Production of a new platform based calixarene nanofiber for controlled release of the drugs

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Materials Science & Engineering C

Production of a new platform based calixarene nanofiber for controlled

release of the drugs

Esra Maltas Cagil

_{, Othman Hameed}

_{, Fatih Ozcan}

A R T I C L E I N F O Keywords: Thiabendazole Donepezil Nanofiber Calixarene Controlled release Pharmaceutics A B S T R A C T

The aim of this study is to develop an electrospun calixarene nanofiber based calixarene for controlled release of hydrophobic drugs. To accomplish this, we have synthesized 5,17-bis-[Methyl-N-Methyltranylate]-25,26,27,28-tet-rahydroxycalix[4]arene (Compound 3) of which nanofiber (F-14) was produced by electrospinning. The fabricated multilayered electrospun nanofiber was first characterized in terms of morphology and then drug loading and release kinetics were studied in different physiological pH. For this purpose, we have selected two fluorescent drugs which are thiabendazole (Tbz) and donepezil (Dnp) as model drugs to show the usage of the synthesized nanofiber in drug delivery system. Drug loading and release kinetics were monitored by using fluorescence spectroscopy. According to the results, maximum amount of loaded Dnp onto nanofiber was found to be as 30.529 μg in 20 mM Tris buffer, pH 7.4 end of 120 min. Data showed that loading amount of Tbz onto the nanofiber was measured to be as 1.688 μg to the 2.25 cm2_{of surface in 20 mM of Tris buffer, pH 7.4 at the end of 120 min. While max release of Dnp from} nanofiber was also 9.720 μg at pH 2.2, that of Tbz from nanofiber was 0.243 μg at pH 7.4 at the end of 90 min. Drug loading to nanofibers was clarified by SEM, TEM, EDX and FT-IR analysis.

1. Introduction

During the past decades, scientists have shown an increased in-terest in multifunctional nanomaterials which are aimed to reach therapeutics and diagnostics goals [1–6]. Among these, electrospun nanofibers produced under a large amount of electric field receive increasing attention in different fields of physics, medicine, biology, and materials science because of excellent properties such as high porosity with very small pore size, diameters ranging from 50 to 500 nm, wide variety and abundant raw materials, transparency, ex-cellent mechanical properties high surface area-to-volume ratio and high permeability [7–12]. Therefore, these materials as natural and synthetic polymers are preferred by researchers in the applications such as carriers in drug delivery systems, matrix in wound healing, scaffolds in tissue engineering, membrane technology, protective clothing and packaging [13–18].

Researchers have recently fabricated different types of controlled drug delivery vehicles to maintain the drug concentration in the body within its therapeutic range for prolonged time [14–22]. The effec-tiveness of the system as controlled drug delivery system is known to depend on loading efficacy. High drug loading capacity is very crucial because of controlling the release rates. It may also provide an

efficient alternative to control the amount of the final dose. A large amount of the studies have been reported on improvement of loading efficiency of the drug delivery systems [23–28]. Simple fabrication process and high surface areas are effective to obtain higher loading capacity of the drugs. The drug release from the matrix such as polymers and nanofibers can be easily controlled by the choice of polymer and nanofiber fabrication techniques such as electrospinning, led to differences in some physicochemical properties like surface area and surface charges. Several factors also seem to influence on the drug loading efficacy of electrospun nanofibers and their controlled release. Polymer/monomer density, method of electrospinning, drug solubility in the selected solvent system, and drug loading technique are among the major factors which affect drug loading capacity and controlled release of nanofibers [29–34].

In this study, we have produced an electrospun calixarene nanofiber for controlled drug release. To examine pH-stimuli controlled release of the drugs, two fluorescent and hydrophobic drugs, thiabendazole (Tbz) and donepezil (Dnp) from the produced nanofiber system were studied. Their fluorescent features allow to determine the loading and release capacity of/from the nanofibers. Their loading and release efficiency were compared for the same nanofiber at a various pH corresponding to physiological microenvironments at acidic region.

https://doi.org/10.1016/j.msec.2019.03.038

Received 20 April 2018; Received in revised form 12 February 2019; Accepted 10 March 2019 ⁎_{Corresponding author.}

E-mail address:esramaltas@gmail.com(E.M. Cagil).

Available online 12 March 2019

0928-4931/ © 2019 Elsevier B.V. All rights reserved.

2. Materials and methods

2.1. Synthesis of calixarene derivative

0.8 g (1.89 mmol) of Calix[4]arene was dissolved in 60 mL of THF, and then 3 mL of CH3COOH, 2.04 g (10.47 mmol) of Methyl N-me-thyltranilate and 1 mL of 37% formaldehyde were added to this mix-ture. The mixture was stirred at room temperature for 4 days. The re-action was checked with TLC. The solvent was evaporated and the remaining solid was dissolved in methanol. The insoluble part was re-moved by filtration. The solvent was evaporated with evaporator. The resulting precipitate was filtered off and dried. Purple colored palms were obtained. Yield 1.41 g (%89), 1_{H NMR (400 MHz DMSO): δ} 1.60 ppm (s, 4H, Ph-CH2-Ph),3.54 ppm (s, 6H, N-CH3), 4.26 ppm (s, 6H, O-CH3), 2.92 ppm (d, 4H, J = 19.6 Hz, ArCH2Ar), 3.86 ppm (d, 4H,

J = 19.6 Hz, ArCH2Ar), 6.73 (s, 6H, ArH), 7.05 (s, 8H, ArH), 7.30 (s, 4H, ArH). MA: 808.96 g/mol, Elemental Analysis (%); C50H52N2O8; C, 74.24; H, 6.48; N, 3.46. Found (%); C, 74.05; H, 6.30; N, 3.52.

2.2. Preparation of calix[4]arene based nanofiber

Spinning solution was prepared by dissolving 2.0 g of Compound 3 called F-14 in 6 mL of DMF. The mixture was vigorous stirred until it was dissolved completely at 35 °C. The prepared F-14 solution was placed in a 10 mL pipette, then extruded at the speed of 1.25 mL/h by a syringe pump. 16.3 kV was applied between ground collector and the spinning needle with a distance of 15.5 cm. The collector was covered with aluminum foil. The experiments were done at room temperature. The obtained nanofiber surface characterization was performed and fiber diameter was measured by SEM. The nanofibers were cut as2.25 cm2_{(1.5 cm × 1.5 cm) for application.}

2.3. Preparation of Dnp and Tbz

1 mM of standard drug solutions were prepared by dissolving in a various buffers with different pH (154 mM NaCl, pH 2.2; 100 mM so-dium acetate pH 4 and 6; 20 mM Tris buffer, pH 7.4) including 5% DMF and then, drug solutions were diluted to appropriate concentration to obtain calibration curves. Emission spectra of Dnp were recorded at 300 nm and 372 nm of excitation and emission wavelengths by fluor-escence spectroscopy, respectively. The calibration curves of Dnp were drawn at a concentration range of 0.005 μM and 0.5 μM at pH 2.2, 4, 6 and 7.4 at 372 nm of emission wavelength (y = 597 x + 40.168 for pH 2.2; y = 8294.7 x + 26.923 for pH 4; y = 1309.1 x + 47.288 for pH 6 and y = 1574.8 x + 82.585 for pH 7.4). The excitation slit width was set at 10 nm and the emission slit width was set at 10 nm.

Emission spectra of Tbz were also obtained at 299 nm and 358 nm of excitation and emission wavelengths, respectively. The calibration curves of Tbz were drawn at a concentration range of 0.6 nM and 0.05 μM at pH 2.2, 4, 6 and 7.4 at 358 nm of emission wavelength at 10 nm of slit widths (y = 597 x + 40.168 for pH 2.2; y = 8294.7 x + 26.923 for pH 4;

y = 1309.1 x + 47.288 for pH 6 and y = 1574.8 x + 82.585 for pH 7.4). 2.4. Drug loading and release

1 mM of the drug solution was added to the 2,25 cm2_{of nanofibers} inside the buffers with different pH (154 mM NaCl, pH 2.2; 100 mM so-dium acetate pH 4 and 6; 20 mM Tris buffer, pH 7.4). The heterogeneous system was incubated for 3 h at RT. For determination of loading effi-ciency to nanofibers, supernatant were separated from nanofibers, and then was analyzed for calculation of unloaded drug. The amount of un-loaded Dnp and Tbz was measured by getting fluorescence spectra at their specific excitation and emission wavelengths. Loading amount of the drugs to nanofibers at each pH was calculated from regression equations of the calibration graphs in terms of the fluorescence intensity at their emission wavelengths. The loading and release amount was

calculated as μg on the surfaces of the nanofiber which is solid materials. So, the amount of loaded drugs was expressed as unit of μg to cm2_of calixarene nanofibers and was given as unit of μg in Figures.

Drug release behaviors of calixarene nanofibers were worked with the same buffers (154 mM NaCl, pH 2.2; 100 mM sodium acetate pH 4 and 6; 20 mM Tris buffer, pH 7.4) equal to physiological pH at RT for 4 h. At predetermined intervals, 500 μL of the incubated solution was taken out and replaced with 2.0 mL of corresponding fresh buffer solution. The amount of released Dnp and Tbz was measured via fluorescence spectra at their specific excitation and emission wavelengths by using regression equations of calibration curves as similar with drug loading method.

2.5. Characterization

FT-IR analysis was done by using a Perkin Elmer spectrum 100 FTIR spectrometer (ATR). SEM analysis was carried out with a Zeiss LS-10 field emission SEM instrument equipped with an Inca Energy 350 X-Max (Oxford Instruments) spectrometer. Samples were sputter-coated with Au (60%) and Pd (40%) alloy using a Q150R (Quorum Technologies) instrument. TEM analysis was performed on JEOL JEM-2100 (UHR) TEM equipment.

3. Results

3.1. Calixarene synthesis

The 5,17-bis-[Methyl-N-Methyltranylate]-25,26,27,28-tetrahydroxycalix [4]arene synthesized via reaction with Methyl-N-Methyltranilate in suitable reaction conditions. The structure of the resulting 5,17-bis- [Methyl-N-Methyltranylate] -25,26,27,28-tetrahydroxycalix[4]arene (F-14) was eluci-dated by1_{H NMR. NMR results were given in supplementary materials. The} e_{OH vibration bands at 3299 cm}−1_{, the CeH vibration bands at} 2985–2924 cm−1_{, and the C]0 carbonyl vibration band at 1661 cm}−1 were seen at the FT-IR spectrum of Compound 3, F-14.

3.2. Nanofiber production

Nanofibers based calixarene was produced by an electrospinning process (Scheme. 1). When a liquid solution of the calix[4]arene deri-vative was loaded to electrospinning equipment, electrical force over-came surface tension and solvent was evaporated. The resulting elec-trically charged nanofibers were collected on a rotating cylinder covered with electrically grounded aluminum foil. Morphological fea-tures of these fibers were characterized with Infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and transmission electron microscopy (TEM).

3.3. Drug loading

Tbz and Dnp are fluorescent drugs which were selected for devel-opment of nanofiber based drug carrier systems. They exhibit maximum fluorescence intensity at 300 nm and 325 nm of excitation wavelengths, respectively (Supp. Mater.). The loading amount of Tbz was measured via regression equation of the drug at different pH values at a con-centration ranges of 0.005–0.5 μM as given in Supp. Mater. Drug loading was studied during 180 min until the fluorescence intensity was stable. The amount of loading was measured by taking samples from the tubes including drug, buffer and nanofibers for each pH value. When the loading amount of the Tbz raised with increase in time at pH 6, that of Tbz at pH 7.4 increased up to 90 min and decreased after 90 min. During 180 min, loading amount at pH 4 and 2.2 was stable and rela-tively close each other. According to the measured loading amount shownFig. 1, maximum loading amount of Tbz onto the nanofiber was found to be as pH 7.4, 6, 4 and 2.2, respectively. The table indicated that 1.688 μg of Tbz was found to bind onto 2.25 cm−2_{of the nanofiber} at pH 7.4 at the end of 90 min (Fig. 1A).

The loading amount of Dnp onto the nanofiber was calculated from regression equation of the Dnp at different pH values at a concentration ranges of 0.005–0.5 μM, as given in Supp. Mater. Dnp was loaded to the nanofibers during 180 min and then, it was measured at each pH values as shown inFig. 1B. Experimental results indicated similar results with Tbz. The amount of the Dnp increased up to 90 min at pH 7.4 and 6. After 90 min, it was decreased at pH 7.4 and increased at pH 6. The loading amount of Dnp at pH 4 and 2.2 has relatively stayed stable during 180 min. As viewed fromFig. 1B, the maximum loading amount of Dnp onto the nanofiber surface was found to be as pH 7.4, 6, 4 and

2.2, respectively. The 2.25 cm−2 _{of the nanofiber exhibited to bind} 30.529 μg of Dnp at pH 7.4 after 90 min.

The loading amount of these two different drugs to the calixarene nanofibers were different at the same pH although both drugs are hydrophobic. This means that they interacted with calixarene via different kind of mechanisms such as He bond and Vander Waals interactions, and hydrophobic forces. This shows that the chemical features of the drug molecules such as chemical structures and mo-lecular weight influence on drug loading capacity to the supporting materials [29].

Fig. 1. Amount of Tbz loading against time (A) Amount of Dnp loading against time (B) at a various pH. Amount of Tbz release against the time (C) Amount of Dnp release against the time (D) at a various pH.

3.4. Drug release

The drug release kinetics from nanofibers can be easily modulated by the choice of matrix materials such as polymer, calixarene, cellulose and also nanofiber fabrication techniques. One of the parameter for controlled drug delivery system is pH dependent release which is ef-fective on microenvironments of different type of tissue and organs. The extended drug release behavior primarily is a function of polyelec-trolyte behavior of the matrix which remains in non-protonated state at the acidic pH, results in controlled the release of therapeutic agent governed by diffusion mechanism [15].

In this study, the drug loading was firstly carried out at determined optimum pH and time for measurements of drug release. They were se-lected as pH 7.4 and 90 min for both drugs according to the obtained re-sults from loading experiments. The release amount of the drugs was again measured via regression equations of the drugs. The release of Tbz from the drug loaded nanofibers was studied and measured by taking samples

from the tubes including drug, buffer and nanofibers incubated during 240 min by shaking for each pH values, as similar to drug loading tech-nique until fluorescence intensity was stable. Each samples were com-pleted to 2 mL with its fresh buffer and then, they were scanned by fluorescence spectroscopy at their specific excitation wavelengths. According to the calculated release amount of Tbz from regression equa-tions as given in Supp. Mater., the amount of the release was increased with increase in time during 240 min.Fig. 1C shows the maximum amount of drug release from Tbz loaded nanofiber which was found to be as 0.243 μg, 0.191 μg, 0.130 μg and 0.002 μg of Tbz at pH 7.4, 6, 4 and 2.2 for 2.25 cm−2_{of the nanofiber at 90 min, respectively.}

The release amount of drug from the Dnp loaded nanofiber was also measured from regression equations of Dnp as given in Supp. Mater. Dnp release was monitored during 240 min and then it was calculated as similar with release method of Tbz at each pH value. The release kinetics given inFig. 1D show that release amount of the Dnp increased up to 120 min, decreased in 120 min and showed linearity after 150 min Fig. 2. FT-IR spectrum of F-14 nanofiber (a), DNP (b), Dnp loaded F-14 nanofibers at pH 7.4 (c), 6.0 (d), 4.0 (e) and 2,2 (f), and F-14 nanofiber (g), TBZ (h), Tbz loaded F-14 nanofibers at pH 7.4 (i), 6.0 (j), 4.0 (k) and 2,2 (l).

at pH 7.4. However, the release raised with increase in time during 240 min at pH 6, 4 and 2.2. When looked at Fig. 1D, the maximum release was occurred at 120 min. According to theFig. 1, the release amount of the drug from the Dnp loaded nanofiber surface was found to be as pH 2.2, 4, 6 and 7.4, respectively. The data indicated that 9.72 μg, 7.712 μg, 4.582 μg and 3.610 μg of Dnp was found to bind onto 2.25 cm−2_{of the nanofiber at pH 7.4. As a result, the release of Dnp was}

almost 10 times higher than that of Tbz. The release from calixarene nanofibers are pH and the structure of the drugs dependent. According to the data, release of Tbz and Dnp from drug loaded nanofibers stopped at the end of 240 min and 120 min, respectively.

When the release ratio of Tbz and Dnp were measured as 14.39% and 31.9%, respectively. This data showed that interactions between Tbz and calixarene nanofiber was stronger than that of Dnp and Fig. 3. SEM images of F-14 nanofibers at 10 μm (500×) and 20 μm (500×) (A-B), F-14 nanofibers at 1 μm (10 Kx) and (5 Kx) (C–D), Dnp loaded F-14 nanofibers at 1 μm (20 Kx) and (10 Kx) (E–F) and Tbz loaded F-14 nanofibers at 1 μm (10 Kx) and (20 Kx) (G-H).

calixarene nanofiber. When considered structures of the Tbz, it can be said that Tbz adsorbed onto calixarene nanofiber surfaces via H– bond and Vander Waals interaction and hydrophobic forces. Unlike, Dnp interacted with the calixarene nanofiber via only hydrophobic forces [30,31]. For this purpose, the percentage of Dnp release from the na-nofiber is higher than that of Tbz release from the nana-nofiber.

3.5. FT-IR analysis

FT-IR spectra inFig. 2showed the looses of the several bands and reduction of the transmittance values after loading of the drugs to na-nofibers. As indicated in FT-IR spectra of Dnp loaded nanofiber in Fig. 2A, the CeH vibration bands of the CH2and CH3,and cyclo CH2 were seen at 3000 cm−1_{and 2346 cm}−1_{, respectively. While the band} at 1591 cm−1 _{belonged to CeO vibrations from OeCH3, the bands} between 1500 and 1300 cm−1_{were attributed to the aromatic rings in} the structure of Dnp. As viewed fromFig. 2B illustrates FT-IR spectra of Tbz loaded nanofiber, the peak at around 3036 cm−1_{belonged to CeH} stretching vibration in the structure of Tbz. The typical band at 2365 cm−1_{which came from eNH group. The peaks between 1500 and}

1300 cm−1_{were observed in the spectrum belonged to C]C stretching} vibrations from aromatic rings in the structure of Tbz [32].

3.6. SEM and TEM analysis

Scanning electron microscopy verified morphological changes on nanofibers after drug loading. SEM images of the F-14 nanofiber and Tbz and Dnp loaded nanofibers at 1 μm, 10 μm and 20 μm were shown inFig. 3A–H. As viewed from Fig. 3C–D, linear structure of F-14 na-nofiber is obviously seen. After loading of Dnp and Tbz, both drugs was seen to cover nanofiber surfaces. Data from SEM analysis that nanofiber of F14 has as a homogeneous fiber surface with 600 nm of diameter.

TEM images of nanofibers are given inFig. 4A–F at 200 nm and 1 μm of scales. As clearly viewed from figures, the linear structure of the nanofibers was surrounded by circular structures of both drug mole-cules at each scale. As a result, SEM and TEM analysis resulted in si-milar views, especially showing A linear structure of F-14 nanofiber. Pore size was found to be between 140 nm and 170 nm.

EDX mapping was indicated atFig. 5A–B which show, the percen-tage of the elements such as C, O and N on the surfaces of Tbz and Dnp Fig. 4. TEM images of F-14 nanofibers at 1 μm/200 nm (A/B), Dnp loaded F-14 nanofibers at 1 μm/200 nm (C/D), Tbz loaded F-14 nanofibers at 1 μm/200 nm (E/F).

loaded F-14 nanofibers. According to the results, the amount of the elements were found to be as 60.26% of C atom, 21.67% of O atom, and 18.07% of N atom for Dnp loaded nanofiber and 61.42% of C atom, 21.47% of O atom and 17.11% of N atom for Tbz loaded nanofibers. 4. Discussion

Nanoobjects such as nanorods, nanofibers, and particularly nano-particles have been widely used for local delivery of drugs into the specific organ or tissues. However, the usage of nanoparticles is limited due to the high interstitial pressure in the tissues such as brain, colon, breast and lung, results in the risk of being expelled out of the target site and high initial burst release of drugs from nanoparticles [33,34]. Therefore, tar-geted therapy concept is very crucial to design the nanoobjects for drug delivery. Controlled release is one of the important aspects of the targeted therapy. The nanofibers prepared by the electrospinning technique are new generation carriers for controlled, sustained and targeted delivery of the drugs due to the large surface area-to-volume ratio and higher porosity [35,36]. The drug delivery systems based nanofibers may increase the drug efficiency and loading amount of the drug to the surface and reduce the toxic side effects of drugs, especially anticancer agents [37]. Their physicochemical behaviors according to pH in their microenvironment are very crucial in order to control the release of the drugs. The changes in morphology and fiber diameter of nanofibers are also fine-tuned to effect the controlled release of the drugs.

Several literatures reported that the main challenge of chemother-apeutic agents loaded nanofiber systems is the initial burst release of drugs from the nanofibers surface when the agents have been directly embedded into the nanofibers for the local chemotherapy of cancers. [37,38]. To overcome this limitations, direct electrospinning of the drug/polymer solution may use, but it led to decrease the efficiency of anticancer agents. The modification of the nanofibers with nano-particles and polymers is a simple novel technique to overcome these problems [36–44]. Particularly, the drug nanocarriers incorporated into electrospun nanofibers results in sustained and a prolonged drug re-lease. Another solution to avoid this problem is the usage of the su-pramolecules such as calixarene, fullerene and cyclodextrin to control drug release instead of the use of polymer or nanoparticles [45–49]. Calixarenes with special three-dimensional shapes and complexation abilities recognize various species such as anions, cations, neutrals and

pharmaceuticals [49]. They are widely used in biological applications such as enzyme immobilization, protein recognition and drug delivery. The calixarene derivatives based nanofibers are commonly produced by incorporating polymer like PAN via electrospun method, result in na-nofibers with a various diameter [50].

In conclusion, we have reported a new controlled release nanofiber incorporated with a calixarene derivative which was newly synthesized. This nanofiber with 600 nm of diameter and 140–170 nm of pore size was fabricated by electrospinning for development of pH stimuli drug delivery system. In order to examine release behavior of the calixarene nanofiber, various type of hydrophobic drugs having completely dif-ferent structures, Tbz and Dnp were used as model drugs. The release behaviors of Tbz and Dnp loaded nanofibers presented differences in terms of pH, quantity and release kinetics due to their structures. Finally, we have produced a calixarene based nanofiber for targeted therapy of the tissues such as stomach and colon by mimicking the pH profile of tissues via in vitro release studies.

Acknowledgement

We would like to thank The Research Foundation of Selcuk University (BAP) for financial support of this work (Grant No:18401041).

Appendix A. Supplementary data

Supplementary data to this article can be found online athttps:// doi.org/10.1016/j.msec.2019.03.038.

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