copolymer was able to recognize Bis F in ethanol solution, however showed higher binding capacity for both Bis A and Bis F in water solution without recognition. Therefore, hydrophobic interaction between Bis A and the imprinted site enhanced the binding capacity with high selectively for the BADM-co-DVB imprinted copolymer.     

茶碱-铜(Ⅱ)离子配位分子印迹膜的制备及表征

以茶碱为模板分子,铜离子为配体、4-乙烯吡啶(4-VP)为功能单体、乙二醇二甲基丙烯酸酯(EDMA)为交联剂,在聚偏氟乙烯(PVDF)基膜上采用表面涂覆热聚合的方法制备了金属配位分子印迹膜,通过平衡结合实验研究了印迹膜对茶碱的结合性能和结合选择性。结果表明,铜离子的配位作用能提高印迹膜的结合性,在茶碱浓度为0.2 mmol/L时结合量从1.61μmol/g提高到了2.69μmol/g。在铜离子配位的作用下印迹膜对茶碱的结合能力高于同样化学组成的非印迹膜。相比于可可碱印迹膜对茶碱有较好的选择性,在浓度为0.05 mmol/L时选择性达到了2.39。     

Atrazine-selective polymers prepared by molecular imprinting of trialkylmelamines as dummy template species of atrazine

Synthetic polymer receptors selective for atrazine have been prepared by molecular imprinting using trialkylmelamines as template molecules in place of atrazine. Trialkylmelamines were shown to be useful as templates for introducing affinity for atrazine into ethylene glycol dimethacrylate-methacrylic acid copolymers. The polymers showed the selective binding capacity for triazine herbicides including atrazine, whereas agrochemicals in other categories were not adsorbed to the imprinted polymers. The group selectivity demonstrated was comparable with that of the original atrazine imprinted polymers. Use of the nonagrochemical template molecules as a substitution to atrazine has made it possible to synthesize herbicide-receptor polymers free from troubles caused by analyte contaminants, which are desired for analytical applications.     

Poly(lactide-co-glycolide)-methoxy-poly(ethylene glycol) nanoparticles: drug loading and release properties

In this work, the drug loading and in vitro release properties of PLGA-mPEG nanoparticles were studied. Three methyl-xanthine derivatives differing significantly in aqueous solubility, i.e., caffeine, theophylline, and theobromine, were employed as model drugs. Two different PLGA-mPEG copolymer compositions, namely PLGA(40)mPEG(5) and PLGA(136)mPEG(5), were included in the study. The nanoparticles were prepared by a double emulsion technique. The drug release properties of the nanoparticles in phosphate buffered saline (PBS) and in human plasma were determined. An increase of the drug proportion in the feed led to increased drug loading. The composition of the PLGA-mPEG copolymer (PLGA/mPEG molar ratio) did not appear to affect drug loading and encapsulation. Caffeine exhibited higher loading in the nanoparticles than theobromine and this exhibited a little higher loading than theophylline. Solid-state solubility of the drug in PLGA-mPEG did not affect drug loading. Drug loading and encapsulation in the PLGA-mPEG nanoparticles appeared to be governed by the partition coefficient of the drug between the organic phase and the external aqueous phase employed in nanoparticle preparation. Relatively low loading and encapsulation values were obtained, suggesting that the physical entrapment of drugs in PLGA-mPEG nanoparticles could only be an option in the development of formulations of potent drugs. Only the release of the least water-soluble theobromine was efficiently sustained by its entrapment in the nanoparticles, indicating that the physical entrapment of drugs provides the means for the development of controlled-release PLGA-mPEG nanoparticulate formulations only in the case of drugs with low aqueous solubility.