Size-dependent adsorption performance of ZnO nanoclusters for drug delivery applications.

We have investigated the size-dependent adsorption performance of ZnO nanoclusters (NCs) as drug delivery carriers for the first time. Our results show that the adsorption energy of the favipiravir drug on the ZnO NCs is predicted in the range of - 26.69 and - 34.27 kcal/mol. The adsorption energy (- 34.27 kcal/mol) between (ZnO)18 NC and the favipiravir is energetically desirable and more favorable than the other interactions. The size of ZnO NCs and the position of the favipiravir on the ZnO NCs cause a decrease in the energy gap, which makes the charge-transfer process easier. The bonds between O-Zn, N-Zn, and F-Zn atoms exhibit dual covalent and ionic natures. The non-covalent interaction analysis shows that the strongest H-bonds are observed near NH2 within the favipiravir molecule. Finally, the acquired results show that the interaction of ZnO NCs with the favipiravir anticancer drug can have the potential as drug delivery carriers. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02063-2.

Introduction

The bulk zinc oxide (ZnO) and its different forms as nanostructure (nanoparticles, nanowires, nanotubes, etc.) have attracted great scrutiny in many areas including solar cells, light-emitting/detecting diodes, and gas sensors [1-9]. ZnO nanoparticles (NPs)/quantum dots (QDs), more specifically, have been significant attention because of their desirable properties such as strong adsorption capability and easily tunable surface used in important areas such as photosensors [10], electronics [11], and biomedical applications [12]. The use of ZnO NPs in biomedicine enables the treatment of different diseases such as bacterial, viral, and carcinogenic due to their remarkable properties such as biocompatibilities, their low cost, biosafety, low toxicity, and heat resistivity in comparison to other metal oxide NPs, which make them suitable for drug delivery systems [13, 14]. Also, ZnO NPs can display inherent anticancer and antimicrobial activities which make them more excellent than other commonly used drug carriers, such as lipid and polymeric NPs [15]. Several reports address the interaction and adsorption behavior of ZnO NPs and nanoclusters (NCs) with different systems [16-21]. The interactions of Zn12O12 NC with 6-thioguanine anticancer drug show that Zn12O12 NC can have the potential as drug delivery carriers [22].

Many treatments including oral and injection medicines can adversely affect healthy cells and cause side and toxic effects [23]. In some cases, furthermore, it can be possible to use higher doses of a drug to get rid of the effect of the disease [24]. Recent studies show that nanotechnology plays a significant role as drug delivery carrier [25] and has always made it easy to control drug release characteristics of time course and/or location in the body [26, 27]. Most importantly, drug delivery systems can deliver a rather high amount of drug molecules and reduce possible severe side effects without producing a toxic effect [28].

Favipiravir has shown efficacy against many RNA viruses [29], but the reported side effects [30] arising during favipiravir treatment have an important place for patients. In this context, it is significant to reduce adverse side and toxic effects of treatment to healthy cells, so ZnO NCs are designed as drug delivery systems for favipiravir treatment. The literature survey showed that ZnO NC has a potential in drug-carrying systems [31].

In this context, the main objective of this study was to clarify the potential mechanism of possible interaction between ZnO NCs with different sizes and favipiravir anticancer drug and to figure out the potential use of ZnO NCs as a drug carrier. Herein, the electronic and energetic properties such as the adsorption energy, binding energy, density of states, and UV–vis spectra were performed using density functional theory (DFT) and time-dependent DFT.

Computational details

The DFT simulations were implemented to understand the interaction mechanisms of the favipiravir drug molecule with ZnO NCs (with different sizes) along with B3LYP functional with the 6-31G(d) basis set [32] and Grimme’s three-parameter which is an empirical dispersion correction [33]. Here, the main reason to use the B3LYP is that it agrees perfectly with the experimental values for the ZnO NCs [34, 35], so the B3LYP was used to study electronic structure of the studied system in this study. To get the possible interactions of the favipiravir drug molecule with ZnO NCs, the favipiravir and ZnO NCs, firstly, were optimized, and later, the structures with the lowest total energy were considered. All calculations were carried out using Gaussian 09 [36]. To calculate the adsorption energy of favipiravir drug and ZnO NCs interactions, the following expression is used:where is the total energy ( of the interacting systems. and are the of isolated NCs and favipiravir, respectively. is known as the “basis set superposition error,” which is calculated by the counterpoise method to obtain highly accurate energy prediction [37].

On the other hand, the vertical ionization potential and vertical electron affinity are performed using [] and [ where the is the energy difference between the ground state of the cation and the of the neutral at the geometry of the neutral. is the energy difference between the of the neutral and the of the anion at the geometry of the neutral. Moreover, the Wiberg bond index (WBI), Fuzzy bond orders (FBO), and Mayer bond order (MBO) are performed using the Multiwfn program [38]. The TD-DFT calculations based on CAM-B3LYP functional [39] with 6-31G(d) basis set are applied for guessing UV–vis spectra.

Results and discussions

The structures, electronic states, and point group symmetries of pure (ZnO)12, (ZnO)15, (ZnO)18, (ZnO)20, (ZnO)22, and (ZnO)24 NCs are optimized and represented in Fig. 1. The (ZnO)12 and (ZnO)18 NCs are found to be the potential energy surface (PES) of the 1AG state, and the (ZnO)15 NC is the ground 1A′ singlet PES. The (ZnO)20, (ZnO)22, and (ZnO)24 NCs are found to be the PES of the 1A state. The point group symmetries of (ZnO)12, (ZnO)15, (ZnO)18, (ZnO)20, (ZnO)22, and (ZnO)24 NCs are Th, C3h, S6, C4h, C3, and S8, respectively. From the harmonic vibrational frequencies, the studied ZnO NC models corresponded to energetic minimum which means the transition state at a saddle point on the PES.

Fig. 1

(Color online) The optimized structures, electronic states, and point group symmetries of pure a (ZnO)12, b (ZnO)15, c (ZnO)18, d (ZnO)20, e (ZnO)22, and f (ZnO)24 NCs (Gray: Zn, Red: O)

All possible interactions of the (ZnO)12, (ZnO)15, (ZnO)18, (ZnO)20, (ZnO)22, and (ZnO)24 NCs with favipiravir drug were carried out, and among them, relaxed structures with the lowest energy are demonstrated in Fig. 2. The binding energy per atom of pure ZnO NCs and adsorption energy of theoretically calculated geometries of the favipiravir adsorbed ZnO NCs are depicted in Fig. 3. The of the ZnO NCs shifts from 5.04 to 5.16 eV, depending on the increase in the size. These results indicate that an increase in the size of the NCs also enhances the stability. The of the ZnO NCs is predicted in the range of − 26.69 and − 34.27 kcal/mol where N–Zn and F–Zn atoms interact between the N and F atoms of favipiravir drug and Zn atoms of the ZnO NCs. The negative means that the adsorption of the favipiravir drug on ZnO NCs is exothermic and energetically favorable. The size of ZnO NC has a significant effect on the between the favipiravir and ZnO NCs. It is important to note that the (− 34.27 kcal/mol) of between (ZnO)18 NC and the favipiravir is more desirable than the other interactions (ZnO)24 (− 26.69 kcal/mol), (ZnO)20 (− 27.14 kcal/mol), (ZnO)12 (− 29.36 kcal/mol), (ZnO)15 (− 29.50 kcal/mol), and (ZnO)22 (− 31.04 kcal/mol) NCs with the favipiravir, which means that ZnO NCs can be used as drug delivery vehicle.

Fig. 2

(Color online) Relaxed structures for favipiravir adsorbed a (ZnO)12, b (ZnO)15, c (ZnO)18, d (ZnO)20, e (ZnO)22, and f (ZnO)24 NCs

Fig. 3

(Color online) Binding energy per atom of pure ZnO clusters and adsorption energy for favipiravir adsorbed ZnO NCs

The HOMO and LUMO energy levels are important parameters to understand perfectly the charge transfer interaction within interacting systems [40]. In this regard, the energy levels using the density of states (DOS) constructed by GaussSum [41] (Fig. 4) and the energy gap that is obtained from HOMO and LUMO energy differences are performed to figure out the stability chemical reaction of the studied systems. The size of ZnO NCs causes changes over valence and conduction levels to shift to higher and lower energies both pure and interacting systems, leading to a shift in the studied systems. Our DFT calculations reveal that the of (ZnO)12, (ZnO)15, (ZnO)18, (ZnO)20, (ZnO)22, and (ZnO)24 NCs is found to be 4.14, 3.93, 3.91, 3.94, 3.64, and 3.88 eV, respectively (Table 1). Compared to studies available in the literature, the of (ZnO)12 was predicted as 4.04 eV [21] wide, i.e., about 0.10 eV smaller than the calculated value in the considered ZnO NC in this study. To the best of our knowledge, the other structures (for n = 15, 18, 20, 22, and 24) studied in the literature are cage structures [42, 43], but they are not symmetric as in our study, so these structures did not compare with our structures, just cited in References [21] and [42].

Fig. 4

(Color online) Density of states (DOS) for pure and favipiravir adsorbed a (ZnO)12, b (ZnO)15, c (ZnO)18, d (ZnO)20, e (ZnO)22, and f (ZnO)24 NCs

Table 1

The calculated binding energy per atom (Eb), adsorption energy (Ead), vertical ionization potential (VIP), vertical electron affinity (VEA), HOMO and LUMO energies, band gap energy (Eg), and reactivity parameters for pure and favipiravir adsorbed ZnO NCs. Ead in kcal/mol. Electronic properties are described in eV

	(ZnO)12		(ZnO)15		(ZnO)18		(ZnO)20		(ZnO)22		(ZnO)24
	Pure	Ads	Pure	Ads	Pure	Ads	Pure	Ads	Pure	Ads	Pure	Ads
Eb	5.04	-	5.08	-	5.11	-	5.13	-	5.15	-	5.16	-
Ead	-	− 29.36	-	− 29.50	-	− 34.27	-	− 27.14	-	− 31.04	-	− 26.69
VIP	8.40	7.46	8.13	7.29	8.03	7.53	7.99	7.31	7.80	7.25	7.84	7.25
VEA	1.64	1.57	1.79	1.67	1.90	1.95	1.87	1.76	2.01	1.86	1.97	1.85
LUMO	− 2.86	− 3.27	− 2.92	− 3.28	− 2.96	− 3.47	− 2.90	− 3.25	− 3.01	− 3.22	− 2.92	− 3.27
HOMO	− 7.00	− 6.12	− 6.85	− 6.05	− 6.87	− 6.38	− 6.84	− 6.19	− 6.65	− 6.19	− 6.80	− 6.20
Eg	4.14	2.85	3.93	2.77	3.91	2.91	3.94	2.94	3.64	2.97	3.88	2.93
ΔEg (%)*	-	31.16	-	29.52	-	25.58	-	25.38	-	18.41	-	24.48
η	2.07	1.43	1.97	1.39	1.96	1.46	1.97	1.47	1.82	1.49	1.94	1.47
ΔNtot	2.38	3.29	2.49	3.37	2.51	3.38	2.47	3.21	2.65	3.17	2.51	3.23

*ΔE (%) denotes the changes after adsorption

The value of the HOMO and LUMO energy levels is found to be about − 6.05 and − 3.28 eV, respectively, and the corresponding is found as 2.77 eV for (ZnO)15 NC and the favipiravir interaction which is the smallest value among the studied models. Moreover, the HOMO and LUMO energy levels for (ZnO)12 NC and the favipiravir interaction are predicted as − 6.19 and − 3.25 eV, respectively. The corresponding is found to be 2.94 eV, which is greater than the other ZnO NC, and the favipiravir interactions change in the range of 2.85–3.94 eV. It is important to note that charge transfer can take place easier between HOMO and LUMO energy levels of (ZnO)15 NC which has the smallest value and the favipiravir interaction, which means a shift in the biological activity of the favipiravir and ZnO NC interaction as shown in Fig. 5. That is, the change in the size of the ZnO NCs and the position of the favipiravir on the ZnO NCs cause a desirable shift in the HOMO and LUMO energy levels due to a decrease in the , which further contributes to the charge-transfer process [44-46]. The percentage value of the difference in the energies for favipiravir adsorbed ZnO NCs is also given in Fig. 5. When compared to pure ZnO NCs, the greatest change in the is predicted between (ZnO)12 NC and favipiravir (31.16%), whereas the lowest change in the is predicted between (ZnO)22 NC and favipiravir (18.41%). The values show that the size of ZnO NCs has an important effect on the of interactions. The ZnO NCs are semi-conducting with the in the range of 2.77–2.97 eV.

Fig. 5

(Color online) The HOMO–LUMO energy gap and the percentage value of the difference in the Eg energies for pure and favipiravir adsorbed ZnO NCs

The vertical ionization potential and vertical electron affinity , which are defined in computational part, are carried out to explore the changes of the reactivity properties of pure ZnO NCs and ZnO NCs with favipiravir drug based on the size of ZnO NCs, as indicated in Fig. 6a, b. The greater value of pure (ZnO)12 NC is 8.40 eV, which decreases to 7.84 eV for (ZnO)24 NC due to the increase in HOMO and LUMO energy levels in terms of the electron-donating ability of the favipiravir towards ZnO NCs. Similarly, the greater value of (ZnO)18 NC with favipiravir drug is 7.53 eV, which decreases to 7.25 eV for (ZnO)22 and (ZnO)24 NCs with favipiravir drug as shown in Fig. 6a. It is important to note that pure (ZnO)12 NC and (ZnO)18 NC with favipiravir drug are more stable than that of the others, so it is difficult to eject the electron from them. This result agrees also with the energy levels of HOMO and LUMO (Table 1). The VIP of the (ZnO)15, (ZnO)18, and (ZnO)20 NCs with favipiravir drug is predicted as 7.29, 7.53, and 7.31 eV. The value of of pure (ZnO)20 is 2.01 eV, which decreases to 1.64 eV for pure (ZnO)20 as shown in Fig. 6b. Similarly, the greater value of (ZnO)18 NC with favipiravir drug is 1.95 eV, which decreases to 1.57 eV for (ZnO)12 NC with favipiravir drug as shown in Fig. 6b. There is not a smooth change for the with increase in the size of ZnO NC where the value of increases for (ZnO)12, (ZnO)15, and (ZnO)18 with the favipiravir drug from 1.64 to 1.95 eV, and then fluctuations are observed from (ZnO)20 to (ZnO)24 with the favipiravir drug.

Fig. 6

(Color online) a VIP and b VEA for pure and favipiravir adsorbed ZnO NCs

Ultraviolet–visible (UV–vis) absorption spectra of interacting pure and favipiravir adsorbed (ZnO)12, (ZnO)15, (ZnO)18, (ZnO)20, (ZnO)22, (ZnO)24 NCs are performed with TD-DFT, and the obtained results are piloted in Fig. 7. An excitation wavelength (electron-transfer wavelength) in the visible region is preferred because ultraviolet light is harmful to living organisms [47]. Our results show that maximum absorption wavelength between 250 and 265 nm was obtained for interacting ZnO NCs and favipiravir systems, which corresponds to the near UV region and the closest visible light.

Fig. 7

(Color online) UV–vis spectra for pure and favipiravir adsorbed a (ZnO)12, b (ZnO)15, c (ZnO)18, d (ZnO)20, e (ZnO)22, and f (ZnO)24 NCs

The bond order analysis of ZnO NCs with different sizes and favipiravir interactions was studied using WBO, MBO, and FBO methods. The values of WBI, FBO, and MBO for the favipiravir on the (ZnO)22 NC were calculated about 0.432, 0.762, and 0.402, respectively, which are greater than other configurations (Table 2, Fig. 8, and Fig. S1 in the Supporting information). WBI, FBO, and MBO values also vary considerably based on the NC size and binding points of favipiravir molecule. Bond order values below 1.0 reflect the fact that bonds between O–Zn, N–Zn, and F–Zn atoms exhibit dual covalent and ionic natures. Besides, the presence of metal ions bonded to oxygen atoms means that the O–Zn bonds are kind of polarized covalent bonds. The Mulliken charge distribution of the atoms in the ZnO NCs with different sizes and favipiravir interactions is also tabulated in Table 2 and shown in Fig. S1 (in the Supporting information). As can be seen from Table 2, the charges on the O–Zn interactions have been calculated between 0.304 and 0.360 |e|, which are significantly bigger than that of N–Zn and F–Zn interactions.

Table 2

Bond orders (Wiberg bond index (WBI), Fuzzy bond order (FBO), Mayer bond order (MBO)) and Mulliken charges based on interactions between O–Zn, N–Zn, and F–Zn atoms (The O, N, and F atoms indicate favipiravir; the Zn is the closest neighbors to these atoms; see Supporting information Fig. S1 for detail)

Configurations	Interactions	WBI	FBO	MBO	Charge
Drug–(ZnO)12	27O–19Zn	0.414	0.732	0.363	0.321
	35 N–19Zn	0.189	0.369	0.115	0.072
	34F–6Zn	0.056	0.105	0.072	0.064
Drug–(ZnO)15	33O–30Zn	0.415	0.732	0.365	0.325
	41 N–30Zn	0.195	0.378	0.117	0.074
	40F–7Zn	0.031	0.041	0.042	0.039
Drug–(ZnO)18	39O–25Zn	0.370	0.675	0.334	0.304
	47 N–9Zn	0.373	0.636	0.259	0.241
	46F–9Zn	0.042	0.079	0.087	0.085
Drug–(ZnO)20	43O–19Zn	0.426	0.750	0.409	0.358
	51 N–19Zn	0.089	0.167	0.061	0.061
	50F–16Zn	0.145	0.312	0.187	0.169
Drug–(ZnO)22	47O–33Zn	0.432	0.762	0.402	0.360
	55 N–33Zn	0.067	0.119	0.029	0.033
	54F–25Zn	0.175	0.371	0.229	0.199
Drug–(ZnO)24	51O–16Zn	0.405	0.725	0.370	0.338
	59 N–16Zn	0.172	0.338	0.092	0.053
	58F–22Zn	0.041	0.060	0.045	0.040

Fig. 8

(Color online) Wiberg bond index (WBO), Mayer bond order (MBO), and Fuzzy bond order (FBO) and Mulliken charges based on interactions between a O–Zn, b N–Zn, and c F–Zn atoms for favipiravir adsorbed ZnO NCs (O, N, and F atoms indicate favipiravir and Zn indicates ZnO NCs; according to Supporting information Fig. S1 for detail)

To get an insight into the non-covalent interactions (NCI) within the studied systems, the NCI isosurfaces for favipiravir adsorbed (ZnO)12, (ZnO)15, (ZnO)18, (ZnO)20, (ZnO)22, and (ZnO)24 NCs are investigated, and plots for studied systems are shown in Fig. 9. As can be seen, disk-shaped blocks that indicate non-covalent interactions and the strongest H-bonds are observed near NH2 within the favipiravir molecule. Furthermore, the reduced density gradient (RDG) scatter plots for favipiravir adsorbed ZnO NCs were presented in Fig. 10. RDG scattered points indicate H-bonding interactions on the negative scale (blue color), indicating the dominance of the effect of strong attractive interactions. The green region in the range of ρ = 0.00 and ρ =  − 0.02 also shows the dominance of the effect of Van der Waals forces between binding atoms. Red areas indicate strong repulsive/steric interactions in a range of 0.01 and 0.05.

Fig. 9

(Color online) The non-covalent interaction (NCI) isosurfaces for favipiravir adsorbed a (ZnO)12, b (ZnO)15, c (ZnO)18, d (ZnO)20, e (ZnO)22, and f (ZnO)24 NCs

Fig. 10

(Color online) The reduced density gradient (RDG) scatter plots for favipiravir adsorbed a (ZnO)12, b (ZnO)15, c (ZnO)18, d (ZnO)20, e (ZnO)22, and f (ZnO)24 NCs. Blue represents strong attractive interactions; green indicates van der Waals interactions; and red indicates repulsive/steric interactions

Conclusions

In this study, the adsorption behavior and electronic and structural properties of the interacting favipiravir drug and ZnO NCs with different sizes were determined using the DFT method. Our results show the size of ZnO NCs, and binding points have an important effect on the interactions. For example, the adsorption energy between (ZnO)18 NC and the favipiravir (− 34.27 kcal/mol) is energetically more favorable than the other interactions. The size of the ZnO NCs causes a decrease in the energy gap, which further contributes to the charge-transfer process. The bonds between O–Zn, N–Zn, and F–Zn atoms exhibit dual covalent and ionic natures. From the non-covalent interaction analysis, the strongest H-bonds are observed near NH2 within the favipiravir. The maximum absorption peaks are predicted in the near UV region and the closest visible light. We can conclude that the ZnO NCs can have potential as drug delivery carriers.

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 293 KB)