Fabrication of temperature and pH sensitive decorated magnetic nanoparticles as effective biosensors for targeted delivery of acyclovir anti-cancer drug

Journal of Molecular Liquids 309 (2020) 113024

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Fabrication of temperature and pH sensitive decorated magnetic nanoparticles as effective biosensors for targeted delivery of acyclovir anti-cancer drug Xianting Xie a, Lu Zhang a,b, Wenjuan Zhang a,c, Reza Tayebee d,f, Atefe Hoseininasr d, Hamid H. Vatanpour e, Zeinab Behjati f, Suying Li c,⁎, Marjan Nasrabadi g, Liuyi Liu a,b a

Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, China c Department of Pharmacy, Henan Medical College, Henan, Zhengzhou 451191, China d Department of Chemistry, Hakim Sabzevari University, Sabzevar 96179-76487, Iran e Farhangian University, Shahid Beheshti Campus of Mashhad, Iran f Chemistry Department, Payam Noor University, 19395-4697 Tehran, Islamic Republic of Iran g Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran b

a r t i c l e

i n f o

Article history: Received 2 February 2020 Received in revised form 24 March 2020 Accepted 30 March 2020 Available online 01 April 2020 Keywords: Magnetite Modified Fe3O4 nanoparticles Drug delivery Acyclovir DFT AIM

a b s t r a c t Magnetic nanoparticles are promising materials for a variety of applications, especially in the delivery and controlled release of various drugs. These compounds present a major obstacle to the treatment of many diseases and have a pivotal role in the future of personalized medicine. In the present study, adsorption and delivery of acyclovir (ACV) on pristine and modified magnetic nanoparticles are investigated. The as-synthesized magnetite nanoparticles are decorated with 3(triethoxysilyl)-propylamine prior loading of ACV and samples are characterized by means of SEM, TEM, VSM, DLS, and zetametry studies. VSM and zeta potential studies show that ACV decreases the saturation magnetization and zeta potential of magnetite nanoparticles. Then, adsorption of ACV in phosphate buffered saline was examined and effects of some variables including pH, loading time and temperature are briefly investigated. Our experimental results revealed the best loading (~80%) can be achieved at pH 9 at 39 °C after 5 h. The loading efficacy may be assigned to the increment of hydrogenic interactions under the loading process. Eventually, a DFT study was fully investigated to provide important theoretical parameters related to the adsorption process. The performed computations on pristine and doped Fe3O4 nanoparticles prove strong interactions between nitrogen and oxygen atoms of acyclovir with Fe+3 ions of magnetic nanoparticles. Moreover, additional hydrogen bonds between active sites of the adsorbed drug molecule and Fe3O4 fragments lead to a significant adsorption and stabilization of the obtained configurations. The nature of intermolecular interactions, electron densities, and Laplacians is also fully investigated at the bond critical points. Natural bond orbital analysis confirms that acyclovir can be adsorbed on the surface of Fe3O4 nanoparticle with a charge transfer from acyclovir to the nanoparticle. In addition, the modified and doped Fe3O4 nanoparticles can absorb drug molecules more strongly compared to the pristine counterpart and generate stable configurations. Interestingly, doping with Zn atom results in an electronic hole, hence, the conductivity of the Fe3O4 may be enhanced. Therefore, Zn impurities can introduce local states inside the Eg and improve reactivity of magnetic nanostructures towards adsorption process. Therefore, the examined metal-doped magnetic nanoparticles in this study can be applied as promising nanobiosensors for detection and delivery of ACV in medicine. © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction The production of adsorbed or confined drugs onto an inorganic matrix is an interesting subject in pharmaceutical and material sciences ⁎ Corresponding author. E-mail address: [email protected] (S. Li).

due to the new features and properties of the nanoadsorbed molecules like progressed chemical stability and controlled release. Appropriate drug delivery systems are conferred as a significant challenge in the targeted drug delivery approaches. Nowadays, nanocarriers have shown unique advantages and are introduced as the most efficient transporters in the field. Inorganic nanocarriers with high mechanical strength and good chemical stability are widely applied in the drug

https://doi.org/10.1016/j.molliq.2020.113024 0167-7322/© 2020 The Authors. Published by Elsevier B.V. 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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delivery systems [1–8]. Gold [9], silver [10], zinc oxide [11], and silicon dioxide [12] nanoparticles are particularly behaved much superior than organic counterparts such as polymers [13] and liposomes [14]. Among various nanoparticles, magnetic ones including Fe3O4 and γFe2O3 have great biocompatibility and low toxicity. Thus, these two nano-oxides are extensively utilized in the targeted drug delivery, bioseparation, magnetic fluid hyperthermia, and magnetic resonance imaging [15–19]. Despite the impressive successful attempts in the field of modern nano-medicine and creating new classes of drug delivery systems, there is still a demand to complete theoretical models, which can describe complex interactions of iron oxide nanoparticles with different drug molecules [20]. Acyclovir (9-[(2-hydroxyethoxy)methyl]guanine) is a synthetic purine nucleoside analogue of guanosine and known as one of the most widely used antiviral agents against herpes simplex virus and varicella-zoster virus infections and also shown anti-cancer and antihepatitis B activity [21–23]. Acyclovir has important undesirable pharmacokinetic properties. For instance, the gastrointestinal absorption of acyclovir is slow, dose-dependent, highly variable and incomplete. In addition, the mean plasma half-life (t½) of acyclovir is ~3 h in adults, hence, repeated administration of a high dose (it is a poorly soluble drug with only 15–30% absorption through bed patient treatment) is required for the effective management of HSV infections (200 mg five times per day) [24]. Therefore, attempts have been performed to improve the bioavailability of acyclovir by using nanoparticles with desirable physicochemical properties on living cells to overcome the mentioned drawbacks. Although there are a number of reports on using magnetic nanoparticles in the delivery of different drugs [25–27], however, this study is

organized to investigate adsorption of ACV onto some important iron oxide based nanoparticles from both experimental and theoretical points of view. Effects of silica coating and doping with some transition metal ions are fully interpreted and their influences are considered on the delivery of acyclovir from a new perspective. To the best of our knowledge, this study is a unique and comprehensive attempt, which considers various affecting parameters on the adsorption and delivery of ACV as a significant drug onto magnetic nanoparticles. First, preparation of magnetite is described. Then, the as-synthesized nanoparticles are decorated with 3-(triethoxysilyl)-propylamine prior loading of ACV and, eventually, characterization of the prepared samples before and after loading of ACV are discussed by means of SEM, TEM, VSM, DLS, and zetametry in detail. In the next part, adsorption of ACV in phosphate buffered saline was examined and effects of pH, contact time, and temperature were investigated. Finally, a DFT study was fully scrutinized to provide important theoretical parameters related to the adsorption behavior of acyclovir on the bare and modified magnetic nanoparticles including silica coated and metal-doped Fe3O4 nanoparticles in a solution phase. Scheme 1 shows a general route for the preparation and application of magnetic nanoparticles in the delivery of ACV. 2. Experimental and computational methods 2.1. Chemicals and characterization data Reagents and solvents purchased from Merck or Fluka and used as received. The powdered XRD patterns were identified by a STOE diffractometer with Cu-Kα radiation (λ = 0.15418 nm) at 40 kV and 40 mA. The diffraction patterns were recorded in the Bragg angle (2θ) range

Scheme 1. A general scheme showing interaction sites of acyclovir with the synthesized magnetic nanoparticles.

X. Xie et al. / Journal of Molecular Liquids 309 (2020) 113024

from 30° to 65°. Particle size and morphology of the magnetic samples were done by TEM (Philips CM-200 and Titan Krios) and SEM (Philips XL 30 and S-4160). Magnetization measurements were carried out on a BHV-55 VSM. Ultraviolet-visible spectra were recorded on a UV–Vis Array Spectrophotometer (Photonix Ar 2015) in the range of 200–800 nm. The zeta potential of nanoparticles was determined using a 90 Plus instrument (Brookhaven, NY). For zeta potential determination, samples were diluted with 0.1 mM KCl in an electrophoretic cell and an electric field of about 15 V/cm was performed. 2.2. Preparation of bare and modified Fe3O4 nanoparticles by the solvothermal method Fe3O4 nanoparticles were prepared using a solution of FeCl3.6H2O (1.8 g), NaNO3·3H2O (0.36 g), and PEG-400 (45 mL) in ethanol (5 mL). Then, the as-prepared solution was mixed under fast stirring at room temperature for 30 min. Thereafter, 2 g of NaAc was added under stirring for 12 h at 25 °C. Thereafter, the reaction mixture was transferred to a 50 mL Teflon-lined stainless steel autoclave and heated to 200 °C for 10 h. Then, dark particles of magnetite were isolated, washed with ethanol, and dried [28]. Thereafter, silica-coated Fe3O4 nanoparticles was synthesized by dispersing 0.1 g of Fe3O4 in a mixture of deionized water (2 mL), absolute ethanol (6 mL), and ammonia (0.2 mL, 25%) with sonication for 30 min. Then, 0.5 mL of TEOS was added to the reaction mixture and stirred for 16 h. Finally, the prepared Fe3O4@SiO2 (0.04 g) was dispersed in 2 mL of dry toluene under ultrasonic for 30 min under N2 and 0.04 mL of 3-(triethoxysilyl)propylamine (TMPA) was added to the resulting mixture and refluxed under nitrogen for 24 h to attain Fe3O4@SiO2-NH2. 2.3. Loading release studies In vitro drug loading was monitored by mixing Fe3O4@SiO2-NH2 nanoparticles (0.02 g) with a phosphate buffer solution (2 mL, pH 7.4) containing acyclovir (2 mg) under stirring for 5 h. Then, the solid material was isolated by an external magnet and the supernatant was tested to determine the amount of loaded drug. To withdraw the unloaded acyclovir, the solid material was dispersed in 2 mL of the above buffer and washed until the filtrate was clear. With the purpose to monitor the interaction of the drug with adsorbent, UV–vis spectroscopy was achieved to measure concentration of ACV in the solution before and after the adsorption process. Thus, the content of free acyclovir in the supernatant was determined by UV–Vis at 253 nm. The amount of loaded drug was calculated by Eq. (1). Loading content ð%Þ ¼ ½M0 −Mt =MN   100

ð1Þ

where, M0 and Mt are concentration of acyclovir in the primary and filtered solutions, respectively. MN is the amount of magnetite nanoparticles used for the loading process. 2.4. Computational methods Fe3O4 nanoparticles are utilized to build a spherical structure by using the Accelrys Materials Studio software package. ACV molecule and Fe3O4 nanoparticle complexes were fully optimized by the DFT method with B3LYP-D [29] at LANL2DZ basis set [30] implemented in G09 suite of the program [31]. We used a popular and general approach to configure the dispersion interactions, which is a semi-empirical dispersion correction (D) in combination with the B3LYP functional. Calculations were performed in an aqueous solution, designed by the polarizable continuum model (PCM) [32]. The adsorption characteristics of ACV molecule on the surface of Fe3O4, were obtained by identifying the adsorption energies (ΔEads) from Eq. (2). ΔEads ¼ Ecomplex −ðEFe3O4 þ EACV Þ þ EBSSE

ð2Þ

3

where Ecomplex, EACV, and EFe3O4 are electronic plus zero point energies of the Fe3O4 nanoparticle with the adsorbed drug molecule, free ACV, and the pristine Fe3O4, respectively. EBSSE is the basis set superposition error (BSSE) correction [33]. Solvation energy (ΔEsolv.) was obtained by Eq. (3). ΔEsolv ¼ Esol: −Egas

ð3Þ

where Egas and Esol. represent the total energies in the gas and solution phases, respectively. The quantum molecular descriptors including chemical potential (μ), global hardness (η) (R), electrophilicity index (ω) and gap energy (Eg) were calculated as follows: Eg ¼ ELUMO −EHOMO

ð4Þ

μ ¼ ðEHOMO þ ELUMO Þ=2

ð5Þ

η ¼ ðELUMO −EHOMO Þ=2

ð6Þ

ω ¼ μ 2 =2η

ð7Þ

where EHOMO is the highest energy level of the occupied molecular orbital and ELUMO is the lowest energy level of the unoccupied molecular orbital, respectively. The nature of intermolecular interactions was investigated by the AIM theory of Bader by means of AIM2000 software [34]. The calculated electron density, ρ, and its second derivative, ∇2ρ, were used to describe the nature of intermolecular interactions. The NBO analysis was carried out to obtain a better understanding of the intermolecular interactions. The density of states (DOS) and molecular electrostatic potential (MEP) were also employed. To carry out the DOS calculations, GaussSum program was used [35]. The fractional number of the transferred electrons (ΔN) between the drug molecule and the Fe3O4 nanoparticles was calculated in order to identify the direction of spontaneous electron-flow in the adsorption process as follows: ΔN ¼ ðμ B −μ A Þ=ðηA þ ηB Þ

ð8Þ

where μA, μB and ηA, ηB are the chemical potential and chemical hardness of the acceptor (A) and donor (B) systems, respectively. 3. Results and discussion Targeting of drug molecules to receptors and transporters by a sitespecific carrier mediator is a clinically significant approach. Application of nanosystems in pharmacy has been surged due to various advantages and may provide targeting of the drug towards a specific place. Some successful drugs in cell culture suffer from different disadvantages and must be used in high concentrations resulting in more intense side effects. Moreover, many drugs require specific instructions to overcome associated problems such as potentially side effects, drug instability, poor solubility, etc. Poor bioavailability often results in higher patient costs, inefficient treatment, and increased risks of toxicity or even death. 3.1. Characterization of magnetic nanoparticles before and after delivery of ACV Size and morphology of Fe3O4@SiO2-NH2 before and after loading of ACV were studied by means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Fig. 1 shows that the prepared magnetic nanoparticles were semispherical in shape with good dispersibility. In addition, TEM shows some aggregation of magnetite nanoparticles after loading of ACV molecules. Fig. 2 describes the Xray diffraction patterns of Fe3O4@SiO2-NH2 nanoparticles before and after loading of ACV. The pattern for magnetite nanoparticles with the characteristic distinct peaks at 30.4 (220), 36.2 (311), 43.4 (400), 57.3 (440), and 63.1 (533) clearly matched with the JCPDS No. 19-0629

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Fig. 1. TEM (a–b) and SEM (c–d) micrographs of Fe3O4@SiO2-NH2 nanoparticles before (a and c) and after (b and d) loading of ACV.

[36,37]. Although, magnetite was observed as the dominant phase, however, some maghemite may be formed due to the sensitive nature of the former to air during the synthesis [36]. The observation of broad and intense peaks confirmed formation of crystalline nanoparticles. It

should be mentioned that incorporation of APTES and ACV did not alter the crystal structure of Fe3O4 nanoparticles. The magnetic properties of drug-loaded magnetite are very important in the environmental and medical applications. The magnetization of acyclovir loaded magnetite was compared to bare magnetite nanoparticles using vibrating sample magnetometry (VSM) at 25 °C (Fig. 3). The saturation magnetization of bare and drug-laded magnetite was 81 and 73 emu/g, respectively. These results confirmed formation of well-defined crystalline structures for magnetite nanoparticles. This study confirmed that ACV decreased the saturation magnetization.

Fig. 2. XRD patterns of Fe3O4@SiO2-NH2 nanoparticles before (a) and after (b) loading of ACV.

Fig. 3. VSM magnetization curves of Fe3O4@SiO2-NH2 nanoparticles before (a) and after (b) loading of ACV.

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However, high saturation magnetization of the drug-loaded nanoparticles guarantee their practical applications in medical sciences.

3.2. Loading studies and zeta potential analysis The efficacy of an ideal drug delivery system can be evaluated through the ability to load the target drug molecule. Drug targeting can ensure high therapeutic efficacy and reduces side effects; thus, preventing side effects because of over loading to the living organism. Drug loading profile can be divided into two distinct phases including an initial burst phase with ~40 up take after 3 h and a plateau phase with ~80% loading of acyclovir after 5 h. Considering the main influence of hydrogen bonding in the loading processes, a study was out lined to investigate the effects of pH, loading time, and temperature. As shown in Fig. 4, the best loading was achieved at pH 9 at 39 °C after 5 h. The loading efficacy was assigned to the increments of the hydrogenic interactions under the reaction conditions. The zeta potential can be commonly used to characterize the surface charge properties of nanoparticles and reflects their electrical potentials, which affects by the composition and surrounding medium of the nanoparticles. Particles with a zeta potential above (±) 30 mV are shown to be stable in suspension and the surface charge prevents aggregation of the particles. The zeta potential values of acyclovir loaded magnetite ranged from 31 to 41 mV and the values alleviated with the increase of acyclovir concentration (Fig. 5a). To illuminate the size distribution of the nanoparticles, particle size histograms were attained for Fe3O4 and Fe3O4@SiO2-NH2 by dynamic light scattering (DLS) analysis (Figs. 5b-c). This main size distribution was centered at 15–20 and 32–40 nm for the mentioned magnetic materials, respectively.

5

3.3. Theoretical studies The optimized structures of Fe3O4 and ACV are represented in Fig. 6. As shown in this figure, Fe8O6 nanoparticle may consist of four hexagonal rings with 18 Fe\\O bonds. Therefore, two different Fe\\O bonds can be recognized, one is shared with two hexagons (1.79 Å) and the other between three hexagons (1.87 Å). The performed calculations revealed the Eg value of 0.8 eV for pristine Fe3O4. The electrostatic potential (ESP) maps over Fe3O4 are also shown in Fig. 6. In these maps, the red (negative areas) and blue (positive areas) colors show the relative accumulation and depletion of charge densities, respectively. The ESP maps revealed that Fe atoms are the most favorable sites to contact with nucleophilic agents [38]. As displayed in Fig. 6, large and negative regions (in red) on ESP surface of ACV were positioned around oxygen and nitrogen atoms due to their strong electronegativity. Accordingly, most positive regions (in blue) were located around hydrogen atoms. The top-views of frontier molecular orbital (FMO) analysis of the pristine nanoparticle are also displayed in Fig. 6. This figure clearly displayed that LUMOs of the studied systems were predominantly distributed on Fe atoms (shared by two hexagons). Therefore, in line with the ESP analysis, FMO analyses also detected Fe atoms as favorable sites for the attraction of nucleophilic species. 3.3.1. Adsorption of ACV on pristine Fe3O4 The optimized geometries of Fe3O4 and ACV are shown in Fig. 7. These geometries and ESP plot of the drug molecule clearly illustrated a relatively strong interaction of Fe3O4 with oxygen, nitrogen, and hydrogen atoms of acyclovir. In order to find the stable adsorption structures on the external surface of nanoparticle, various initial structures were selected which were attributed to locate the drug molecule

Fig. 4. Effect of pH, contact time, and temperature on the loading of acyclovir onto magnetite nanoparticles.

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Fig. 5. Zeta potential of acyclovir loaded Fe3O4@SiO2-NH2 nanoparticles (a). Particle size histograms of Fe3O4 (b) and Fe3O4@SiO2-NH2 (c) by DLS analysis.

above the nanoparticle. Finally, the four local minima were attained, as shown in Fig. 7. The obtained results revealed three types of intermolecular interactions in the introduced configurations, as Fe atom of nanoparticle with O atom of ACV (Fe⋯O), Fe atom of nanoparticle with N atom of ACV (Fe⋯N) and hydrogen bonds (N\\H⋯O\\Fe and O\\H⋯O\\Fe). The detailed analysis of hydrogen bonds will be performed in the next section by AIM calculations. As seen in Fig. 7, the most significant interaction of acyclovir and Fe3O4 nanoparticle occurred with Fe+3. In addition, hydrogen bonds further helped stability of the presented complexes. Some intermolecular interactions were monitored between ACV and the surface of Fe3O4, as shown in complex (A), involving a charge transfer interaction originated from Fe+3 1 of the nanoparticle with nitrogen atom (N3) of the drug. In addition, one HB interactions was detected in this complex O1… H11-N5. In complex (B), it was found nitrogen of the 5-membered ring of ACV was the most likely atom, interacting with Fe3O4 and no hydrogen bond interaction was suggested for complex (B). In complex (C), hydrogen bond interactions were detected between H10 atom of ACV and O2 atom of Fe3O4. Finally, the interactions would happen between Fe1 and O9 of the drug in complex (D) together with a hydrogen bond interaction between O4 of the nanoparticle with H9 of the drug molecule. The intermolecular distances and adsorption energies were calculated at B3LYP-D functional for adsorption of acyclovir on the surface of Fe3O4 in a water phase (Table 1). It can be seen that the pristine Fe3O4 nanoparticle interacted with the drug molecule for all ACV/Fe3O4 complexes. The high interaction energies led to a strong adsorption of ACV on the surface of nanoparticle. Configurations A and D show stronger interactions than the two other systems, because these configurations have both hydrogen bonds and Fe-N(O) interactions at the same time. This finding can be interpreted by a shorter interaction distance between the adsorbed H atom of ACV and O atom of the nanoparticle in the corresponding system. The possible modes for intermolecular interaction of ACV with Fe3O4 nanoparticle obeyed the stability order of A N D N B N C. The solvation energies (ΔEsolv) of Fe3O4, ACV and ACV/Fe3O4 (A-D) were calculated using Eq. (3) (Table 1). Because of the negative values of solvation energies, this process would be spontaneous [39].

In addition, thermochemistry of the adsorption process was attained by the frequency calculations at 298 K and 1.0 atm in an aqueous solution at the PCM/B3LYP-D/Lanl2dz level of theory with considering BSSE (Table 1). The negative values of enthalpy and Gibbs free energies obtained from DFT calculations indicated that ACV adsorption on the surface of Fe3O4 was exothermic and spontaneous. According to the spontaneity of the process and from negative values of ΔH and ΔG, it can be envisaged that adsorption of systems (A) and (D) had been more favorable and drug was adsorbed more spontaneously onto the carrier surface than that on the tested complexes [40]. Furthermore systems (A) and (D) with the maximum adsorption energy had the most negative values of the thermochemical parameters compared to two other systems and the lowest ΔG values were obtained for these configurations with the highest stability. On the other hand, it was found that formation of ACV/Fe3O4 complexes was favorable from enthalpy points of view. The obtained results confirmed that there is an evident correlation between ΔH and Eads values [41,42]. To get a deeper insight on the effects of ACV adsorption on electronic properties of the nanoparticles, these factors were also studied, as shown in Table 1. The energy of frontier molecular orbitals, energy of the lowest unoccupied molecular orbital (ELUMO), energy of the highest occupied molecular orbital (EHOMO), and their energy gaps (Eg) as well as hardness (η), and electrophilicity index (ω) were calculated for the studied configurations. Results in Table 1 show that the energy gap for all the studied systems was increased with respect to the pristine nanoparticle. Higher Eg values of the nanoparticle after drug adsorption proved relative stability compared to the pristine Fe3O4 [43]. In the four systems of A, B, C and D, the Eg values are larger than that of Fe3O4. Generally, any changes in the Eg value upon adsorption can modify emission of the adsorbed system and help to track the drug pathway in the body [44,45]. The DOS of complexes are shown in Fig. 8. The uptake of AVC implicitly changed the energy of HOMO and LUMO from −3.6 and −2.8 eV in the bare Fe3O4 to −3.75 and −2.02 eV in complex A, respectively (Table 1). As seen in Fig. 8, upon adsorption the HOMO level was more located at the proximity of interaction site, whereas the LUMO level was more expanded at other regions of the nanoparticle [43].

X. Xie et al. / Journal of Molecular Liquids 309 (2020) 113024

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Fig. 6. The optimized structures, ESP maps on electron density iso-surfaces, HOMO, and LUMO profiles of Fe3O4 nanoparticle and acyclovir at the B3LYP-D/Lanl2dz method in a water phase.

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The direction of electron flow can be estimated by the electronegativity and electronic chemical potential. When, ACV molecule approaches Fe3O4, electrons start to transfer from the higher chemical potential to the lower potential, until the same electronic chemical potential [46]. The potential values in Table 1 confirmed the electron flow from a definite occupied orbital in ACV to a specified empty orbital of Fe3O4. These results are well in accord with the obtained electrophilicity index values for the studied fragments of the selected complexes in Table 1. These data showed that Fe3O4 was more electrophilic than ACV and behaved as a nucleophile. When ACV interacted with Fe3O4 nanoparticle, the chemical hardness (η) for all studied configurations were enhanced, which means an increase in the chemical stability of the studied complexes. Thus, the chemical activities of complexes were alleviated. Presumable, Fe3O4 nanoparticles attracted ACV molecule due to their positive charge accumulated on Fe+3 ions and the negative charge aggregated on the

oxygen and nitrogen atoms of the considered segments in the studied configurations. Undoubtedly, a positive electron transfer parameter, ΔN = 0.120, confirmed that the drug molecule behaved as a charge donor and Fe3O4 as a charge acceptor. Molecular electrostatic potential (MEP) plots for all designed adsorption systems are displayed in Fig. 7. The MEP is a representation that signifies a region in the molecule as nucleophilic and/or electrophilic. This point of view is significant in various biological processes and hydrogen bond interactions [47]. The negative and positive electrostatic potential regions in MEP plots are represented by the red and blue colors, respectively. Therefore, the color intensity had been altered after adsorption of the drug molecule for each configuration, and well collaborated with the results of NBO charge transfer calculations. This finding obviously indicated that the negative and positive charges of the nanoparticle were altered upon complexation and more pronounced changes were detected in the area of interaction.

Fig. 7. Optimized structures of ACV/Fe3O4 complexes and MEP of the investigated complexes at different configurations at the B3LYP-D/Lanl2dz method.

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Fig. 7 (continued).

3.3.2. AIM analysis The electron density (ρBCP) and its Laplacian (∇2ρBCP), the total electron energy density (HBCP) at a bond critical point (BCP) and its components involving the local kinetic energy density (GBCP), local potential energy density (VBCP), as well as the hydrogen bonding energy (EHB) were calculated according to the Espinosa method and the relevant results are displayed in Table 2 [48]. From AIM analysis, different contacts were suggested for ACV/Fe3O4 complexes, as introduced in Table 1 including Fe⋯O\\H, Fe⋯N and O⋯H\\X, X_N, O. As Table 2 shows, all examined ACV/Fe3O4 complexes have low ρBCP (ranging from 0.04–0.06 in a.u) and ∇2ρ BCP values (ranging from −0.03 to −0.08 in a.u). Negative ∇2ρBCP values mean a local charge concentration in the critical point. The total electronic energy density, HBCP, at a BCP is a suitable index to investigate weak non-bonded interactions [49], and its sign denotes

whether the interaction is electrostatic (HBCP N 0) or covalent dominant (HBCp b 0). Thus, the negative values of HBCP and ∇2ρBCP for the intermolecular interactions proposed that the monitored interactions had some degrees of covalent character in nature. The calculated ρBCP (electron density) and its second derivative, ∇2ρBCP were applied to describe the nature of intermolecular hydrogen bonds. The hydrogen bond energy (EHB) was evaluated by the Espinosa method [48], which showed that the HB energies can be estimated from the properties of bond critical points. A simple relationship between HB energy and potential energy density of VBCP at BCPs due to the intermolecular hydrogen bond contacts, is assigned as EHB = 1/2 VBCP. Tables 1 and 2 proved that an intermolecular hydrogen bond with the shortest distance can lead to the largest ρBCP at the inter-atomic BCP. Table 2 revealed a significant accumulation of electron density in the region of

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Table 1 The calculated intermolecular distances (Å), adsorption energy (Eads, kcal/mol), thermodynamic parameters, salvation energies (ΔEsolv, kcal/mol), HOMO and LUMO energies, band gap energy (Eg), and the reactivity parameters (eV) for ACV/Fe3O4 configurations at the B3LYP-D/LANL2DZ level of theory in a water phase. System

Fe3O4

ACV

A

B

C

D

Fe…OACV

–

–

–

–

–

Fe…NACV

–

–

OFe3O4…HNACV

–

–

OFe3O4…HOACV

–

–

Fe1…N3 r = 2.18 O1… H11-N5 r = 1.69 –

Fe1…N1 – r = 2.09 – O2… H10-N5 r = 1.74 – –

Fe1…O9 r = 2.05 –

Eads(PCM/B3LYP-D) (eV) ΔH (Kcal/mol) ΔG (Kcal/mol) ΔEsolv (Kcal/mol) EHOMO ELUMO Eg μ η ω

–

–

−1.64

−1.06

−0.62

O4… H9-O9 r = 2.14 −1.61

– – – −3.60 −2.80 0.80 −3.19 0.39 12.92

– – – −6.18 −0.96 5.22 −3.57 2.61 2.44

−37.82 −21.24 −43.90 −3.75 −2.02 1.73 −2.88 0.86 4.81

−24.36 −10.29 −47.69 −3.56 −1.87 1.69 −2.71 0.84 4.36

−14.32 −1.48 −40.78 −3.75 −2.02 1.73 −2.88 0.86 4.81

−37.03 −21.54 −52.71 −3.75 −2.02 1.73 −2.88 0.86 4.81

–

The thermodynamic parameters (ΔH and ΔG, kcal/mol) are calculated at 298 K in 1 atm. The reactivity parameters refer to chemical potential (μ), chemical hardness (η), and electrophilicity index (ω).

O1…H11-N5 intermolecular interaction at configuration (A). The maximum electron density of FeO1…H11-N5 interaction at configuration (A) was associated with a minimum hydrogen bond length (see Tables 1 and 2). In fact, these results are in agreement with the most negative hydrogen bond energy for this intermolecular interaction [50]. 3.3.3. Adsorption of ACV on Fe3O4/SiO2 Among different modifiers, mesoporous silica has been widely utilized in the modification of Fe3O4 nanoparticles because of its high surface area, large pore volume, tunable pore size, low cytotoxicity, and biodegradability. Therefore, we studied adsorption of acyclovir onto Fe3O4/SiO2 in PCM/B3LYP-D/Lanl2DZ. (Fig. 9) According to the obtained results from Table 3, the calculated adsorption energy of ACV on the surface of Fe3O4/SiO2 was −7.5 eV in an aqueous solution. As shown in Table 3, the HOMO level was significantly shifted to lower energies in Fe3O4/SiO2 after the modification process, and Eg was considerably widened. The molecules having small Eg and excitation energy are introduced as soft molecules and are polarizable. Thus, soft molecules can bring electron density changes more easily than the hard ones with high Eg values, leading to a higher chemical reactivity. According to the calculated η, the stability of Fe3O4/SiO2 was more than Fe3O4. Due to the increased stability of the modified nanoparticles, it can be envisaged that the release process can be slower for this nanoparticle. 3.3.4. Adsorption of ACV on M (Mg, Zn) doped Fe3O4 In this study, Zn and Mg were inserted into Fe3O4 nanoparticle to study effect of doping on the drug adsorption. The optimized structures and their DOS diagrams are shown in Fig. 10. To do doping, one Fe atom of Fe3O4 was replaced by Zn and Mg atoms. The adsorption and sensitivity of (Mg, Zn) doped Fe3O4 relative to ACV drug was explored. According to the obtained results in Table 3, the calculated adsorption energy of ACV on the surface of Mg and Zn doped Fe3O4 were −8.62 and −8.48 eV, respectively. Moreover, the ESP plots of (Mg, Zn) doped Fe3O4 in Fig. 10 revealed that active sites in these nanocages had been localized on Mg and Zn atoms, respectively. Fig. 10 depicts the most stable structures of M-doped (Mg, Zn) Fe3O4-drug complexes in the solution phase. Among all of considered structures, the configuration which ACV molecule approaches to Mg or Zn atoms of the nanoparticle

Fig. 8. DOS, HOMO, and LUMO profiles for complexes A, B, C, and D.

X. Xie et al. / Journal of Molecular Liquids 309 (2020) 113024 Table 2 The topological parameters HBCP, GBCP, VBCP (a.u.) and EHB (kcal/mol) for the intermolecular interactions between ACV and Fe3O4 in the designated complexes. Complex

Atoms

ρ

Δ2ρ

G

V

H

E(HB)

A A B C D D

Fe1-N3ACV O1-H11ACV Fe1-N1ACV O2-H10ACV Fe1-O9ACV O4-H9ACV

0.069 0.058 0.064 0.043 0.056 0.053

−0.048 −0.070 −0.087 −0.036 −0.103 −0.0771

0.025 0.010 0.015 0.009 0.006 0.016

0.062 −0.038 −0.052 −0.028 −0.039 −0.030

−0.037 −0.028 −0.037 −0.018 −0.032 −0.027

– −17.42 −0.16 – −8.62 −11.86

ρ is the charge density in the bond critical point and ∇2ρ is the corresponding Laplacian. HBCP is the density of total energy for electrons. GBCP and VBCP are kinetic and potential electron energy densities, respectively. E(HB) is the hydrogen bond energy.

through its O atom had the strongest adsorption. This result was clearly in accord with ESP plots of the doped nanoparticles. According to the calculated η, the stability of Zn, Mg doped Fe3O4 was more than that of Fe3O4. Moreover, DOS plot (Fig. 10) confirmed that Eg was inclined to 1.94 and 2.34 eV for Mg and Zn doped Fe3O4,

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respectively. In addition, a new local energy band was appeared on top of the valence band. Doping with Zn led to an electronic hole, hence, the conductivity of Fe3O4 was enhanced. Therefore, Zn impurities can introduce local states inside the Eg and improve reactivity of Fe3O4 towards adsorption process. 4. Summary and conclusions Adsorption and delivery of acyclovir on pristine and modified magnetite nanoparticles are investigated. The as-synthesized magnetite nanoparticles before and after loading of ACV are characterized by means of common spectroscopic techniques such as SEM, TEM, VSM, DLS, and zetametry studies. VSM and zetametry studies show that ACV decreases the saturation magnetization and zeta potential of magnetite nanoparticles. Then, adsorption of ACV in phosphate buffered saline is examined and effects of some variables including pH, loading time and temperature are briefly investigated. The experimental results reveal that the best loading (~80%) can be achieved at pH 9 at 39 °C after 5 h. In continuation, a DFT study is fully investigated to provide

Fig. 9. The ESP map on electron density iso-surfaces of Fe3O4/SiO2 (a); optimized structures of ACV Fe3O4/SiO2 complex at B3LYP-D (b); DOS diagrams of Fe3O4/SiO2 before and after adsorption (c). Distances are in Å.

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X. Xie et al. / Journal of Molecular Liquids 309 (2020) 113024

Table 3 Calculated E ads, E HOMO, E LUMO, and Eg (all in eV) and reactivity parameters (in eV) for pristine Fe3O4, Fe3O4/SiO2, and (Mg, Zn)-doped Fe3O4 at B3LYP-D/LANL2DZ. EHOMO ELUMO

System

Eads

ACV Fe3O4 ACV/Fe3O4 Fe3O4-SiO2 ACV/Fe3O4-SiO2 Mg doped Fe3O4 ACV/Mg doped Fe3O4 Zn doped Fe3O4 ACV/Zn doped Fe3O4

−6.18 – −3.6 −1.64 3.75 – −4.40 −7.61 −4.55 – −3.52

−0.96 −2.8 −2.02 −2.50 −2.53 −1.58

Eg 5.22 0.8 1.73 1.89 2.02 1.94

ΔEg% – 116.25 6.43 –

−8.62 −3.69 −1.59 2.11 8.76

μ

ŋ

−3.57 −3.195 −2.885 −3.45 −3.54 −2.55

2.61 2.44 0.395 12.92 0.865 4.81 0.95 6.26 1.01 6.20 0.97 3.35

−2.635 1.055

– −3.81 −1.47 2.34 – −2.64 −8.48 −3.7 −2.02 1.7 −27.35 −2.86

1.17 0.84

ω

3.29 2.97 4.86

ΔEg% = [(Eg2 − Eg1) ∕ Eg1] × 100, where Eg1 and Eg2 are the initial value of the Eg and the value after ACV adsorption, respectively.

important theoretical parameters related to the adsorption process. The performed computations on pristine and doped Fe3O4 nanoparticles proved strong interactions between nitrogen and oxygen atoms of acyclovir with Fe+3 ions of magnetic nanoparticles. Moreover, additional hydrogen bonds between active sites of the adsorbed drug molecule and Fe3O4 fragments lead to a significant adsorption and stabilization of the obtained configurations. The nature of intermolecular interactions, electron densities, and Laplacians at the bond critical points is also investigated. Furthermore, natural bond orbital analysis indicates that acyclovir molecule has been adsorbed on Fe3O4 nanoparticle surface with a charge transfer from acyclovir to the nanoparticle. Findings show that the modified and doped Fe3O4 nanoparticles can absorb drug molecules more strongly compared to the pristine counterpart and generate stable configurations. Interestingly, doping with Zn atom results in an electronic hole, hence, the conductivity of the Fe3O4 may be enhanced. Therefore, Zn impurities can introduce local states inside

Fig. 10. The ESP maps on electron density iso-surfaces of Zn/Mg doped Fe3O4 (a); optimized structures of the ACV/Zn, Mg doped Fe3O4 complexes (b); DOS diagrams of Zn, Mg doped Fe3O4 before and after adsorption (c). Distances are in Å.

X. Xie et al. / Journal of Molecular Liquids 309 (2020) 113024

the Eg and improve reactivity of magnetic nanoparticles towards adsorption process. As a result, the examined metal-doped magnetic nanoparticles in this study can be applied as promising nanobiosensors for detection and delivery of ACV in medicine. Eventually, it should be mentioned that the obtained theoretical results may not be correlated well with the experimental findings because of some limitations such as uncertainty of theoretical models and calculations and many uncontrolled affecting parameters in the practical experiments. CRediT authorship contribution statement Xianting Xie:Methodology.Lu Zhang:Conceptualization.Wenjuan Zhang:Software.Reza Tayebee:Supervision.Atefe Hoseininasr:Writing - original draft.Hamid H. Vatanpour:Visualization.Zeinab Behjati:Investigation.Suying Li:Supervision, Software.Marjan Nasrabadi:Validation.Liuyi Liu:Writing - review & editing. Declaration of competing interest 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. References [1] A.S. Hoseininasr, R. Tayebee, Synthesis and characterization of superparamagnetic nanohybrid Fe3O4/NH2-Ag as an effective carrier for the delivery of acyclovir, Appl. Organomet. Chem. 32 (12) (2018), e4565. [2] A.S. Hoseininasr, H. Akbarzadeh, R. Tayebee, Adsorption mechanism of different acyclovir concentrations on 1–2 nm sized magnetite nanoparticles: a molecular dynamics study, J. Mol. Liq. 254 (2018) 64–69. [3] A. Elsagh, H. Jalilian, Quantum study of solvent effect with POPC phospholipid bilayers in a cell membrane and its impact on active and targeted drug delivery, Eurasian Chem. Commun. 2 (4) (2020) 440–455. [4] H.C. Huang, S. Barua, G. Sharma, S.K. Dey, K. Rege, Inorganic nanoparticles for cancer imaging and therapy, J. Control. Release 155 (3) (2011) 344–357. [5] A.H. Magham, A. Morsali, Z. Eshaghi, S.A. Beyramabadi, H. Chegini, Density functional theoretical study on the mechanism of adsorption of 2-chlorophenol from water using γ-Fe2O3 nanoparticles, Prog. React. Kinet. Mech. 40 (2015) 119. [6] E. Masoudipour, S. Kashanian, N. Maleki, A targeted drug delivery system based on dopamine functionalized nano graphene oxide, Chem. Phys. Lett. 668 (2017) 56–63. [7] M. Auffan, J. Rose, J.Y. Bottero, G.V. Lowry, J.P. Jolivet, M.R. Wiesner, Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective, Nat. Nanotechnol. 4 (2009) 634. [8] Z.P. Xu, Q.H. Zeng, G.Q. Lu, A.B. Yu, Inorganic nanoparticles as carriers for efficient cellular delivery, Chem. Eng. Sci. 61 (2006) 1027–1040. [9] P. Ghosh, G. Han, M. De, C.K. Kim, V.M. Rotello, Gold nanoparticles in delivery applications, Adv. Drug Deliv. Rev. 60 (2008) 1307–1315. [10] L. Wei, J. Lu, H. Xu, A. Patel, Z.S. Chen, G. Chen, Silver nanoparticles: synthesis, properties, and therapeutic applications, Drug Discov. Today 20 (2015) 595–601. [11] Y. Zhihong, Y. Ye, A. Pejhan, A.H. Nasr, N. Nourbakhsh, R. Tayebee, A theoretical study on the pure and doped ZnO nanoclusters as effective nanobiosensors for 5fluorouracil anticancer drug adsorption, Appl. Organomet. Chem. 34 (4) (2020), e5534. [12] S. Kwon, R.K. Singh, R.A. Perez, E.A. Abou Neel, H.W. Kim, W. Chrzanowski, Silicabased mesoporous nanoparticles for controlled drug delivery, J. Tissue Eng. 4 (2013) 1. [13] C. Vauthier, G. Ponchel, Polymer Nanoparticles for Nanomedicines, Springer, 2017. [14] B.S. Pattni, V.V. Chupin, V.P. Torchilin, New developments in liposomal drug delivery, Chem. Rev. 115 (2015), 10938. [15] M. Shamsi, A. Sedaghatkish, M. Dejam, M. Saghafian, M. Mohammadi, A. SanatiNezhad, Magnetically assisted intraperitoneal drug delivery for cancer chemotherapy, Drug Delivery 25 (1) (2018) 846–861. [16] M.K. Manshadi, M. Saadat, M. Mohammadi, M. Shamsi, M. Dejam, R. Kamali, A. Sanati-Nezhad, Delivery of magnetic micro/nanoparticles and magnetic-based drug/cargo into arterial flow for targeted therapy, Drug delivery 25 (1) (2018) 1963–1973. [17] A. Akbarzadeh, M. Samiei, S. Davaran, Magnetic nanoparticles: preparation, physical properties, and applications in biomedicine, Nanoscale Res. Lett. 7 (2012) 144. [18] T. Higashi, Y. Nagaoka, H. Minegishi, A. Echigo, R. Usami, T. Maekawa, T. Hanajiri, Regulation of PCR efficiency with magnetic nanoparticles in a rotating magnetic field, Chem. Phys. Lett. 506 (2011) 239. [19] J.L. Viota, A. Carazo, J.A. Munoz-Gamez, K. Rudzka, R. Gómez-Sotomayor, A. RuizExtremera, J. Salmerón, A.V. Delgado, Functionalized magnetic nanoparticles as vehicles for the delivery of the antitumor drug gemcitabine to tumor cells. Physicochemical in vitro evaluation, Mater. Sci. Eng. c 33 (2013) 1183.

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