Green biosynthesis of magnetic iron oxide nanoparticles using Mentha longifolia for imatinib mesylate delivery.

In this work, the rapid, facile, and eco-friendly green process was introduced in the preparation of β-cyclodextrin/magnetic iron oxide nanoparticles by using the aqueous Mentha longifolia extracts of Mentha longifolia. The obtained nanoparticles were characterised by Fourier transform infrared spectroscopy, x-ray powder diffraction, field emission scanning electron microscope, and thermogravimetric analysis. Also, effective factors on the synthesis of magnetic nanocomposites including temperature, concentration of the Mentha longifolia extract, and concentration of FeSO4 solution were optimised by Taguchi design. Moreover, important effective parameters on the adsorption efficiency; such as adsorbent dosage, pH, contact time, and temperature were investigated. The prepared magnetic nanocomposite was applied as a nanocarrier for imatinib mesylate delivery. In vitro studies confirmed imatinib mesylate release over 6 h. The nanocarrier showed pH-dependent imatinib mesylate release with higher drug release at simulated cancer fluid (pH = 5.6) compared to neural fluid (pH = 7.4). Moreover, the sorption isotherms and kinetics for the magnetic nanocomposite were fitted into Langmuir and pseudo-second order models, respectively. Based on the thermodynamic results, the adsorption of imatinib mesylate onto the nanoadsorbent was found to be spontaneous and exothermic.

INTRODUCTION

Cancer is a disease with high mortality rate, high incidence rate, and has extremely exposed human health. The considerable adverse effects recorded by chemotherapeutic drugs usually due to their lack of selectivity for cancer tissues and cells, non‐specific targeting, short blood half‐life, and elimination by the immune system often lead to the failure of chemotherapy. To remove these adverse effects, nanocarriers can be used as drug carriers in drug delivery systems [1, 2]. The use of nanotechnology for targeted delivery of drugs has shown considerable prospective in enhancing medicine safety and diminishing medicine relevant toxicity [3].

Magnetic nanoparticles (MNPs) can be used in the field of medical [4, 5], environmental [6, 7, 8], and chemical engineering [9, 10]. Recently, MNPs as drug delivery systems have attracted an enormous attention. Among them, iron oxide‐based MNPs can be effectively utilised for controlled drug‐delivery applications because of its biocompatibility, magnetic properties for selective targeting, and low toxicity [11]. Drug molecules can be conjugated to the shell of MNPs to be injected into the human body and be concentrated in a local tissue due to the effect of an external magnetic field. Owing to the MNPs’ large surface‐to‐volume ratio, it suggests several chemically active sites for drug conjugation [12]. Different methods have been developed to synthesise metal and metal oxide NPs either physically or chemically. These techniques are toxic, expensive, and have high energy requirements [13].

Thus, some efforts have been applied to develop green procedures for the synthesis of NPs to eliminate the disadvantages of previous techniques. The green synthesis of metal and metal oxide NPs using plant extracts is a good alternative technique [14]. Karthick et al. synthesized the gold nanoparticles (AuNPs) by using medicinally valued Adhatoda vasica Nees [15]. Shankar et al. synthesised thepure metallic silver, AuNPs, and bimetallic Au/Ag nanoparticles by using Neem (Azadirachta indica) leaf broth [16].

Green synthesised MNPs further play a significant role for the delivery of drugs, gens or therapeutic agents, and display several advantages over conventional chemical‐based drug delivery systems. This green technique is simple, eco‐friendly nature, and cost effective [17].

In recent years, there have been few published studies on the green synthesis of NPs using plant extracts. Ahmadi and co‐workers described green synthesis of MNPs using Satureja hortensis essential oil. The synthesised MNPs were explored for in vitro anticancer drug delivery [18]. Sathishkumar et al. successfully synthesised the MNPs using Couroupita guianensis Aubl fruit extract for antibacterial and cytotoxicity activities [19].

The Mentha longifolia L. (Mentha longifolia), usually known as wild mint or horsemint, is an aromatic and medicinal herb which belongs to Labiataes family. The major constituents of this plant include flavonoids, polyphenols, terpenes, carbohydrates, cinnamates, ceramides, and etc [20, 21, 22]. During the last decade, extracts of plants such as Moringa oleifera, Aspalathus linearise, Tabernaemontana divaricata green, Aegle marmelos leaves and Hibiscus rosa sinensis have been used in the synthesis NPs of NiO, NiFe2O4, ZnSnO3, ZnFe2O4, NiO, and ZnO, respectively [23, 24, 25].

Cyclodextrins (CDs) are cyclic oligosaccharides consisting of alpha (six‐membered), beta (seven‐membered), and gamma (eight‐membered sugar ring molecules) or more glucopyranose units joined by α‐(1→4) linkage. The advantage of CDs in parenteral formulation includes stabilisation of drugs unstable in an aqueous environment, reduction of drug irritation at the site of administration, solubilisation of drug, and so forth. CDs, cyclic oligosaccharides, have been used for targeting drug delivery due to a distinctive structure, inherent biocompatibility and amphiphilicity. All the groups of drugs are not appropriate substrates for CDs complexation. Drug molecules to be complexed with CDs should have certain characteristics described below. Melting point temperature of the substance is below 250°C; more than five atoms (C, P, S, and N) form the skeleton of the drug molecule; molecular weight is between 100 and 40 g mol ; and solubility in water is less than 10 mg ml [26, 27, 28].

Among the CDs, β‐cyclodextrins (beta‐CD; β‐CD) have been the most widely used for delivering several kinds of drugs. β‐CD is a non‐toxic cyclic oligosaccharide with a molecular structure having a hydrophobic internal cavity [29]. β‐CD nanostructures make them appropriate for numerous applications in food [30], agriculture [31], and pharmaceutical [32] industries. β‐CD is ideal for DDS due to efficient drug complexation and loading, perfect cavity size, relatively low cost, and availability [33].

Imatinib mesylate (IM; C29H31N7O_CH3SO3H), the mesylate salt of imatinib, is the first targeted anticancer drug to be clinically confirmed. Imatinib mesylate is one of the most commonly used anticancer drugs for the treatment of chronic myeloid leukaemia and acute lymphocytic leukaemia [34, 35].

Experimental design is an effective technique to reduce the number of experiments as well as the cost of experimentation.

Various design of experiments methods have been proposed to enhance the efficiency of synthesis processes such as Taguchi, Box–Behnken, central composite design, D‐optimal etc. Response surface methodology as a statistical technique, is useful to study the influence of the individual parameters and their possible interaction besides the optimization of the condition, with the minimized error of the experiments and least number of experiments. Also, the use of the Taguchi orthogonal array would obviously minimize the number of experimental runs. It is important to analyse all parameters simultaneously using a few tests [36, 37, 38].

The plant‐based biological method is a deliberated ideal method due to high reproducibility, low cost, less reaction time, eco‐friendliness, and elimination of the cell culture step. Plant extracts contain various kinds of phytochemicals that serve as stabilizing agents and are strong reducing, which drive the synthesis of nanoparticles. Thus, the shape, size, and other properties may vary depending on the source and nature of the plant being used [39]. The novelty of this research focusses on the utilization of these plant extract. The main advantage of using extracts is that they are the mild, renewable and non‐toxic reducing and stabilizing agents, eliminating the need for expensive polymeric capping agents and stabilizers. In comparison with the previous work, few studies have presented on the synthesis of Fe3O4 nanoparticles from Mentha longifolia. Also, iron is a cost‐effective alternative compared with other expensive metals. In this paper, magnetic Fe3O4 nanoparticles were synthesized using Mentha longifolia leaf extract. In addition, Fe3O4 NPs/3‐(glycidoxypropyl) trimethoxysilane (GPTMS) were coated with β‐CD and compared to unmodified Fe3O4. The as synthesized β‐CD @ Fe3O4 NPs/GPTMS were characterized with analytical techniques such as FT‐IR, FE‐SEM/EDX, XRD and thermo gravimetric analyser (TGA). The mechanisms of the release of IM from the β‐CD @ Fe3O4 NPs/GPTMS in various environment; namely simulated human blood and cancer fluids were studied.

EXPERIMENTAL SECTION

Reagents and chemicals

Standard IM was bought from Arastoo pharmaceutical company (Iran, Tehran). GPTMS (C9H20O5Si), iron (II) sulphate heptahydrate (FeSO4.7H2O), β‐CD (C42H70O35), sodium dihydrogen phosphate monohydrate (NaH2PO4) and disodium hydrogen phosphate (Na2HPO4) were purchased from Merck Co (Darmstadt, Germany). All of the other chemical reagents were of analytical grade and were obtained from Merck. Ultrapure deionized water (Milli‐Q) was used throughout the work. In all experiments, the stock standard solutions of IM (500 mg L ) were prepared in deionised water.

Instruments

The morphological characteristics of nanoparticles were characterised using a field emission scanning electron microscope (FE‐SEM, KYKY‐EM3200, China) at the voltage of 10 kV. Fourier transform infrared spectra of the nanoparticles were acquired using a Thermo Nicolet IR100 FTIR instrument (Waltham, Mas‐sachusetts, USA) in the range of 400–4000 cm in KBr discs. X‐ray diffraction (XRD) patterns of nanoparticles were identified using X‐ray diffractometer (STOE‐STADV, Germany). The thermal behaviour of nanoparticles was carried out using a thermogravimetric analyser (TGA‐TA, Q600, USA). UV–Vis spectrophotometry was evaluated by using a UV‐2100 spectrophotometer (Shimadzu, Japan).

Plant material and extract preparation

The leaves of Mentha longifolia plant were bought from local market (Iran, Tehran). The leaves of Mentha longifolia were washed several times using deionised water, dried at room temperature, and powdered using an electrical mill (Basic Analytical Mill, Germany). For Mentha longifolia extract, 2 g of chopped plant was added to 100 ml of deionised water and then decanted for 20 min at high temperature. The plant extract was filtered with filter paper (No.1) and Whatman filter paper (No.2), respectively. The plant extract was preserved in the refrigerator at 4°C until use. Preparation of Mentha longifolia extracts (1 and 3 g) was carried out according to the same procedures.

Experimental design for synthesis of Fe3O4 nanoparticles (Fe3O4 NPs)

The synthesis of Fe3O4 NPs were designed by applying the Taguchi experimental design to predict the optimised preparation conditions. Here, three selected parameters, including the temperature (°C), concentration of the extracted Mentha longifolia (%), and concentration of FeSO4 solution (M) were used. As can be seen in Table 1, the temperature was within 25°C–70°C, the concentration of extracted Mentha longifolia was varied from 1% to 5%, and the concentration of FeSO4 was varied from 0.1 to 5 M. This design requires nine runs with three parameters at three levels. Numerical optimization for the synthesis of Fe3O4 NPs was carried out using Minitab software (Minitab®16.1.1).

TABLE 1

The studied factors and their levels in the Taguchi design

	Factor	Level 1	Level 2	Level 3
A	FeSO4 concentration (mol L−1)	0.1	0.5	1
B	Plant extract concentration (%)	1	3	5
C	Temperature (°C)	25	50	70

Synthesis of Fe3O4 NPs

Initially, FeSO4 solutions at three concentrations, 0.1, 0.5, and 1 mol L were prepared by dissolving 2.78, 13.9, and 27.8 g in 100 ml of deionised water, respectively. 15 ml of the extracted Mentha longifolia was added drop‐wise to the above solutions. Complete reduction of the iron ions was performed by stirring for 24 h at 25°C–70°C. The colour of the solution converted from yellow to brown which indicated formation of Fe3O4 NPs. The solutions were centrifuged at 1000 rpm for 5 min, washed with deionised water, and finally dried for 12 h.

Synthesis of Fe3O4 NPs modified with GPTMS (Fe3O4 NPs/GPTMS)

In brief, 0.5 g of Fe3O4 NPs, 2.5 ml of GPTMS, and 47.5 ml of toluene were added to 100 ml of the volumetric flask. The mixture was stirred at gentle reflux at 95°C. After 48 h, the solution was centrifuged at 10,000 rpm for 10 min. After that, 30 ml of toluene was added into the above solution drop‐wise under stirring for 15 min. Then, the above solution was immediately centrifuged at 10,000 rpm for 10 min.

Synthesis of β‐CD‐coated Fe3O4 NPs/GPTMS (β‐CD@Fe3O4 NPs/GPTMS)

For the synthesis of Fe3O4 NPs/GPTMS modified with β‐CD, 0.5 g of Fe3O4 NPs/GPTMS and 0.5 g of β‐CD were added in the round‐bottom flask after the addition of acetate buffer and refluxed for 48 h at 45°C. Next, the precipitates of β‐CD@Fe3O4 NPs/GPTMS were washed with acetate buffer and deionised water two times sequentially, and dried in an oven (Memmert, Germany) at 40°C for 24 h. The schematic diagram of β‐CD @Fe3O4 NPs/GPTMS is presented in Figure 1.

FIGURE 1

Schematic diagram of the preparation of β‐CD @Fe3O4 NPs/(glycidoxypropyl) trimethoxysilane (GPTMS)

Adsorption of IM using β‐CD @Fe3O4 NPs/GPTMS nanoadsorbent

All the batch adsorption tests were carried out on a rotary shaker (KS 4000i control, Germany) with a speed of 250 rpm. Typically, 0.01 g of β‐CD @Fe3O4 NPs/GPTMS and 20 ml of IM solution were mixed at pH = 5 for 15 min. After that, the solution was centrifuged at 6000 rpm for 15 min. Next, the supernatant was filtered through a 0.22 μm syringe filter (Millipore, Bedford, MA). Finally, the amount of drug concentration in supernatant was analysed using the UV‐Vis spectrophotometer at 256 nm in triplicate. The adsorption capacity of IM was calculated by following equation: Here, q (mg g ) denotes the adsorption capacity, C (mg L ) denotes the equilibrium concentration, C0 (mg L ) denotes the initial concentration of IM in solution, V (L) denotes the volume of solution, and M (g) denotes the amount of β‐CD @Fe3O4NPs/GPTMS.

Loading and in vitro release of IM onto the β‐CD @Fe3O4 NPs/GPTMS

Loading of β‐CD@Fe3O4NPs/GPTMS with IM was investigated as follows: Firstly, 0.2 g of the β‐CD @Fe3O4 NPs/GPTMS was added to 50 ml of IM solution at 25°C and stirred for 1 h at 270 rpm using a magnetic stirrer. The precipitate was collected from the solution, and the amount of loaded IM in the β‐CD@Fe3O4 NPs/GPTMS was measured at 256 nm.

In vitro drug release from β‐CD @Fe3O4 NPs/GPTMS was conducted at 37°C on a stirrer at 270 rpm in a phosphate buffer saline (PBS; 50 ml) with the pH value of 7.4 and 5.6. At certain time points, 3 ml of solution was collected and 3 ml of fresh PBS was added. The amount of the collected medium was analysed using UV–Vis spectrophotometry at 256 nm.

Isotherm, kinetic, and thermodynamic experiments

Adsorption isotherm experiments were studied by adding 0.01 g of β‐CD @Fe3O4 NPs/GPTMS to 20 ml solutions containing a different initial IM concentration of 2–100 mg L , and the solutions were shaken for 1 h. Four adsorption isotherms, such as Langmuir [40], Freundlich [41], Temkin [42], and Dubinin‐Radushkevich (D‐R) [43] models, were used to describe the equilibrium adsorption of IM from the aqueous solution.

In which, q (mg g ) and q max (mg g ) were the capacity of IM adsorbed per gram onto β‐CD @Fe3O4 NPs/GPTMS at equilibrium and the maximum IM sorption capacity corresponding to complete monolayer coverage onto β‐CD @Fe3O4 NPs/GPTMS, respectively. C (mg L ) was the equilibrium IM concentration in the aqueous solution. K (L mg ), K (mg g ) (L mg ) , and KDR (mol kJ ) were model constants related to the Langmuir, Freundlich, and D‐R isotherm models, respectively. The parameter of ‘n’ was related to the adsorption intensity. R was represented by the ideal gas constant (8.314 J mol  K ); T was the temperature (K); b was constant associated to the heat of IM sorption (J mol ), and A was the Temkin constant. Also, the parameter of Ɛ was related to the Polanyi potential.

For kinetic studies, the synthesised nanoadsorbent with a 20 mg L solution of IM was performed at different contact times. On the other hand, the influence of temperature on the adsorption of IM by β‐CD @Fe3O4NPs/GPTMS was studied with 20 mg L of IM at different temperatures (298–323 K). The solution was centrifuged, and the residual IM concentration was analysed using UV‐Vis spectrophotometer. Also, three kinetic models (pseudo‐first order (PFO) [44], pseudo‐second order (PSO) [45], and intra‐particle diffusion (IPD) [46] models were tested for studying the adsorption mechanism.

Here, q (mg g ) was the adsorption capacity at time t; the parameter of ‘t’ was the adsorption time of IM on β‐CD @Fe3O4 NPs/GPTMS; and C was the thickness of the boundary layer of the ID kinetic model. K1 (min ), K2 (g mg min ), and K (g mg min ) were model constants associated to the PFO, PSO and, IPD kinetic models, respectively.

The enthalpy change (ΔHo; J mol ), the entropy change (ΔSo; J mol K ), and the Gibbs‐free energy (ΔGo; kJ mol ) were calculated to describe the influence of rising temperatures on the adsorption of IM onto β‐CD @Fe3O4 NPs/GPTMS. The thermodynamic parameters for the adsorption procedure can be evaluated from the relationship of adsorption isotherms and temperature. Thermodynamic parameters are obtained from the following equations:

In the above equation, R (J mol  K ), T (K), and m (g) are the ideal gas constant, the temperature, and the adsorbent dose. Also, K (L mol ) represents the equilibrium constant which denotes the ratio of equilibrium concentration of IM adsorbed onto the nanoadsorbent. Upon the above equations, the curve of Ln K versus 1/T provides a straight line and from the intercept and slope of the line, ΔS° and ΔH° were calculated.

RESULTS AND DISCUSSION

Taguchi method

In this study, the synthesis of Fe3O4 NPs was designed by applying the Taguchi OA method to predict the optimised preparation conditions. The experiments were conducted based on the L9 orthogonal array (three variables, three levels, and nine experimental runs). All the tests were performed in triplicates and mean values of response were reported. Experimental conditions and the results of the size and morphology of the nanoparticles were shown in Table 2. At first, the size of biosynthesised nanoparticles was chosen as a response. The FE‐SEM images showed that all the nanoparticles from all experiments have an average diameter of 14–23 nm, which means no significant change in size occurred from different conditions of experiments. After that, the response was changed to the morphology of nanoparticles and they were divided into 3 groups (good, medium, and bad) which are illustrated in Table 2. The FE‐SEM images of Fe3O4NPs are shown in Figure S1a‐i. Figure S1f, h, i shows the FE‐SEM images of Fe3O4NPs, which are spherical with a smooth surface (good; 3000). On the other hand, Figure S1a, d, g displays the FE‐SEM images of Fe3O4NPs with some deformation in apparent and high agglomeration in morphology, due to the sticking effect of MNPs (medium; 2000). Also, images (Figure S1b–e) show the FE‐SEM images of biosynthesised Fe3O4NPs with hexagonal structure (bad; 1000).

TABLE 2

Experimental results: A factor denotes the first variable (FeSO4 concentration), B factor denotes the second variable (plant extract concentration), and C factor denotes the third variable (temperature)

Exp.No	A	B	C	Morphology	Mean diameter NP (nm)	StDev (m 3 s −1 )
1	1	1	25	2000	16.40	5.77
2	1	3	50	1000	16.43	4.90
3	1	5	70	1000	14.69	4.64
4	0.5	1	50	2000	15.57	5.89
5	0.5	3	70	1000	20.24	9.23
6	0.5	5	25	3000	18.97	6.95
7	0.1	1	70	2000	18.53	6.06
8	0.1	3	25	3000	23.37	7.61
9	0.1	5	50	3000	22.28	7.73

Main effect plot

In this study, the effects of FeSO4 concentration, plant extract concentration, and temperature on the particle size at three different levels (1, 2 and 3) were studied. The main effect plot of the nanoparticles’ size is displayed in Figure S2. The main effect plot was used to show the relationship between the factors and their response in the form of the morphology of the nanoparticles. It was observed that by transferring the concentration of FeSO4 from level 1 (1 M) to level 3 (0.1 M), the nanoparticle morphology improved. In other words, with decreasing FeSO4 concentration, the particle morphology is more favourable. The results indicate that changing this parameter is effective on the response variable. Besides, the temperature is a significant factor on the response. As temperature rises from level 1 (25°C) to level 3 (70°C), the morphological quality of the nanoparticles was reduced.

Contour plots

In this study, the effects of FeSO4 concentration, plant extract concentration, and temperature on the morphology of nanoparticles were investigated at three different levels, and the obtained results are expressed as contour plots. These contour plots analysed by Taguchi design to determine the optimal conditions and the simultaneous effect of two factors on the morphology of Fe3O4 NPs and the obtained results are shown in Figure 2. Figure 2a displays the 2‐D contour plot of FeSO4 concentration and temperature against the morphology quality of nanoparticles. As can be seen, the quality of nanoparticles morphology was reduced by increasing the temperature from level 1 (25°C) to level 3 (70°C), and decreasing the FeSO4 concentration from level 3 (0.1 M) to level 1 (1 M). Figure 2b shows the simultaneous effect of temperature and plant extract concentration on the response. As observed, the best response was obtained in the highest plant extract concentration (level 3; 5%) and lowest temperature (level 1; 25°C). Figure 2c indicated the contour plot of FeSO4 concentration and plant extract concentration on response. As shown, the morphology of the nanoparticles improves with increasing concentration of FeSO4 from level 1 (0.1 M) to level 3 (1 M) as well as increasing concentration of plant extract from level 1 (1%) to level 3 (5%).

FIGURE 2

Contour plots for the mutual effects of (a) FeSO4 concentration and temperature; (b) temperature and plant extract concentration; and (c) FeSO4 concentration and plant extract concentration on the nanoparticle size of synthesised Fe3O4 NPs

Regression analysis

In this paper, only effective variables such as FeSO4 NPs concentration, plant extract concentration, and temperature were analysed. The least square linear regression was used. Regression analysis was investigated to develop the relationship between the parameters. The related equation is described as

Result = 1667 + 667 FeSO4 concentration +167 plant extract concentration %−667 Temperature.

Optimal conditions according to this plot were level 1 for temperature, level 3 for FeSO4 concentration, and level 3 for plant extract concentration.

Optimization of parameters

Effects of adsorbent dosage and contact time

The effects of nanoadsorbent dosage and contact time on IM sorption at pH = 5 and 25°C are shown in Figure S3. In these tests, the amount of β‐CD @Fe3O4 NPs/GPTMS at a range of 0.005–0.015 g was investigated. By increasing β‐CD @Fe3O4 NPs/GPTMS dosage and contact time, the removal percentage of IM was increased. The removal efficiency for IM at equilibrium time was estimated to be 30% using 0.015 g of the nanoadsorbent. The adsorption capacity of β‐CD @Fe3O4 NPs/GPTMS for IM increased very fast within 30 min, slightly after 30 min and the removal of IM was almost constant. On the other hand, by increasing β‐CD @Fe3O4 NPs/GPTMS dosage and contact time, the adsorption capacity of IM was decreased.

Effects of temperature

Figure S4 shows the adsorption capacity of the IM solutions under pH = 5 at different temperatures. As shown in Figure S4, adsorption capacity of IM increases as the temperature decreases. Also, the adsorption capacity increased when the amount of initial concentration raised from 1 to 100 mg L , and the maximum adsorption capacity of IM was about 45% (T = 25°C). Additionally, increasing the initial IM concentration from 1 to 100 mg L at 298 K has shown the increase in the adsorption efficiency from 2% to 46%.

Effect of contact time

The effect of contact time of IM onto the β‐CD @Fe3O4 NPs/GPTMS at different contact time (2, 5, 10, 20, 30, 45, 60, 90 and 120 min) are shown in Figure S5. The maximum adsorption efficiency of 100% was observed at the contact time of 30 min while the other factors were temperature 25°C, pH = 5, and adsorbent dosage 0.015 g. It can be observed that the adsorption efficiency of β‐CD @Fe3O4 NPs/GPTMS for IM was significantly increased during the first 30 min, after which it remained almost constant. Rapid adsorption efficiency of IM at the initial time of the adsorption procedure could be related to the active sites on the β‐CD @Fe3O4 NPs/GPTMS surfaces.

Effect of pH

For investigating the influence of the pH value on the β‐CD @Fe3O4 NPs/GPTMS adsorption efficiency, the pH of solutions were tested in the range of 3–8. Based on the results (Figure 3a), by increasing the solution pH from 3 to 5, the adsorption capacity was enhanced, reaching the maximum value of 9.6 mg g at pH = 5. On the other hand, the decrease in the adsorption capacity at pH higher than 5 could be attributed to the decomposition of β‐CD @Fe3O4 NPs/GPTMS in an alkaline pH. Consequently, pH = 5 was chosen as an optimum pH in the next experiments.

FIGURE 3

The effect of pH (a) and pH PZC (b) on the adsorption of Imatinib mesylate (IM) using β‐CD @Fe3O4 NPs/(glycidoxypropyl) trimethoxysilane (GPTMS) (Experimental conditions; initial concentration, 20 mg L−1; nanoadsorbent dosage, 0.015 g; contact time, 30 min; and temperature = 25°C)

Additionally, to confirm the accuracy of evaluating the optimal pH, the pH PZC was investigated. The results of this study indicated that the zeta potentials of β‐CD @Fe3O4 NPs/GPTMS decreased when the pH increased from 3 to 9. At pH < 6.8, the surfaces of β‐CD @Fe3O4 NPs/GPTMS are positively charged. At pH > 6.8, the zeta potential of β‐CD @Fe3O4 NPs/GPTMS is negative. Thus, the pH PZC value for IM adsorption was 6.8 (Figure 3b).

Characterisation

XRD analysis

The crystalline phase of Fe3O4 NPs and β‐CD @Fe3O4 NPs/GPTMS were identified with XRD analysis (Figure S6). For Fe3O4 NPs (Figure S6a), diffraction peaks with 2θ = 31.1°, 36.8°, 53.1°, and 78.0° appeared, which were attributed to the crystal planes of (220) (311) (422), and (440), respectively. The XRD pattern of β‐CD @Fe3O4 NPs/GPTMS (Figure S6b), shows characteristic peaks at 2θ = 30.9°, 34.4°, 45.6°, 67.8°, and 78.0° corresponding to the (220) (311) (400) (511), and (440), respectively (ICDD Reference card No: 19‐0629). These results confirmed that Fe3O4 NPs/GPTMS was successfully modified by β‐CD.

FT‐IR analysis

FT‐IR spectra of Fe3O4 NPs and β‐CD @Fe3O4 NPs/GPTMS were characterised in the range of 400–4000 cm (Figure 4). As observed in Figure 4a, frequencies observed at 1629 and 3373 cm were attributed to the stretching vibrations of C = O and OH groups, respectively. The peaks ranging from 1000 to 1300 cm were assigned to the C‐O and C‐C stretching vibrations. The resulting peak at 529 cm in this spectrum indicates the formation of magnetite nanoparticles (Fe3O4 NPs). In the β‐CD @Fe3O4 NPs/GPTMS spectrum, the broad peak at 3396 cm were related to the stretching vibration of OH. The band at 1046, 1263 and 1417 cm were ascribed to the C‐O, C‒O‒C, and CH2, respectively. In addition, the peaks at 1631 cm related to the out of plane stretching vibration of the OH group (Figure 4b). The stretching vibration for Fe–O groups of Fe3O4 particles was observed at 529 cm , which shifted to 498 cm−1 after coating with β‐CD.

FIGURE 4

FT‐IR spectra of Fe3O4 NPs (a) and β‐CD @Fe3O4 NPs/(glycidoxypropyl) trimethoxysilane (GPTMS) (b)

TGA analysis

Thermogravimetric curves of Fe3O4 NPs and βCD@Fe3O4 NPs/GPTMS were obtained from room temperature to 600ºC at 10ºC min . Results of TGA were indicated in Figure S7. Weight loss of 59.03% and 68.5% were detected for Fe3O4 NPs and β‐CD @Fe3O4 NPs/GPTMS, respectively. Based on thermograms, 9.5% weight loss was observed for samples due to the modification of Fe3O4 NPs with polymer and the decomposition of β‐CD. Thermal resistance of the samples occurred at about 400°C.

FE‐SEM analysis

FE‐SEM images were investigated to estimate the surface morphology of the Fe3O4NPs and β‐CD @Fe3O4 NPs/GPTMS as shown in Figure 5. As can be seen in Figure 5a, the images indicated that the particles have spherical shape. The average diameter of Fe3O4 NPs was approximately 38 nm. After coating, the FE‐SEM images of β‐CD @Fe3O4 NPs/GPTMS indicated that the surface of agglomerated nanoparticles have spherical shapes with particle size of 61–103 nm (Figure 5b). Accordingly, the average size of β‐CD @Fe3O4 NPs/GPTMS will increase with agglomeration.

FIGURE 5

FE‐SEM images of Fe3O4 NPs (a), β‐CD @Fe3O4 NPs/(glycidoxypropyl) trimethoxysilane (GPTMS) (b) and EDX results of Fe3O4 NPs (c), β‐CD @Fe3O4 NPs/GPTMS (d)

Also, Figure 5 shows the EDX elemental mapping images of Fe3O4 NPs and β‐CD @Fe3O4 NPs/GPTMS. As can be seen in Figure 5c, the EDX image of Fe3O4 NPs indicate the presence of C (35.26 w %), Fe (14.53 w %), Si (1.91 w %), O (44.63 w %), Na (0.84 w %) and p (2.32 w %) elements and for β‐CD @Fe3O4 NPs/GPTMS, Figure 5d indicates the presence of C (35.35 w %), Fe (12.69 w%), Si (1.66 w%), O (47.41 w%), Na (0.57 w %) and p (1.66 w %) elements which confirm the presence of Fe3O4 and β‐CD nanoparticles on the surface. After surface modification of Fe3O4 NPs with β‐CD, the atomic weight ratio of C and O were increased; however, in contrast, the weight percentage of Fe and Si were decreased. As the results were confirmed, coating of β‐CD particles on the Fe3O4 NPs/GPTMS surface was successful.

Investigation of adsorption behaviour of β‐CD @Fe3O4 NPs/GPTMS

Isotherm study

The adsorption isotherms of IM on the β‐CD @Fe3O4 NPs/GPTMS were investigated at various temperatures of 298, 308, and 323 K. According to Table 3, the adsorption capacity (q max) of β‐CD @Fe3O4 NPs/GPTMS for IM decreased with increasing the temperature. The q max for IM on β‐CD @Fe3O4 NPs/GPTMS, evaluated from the Langmuir isotherm model, was 62.11 mg g at 298 K. High correlation coefficient (R 2) values obtained for the Langmuir isotherm model suggest that the Langmuir model was quite fitted to the isotherm data. Table 3 has shown that the R 2 for the Langmuir isotherm model were 0.9912, 09,946 and 0.9941 at 298, 308, and 323 K, respectively. The R value of the β‐CD @Fe3O4 NPs/GPTMS for IM was observed to be 0.21 at 325 K. In addition, the value of ‘n’ was estimated to be from 1.55 to 1.84 for the adsorption of IM using β‐CD @Fe3O4 NPs/GPTMS. The ‘n’ value greater than one represents that the adsorption of IM on the nanoadsorbent is undesirable. In the 298–325 K range, the b parameter values of the Temkin isotherm model increase with the increase of temperature. In contrast, the q values of the D‐R isotherm models decrease with the increase of temperature range from 298–323 K.

TABLE 3

Equilibrium isotherm parameters for adsorption of Imatinib mesylate (IM) on β‐CD @Fe3O4 NPs/(glycidoxypropyl) trimethoxysilane (GPTMS) (Experimental conditions: nanoadsorbent dosage: 0.015 g; contact time: 30 min; and pH = 5)

Isotherm model	Parameters	T = 298K	T = 308K	T = 323K
Langmuir	q max (mg g −1 )	62.11	48.31	42.55
	K L (L mg −1 )	0.04	0.038	0.036
	R L	0.201	0.207	0.21
	R 2	0.9912	0.9946	0.9941
Ferundlich	K F (mg g −1 )	3.45	2.91	3.2
	(L mg −1 ) 1/n n	1.55	1.64	1.84
	R 2	0.9556	0.9805	0.9794
Temkin	A (L mg −1 )	0.48	0.34	0.33
	b (J mol −1 )	193.89	231.87	276.57
	R 2	0.982	0.9905	0.9903
Dubinin‐radushkevich	q s (mg g −1 )	40.87	32.73	28.81
	KDR (mol 2 kJ −2 )	0.00002	0.00002	0.00002
	R 2	0.9561	0.8528	0.8504

Kinetic study

The kinetic study for the adsorption of IM onto β‐CD @Fe3O4 NPs/GPTMS at various adsorbent dosage (i.e., 0.005, 0.01, and 0.015 g) was investigated using three kinetic models, including the PFO, PSO, and IPD. Kinetic parameters of the adsorption process were calculated and listed in Table 4. As shown in Table 4, the adsorption kinetic data in this study could be well explained by the PSO kinetic model. However, the calculated equilibrium constant (q , cal) for β‐CD @Fe3O4 NPs/GPTMS decreased as the adsorbent dosage was increased from 0.005 to 0.015 g. Noticeably, the PSO rate constant, k2 was increased for IM as the adsorbent dosage of the nanoadsorbent was raised. Furthermore, if the PSO kinetic model provides the best fit to the adsorption process, physisorption mainly controls the adsorption process.

TABLE 4

Kinetic parameters for adsorption of Imatinib mesylate (IM) on β‐CD @Fe3O4 NPs/(glycidoxypropyl) trimethoxysilane (GPTMS) (Experimental conditions: initial concentration: 20 mg L ; pH = 5; and temperature = 25°C)

Kinetics models	Parameters	0.005	Adsorbent dosage (g) 0.01	0.015
PFO	K1 (min −1 )	0.11	0.15	0.07
	q e (mg g −1 )	8.43	6.26	1.34
	R 2	0.994	0.9639	0.9994
PSO	q e (mg g −1 )	13.99	11.27	8.13
	k2 (g mg −1 min −1 )	0.03	0.07	0.17
	R 2	0.9996	0.9998	0.9999
IPD	Ki1 (g mg −1 min −0.5 )	1.94	1.45	0.24
	Ki2 (g mg −1 min −0.5 )	0.5	0.19	0.17
	C1 (mg g −1 )	4.59	4.91	6.59
	C2 (mg g −1 )	10.44	9.88	6.92
	R1 2	0.9903	0.9987	0.9673
	R2 2	0.9335	0.8126	0.9938

Abbreviations: IPD, intra‐particle diffusion; PFO, pseudo‐first order; PSO, pseudo‐second order.

Thermodynamic study

The influence of temperature on the adsorption of IM by β‐CD @Fe3O4 NPs/GPTMS was examined by using 25 mg L of IM at different temperatures (298–323 K). As can be seen in Table S1, the value of ∆Go decreased from −9.12 to −9.67 with increasing temperature. The negative values of ΔGo confirmed that the adsorption efficiency of IM on β‐CD @Fe3O4 NPs/GPTMS was feasible and spontaneous. Meanwhile, the negative value (−2506.01) of ΔHo confirmed the exothermic nature of the adsorption process. Moreover, the positive value of ΔSo confirmed that the degree of freedom of the β‐CD @Fe3O4 NPs/GPTMS increased during the adsorption process. The ΔGo range for physical adsorption is between 0 and −20 kJ mol .

Drug release study

The release behaviour of IM from β‐CD @Fe3O4 NPs/GPTMS was studied in simulated human blood fluid (SHF, pH = 7.4) and simulated cancer fluid (SCF, pH = 5.6) as the release fluid. For the first 1 h, under SHF, about 12% of IM was released from the nanocarrier (Figure S8). However, only approximately 54% of drug was released from the nanocarrier after 6 h. In contrast, at pH = 5.6, the IM loaded β‐CD @Fe3O4 NPs/GPTMS released about 37% of IM after 1 h and 97% after 6 h. The nanocarrier in the SCF (pH = 5.6) has shown that the release of IM was faster than that at pH = 7.4. It may due to the OH groups on the surface of β‐CD. H‐bonding interaction between the drug and nanocarrier at acidic pH (SCF; pH = 5.6) is weak and drug release increases.

In order to indicate the advantage of the present method, we have compared the obtained results in the drug release of IM over the β‐CD @Fe3O4 NPs/GPTMS with some reported nanocarriers in the viewpoint of drug release. Table 5 displays drug release percentages of various nanocarriers for IM release as noted in previous works [47, 48, 49, 50]. The release of the IM depends on the interaction between the drug molecule and nanocarrier, that is, π–π interaction between β‐CD @Fe3O4 NPs/GPTMS and IM. The comparison data shown that β‐CD @Fe3O4 NPs/GPTMS indicated higher the release percentage compared with other nanocarriers.

TABLE 5

Comparison of the release of Imatinib mesylate (IM) drug with various reported nanocarriers

Nanocarrier	Drug release (%)	Time (h)	Ref.
FPL‐DOX/IM	72	13	[47]
IM/GNP‐HCIm	30	8	[48]
IM/MNs@p (NVCL‐co‐VAc)‐DABA	80	6	[49]
PBCA nanoparticles	10	48	[50]
β‐CD @Fe3O4 NPs/GPTMS	97	6	This work

CONCLUSION

In conclusion, Fe3O4NPs were produced by an environmentally friendly approach using aqueous extract of Mentha longifolia leave as a nanocarrier. Green chemistry is the preferred route for synthesis of metal nanoparticles because of it is non‐noxious, viable, ecological friendly, fast, and cost effective. We reported a suitable method for the attaching of β‐CD onto the surface of Fe3O4 NPs/GPTMS. By using the Taguchi orthogonal array, the effective parameters on the synthesis of Fe3O4NPs were optimised (pH = 5, temperature = 25 C, adsorbent dosage = 0.015 g, and contact time = 30 min). According to the release curve, β‐CD @Fe3O4 NPs/GPTMS released 54% and 97% of drug after 6 h in neutral and acidic fluids, respectively. Also, adsorption results were consistent with the Langmuir isotherm model and PSO kinetic model. The positive value of ΔS° suggests that the adsorption increased the randomness during the adsorption of IM by β‐CD @Fe3O4 NPs/GPTMS. According to the thermodynamic results, the adsorption method was exothermic (ΔH°<0) and spontaneous (ΔG°<0) in nature.

CONFLICT OF INTERESTS

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PERMISSION TO REPRODUCE MATERIALS FROM OTHER SOURCES

None.

Supporting Information S1

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