ETEBARI Nasrin MORSALI Ali BEYRAMABADI S. Ali

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Structural and Mechanistic Studies of-Fe2O3Nanoparticle as Capecitabine Drug Nanocarrier①

ETEBARI Nasrin MORSALI Ali②BEYRAMABADI S. Ali

(917568)

Using density functional theory, noncovalent interactions and four mechanisms of covalent functionalization of capecitabine anticancer drug onto-Fe2O3nanoparticles have been investigated. Quantum molecular descriptors of noncovalent configurations were studied. It was specified that binding of capecitabine onto-Fe2O3nanoparticles is thermodynamically suitable. Hardness and the gap of energy between LUMO and HOMO of capecitabine are higher than the noncovalent configurations, showing the reactivity of capecitabine increases in the presence of-Fe2O3nanoparticles. Capecitabine can bond to-Fe2O3nanoparticles through OH(1mechanism), NH (2mechanism), CO (3mechanism) and F (4mechanism) groups. The activation energies, activation enthalpies and activation Gibbs free energies of these reactions were calculated. It was specified that the1and2mechanisms are under thermodynamic control andkandkunder kinetic control. These results could be generalized to other similar drugs.

-Fe2O3nanoparticles, capecitabine, density functional theory, noncovalent and covalent functionalization, mechanism;

1 INTRODUCTION

One of the nanoscale materials being extensively utilized is magnetic nanoparticles (MNPs)[1-4]. MNPs are made of elements such as iron, nickel, cobalt and their oxides and many of their applications are related to iron oxide nanoparticle. MNPs show unique magnetic, electronic and chemical properties, causing them to be used for biological and pharma- ceutical researches[5-13]. The large surface to volume ratio provides the possibility of functionalization of different molecules, including the therapeutic agents, to them[14-19].

Many efforts have been made to overcome cancer through chemotherapy, but unfortunately, the old strategies and approaches produce many side effects such as vomiting, hair loss, cardio-toxicity and breathing troubles in the patients. The higher the dose of anti-cancer drugs prescribed and used, the higher the increase of toxicity in the tissues and immune system of the body[20,21].

The magnetic properties of MNPs make them have numerous applications in connection with the drug delivery and diagnostics and therapeutics. The drug delivery systems, using MNPs as carrier, have been based on the fact that they could be guided to a specific location such as a cancerous tumor by using external magnetic field[8,22,23]. After the arrival of MNPs at the target site, the drug is released through the enzymatic activity or through changes in pH, temperature and osmolality[24,25].

Iron oxide could exist along with different che- mical compositions, such as magnetite (Fe3O4) and maghemite (-Fe2O3). Magnetite and maghemite have the utmost usage in biomedical applications. Covalent and noncovalent (hydrogen bonds and van der Waals interactions) functionalizations play a principle role in the drug delivery systems. The possibility of targeted drug delivery causes reduction of the amount of drugs consumed and consequently the reduction of their side effects[26-28].

Capecitabine or Xeloda (pentyl[1-(3,4-dihydroxy- 5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate) has antitumor, antiviral and anticancer activities and is highly effective in the treatment of breast, gastric and colorectal cancers[29-31].

For the development of drug delivery systems by using MNPs, it is necessary to present molecular models for understanding the mechanism of func- tionalization of drugs to these nanoparticles in solvents (especially water).

Quantum calculations could be of great assistance to the design and analysis of drug delivery systems. The granting of Nobel Prize for chemistry in 2016 for the design and manufacturing of molecular machines, capable of being used in drug deliverance as well, confirms our statement[32-34].

We have used quantum calculations for the analysis of more stable structures and the mechanism of functionalization of capecitabine drug to-Fe2O3nanoparticles. Such calculations could inspire researchers to manufacture new drug delivery sys- tems. In spite of different theoretical studies on MNPs, so far few studies have been done on the mechanism of functionalization in solution.

2 COMPUTATIONAL METHOD

All calculations have been done with the B3LYP[35-37]hybrid density functional level using the GAUSSIAN 09 package[38]. The 6-31G(d,p) basis set was used except for Fe where the LANL2DZ basis set was employed with effective core potential (ECP) functions.

The solvent plays a key role in chemical systems explicitly[39-46]or implicitly. Polarized continuum model (PCM) was used for the consideration of implicit effects of the solvent[47,48]. For all species, all degrees of freedom were optimized. The tran- sition state obtained was confirmed to have only one imaginary frequency of the Hessian. The zero-point corrections were also considered to obtain activation energy.

3 RESULTS AND DISCUSSION

3.1 Noncovalent functionalization

Capecitabine (CAP) is a nonplanar molecule with OH, NH, CO and F groups as presented in Fig. 1.-Fe2O3nanoparticle was modeled using Fe6(OH)18(H2O)6ring clusters of six-edge sharing octahedra joining via 12 OH groups[49]. The opti- mized geometries of-Fe2O3nanoparticle (MNP) and capecitabine (CAP) in solution phase are presented in Fig. 1.

Fig. 1. Optimized structures of MNP and CAP

The interaction between CAP and MNP through OH (MNP/CAP1), NH (MNP/CAP2), CO (MNP/CAP3) and F (MNP/CAP4) groups was considered in gas and solution phases. These four configurations have been shown in Fig. 2.

The solvation energies of CAP, MNP, MNP/CAP1-4 have been shown in Table 1. The binding energies (Δ) of CAP to MNP in gas and solution phases were calculated using the following equation and presented in Table 1:

The calculated solvation energies show that CAP solubility increases in the presence of MNP. The calculated binding energies of MNP/CAP1 and MNP/CAP3 are negative in gas and solution phases. MNP/CAP1 is the most stable configuration in both phases.

Table 1. Solvation and Binding Energies of Different Configurations (kJ×mol-1)

Fig. 2. Optimized structures of MNP/CAP1-4

Quantum molecular descriptors such as hardness and electrophilicity index could be used to describe chemical reactivity and stability. The global hardness () indicates the resistance of one molecule against the change in its electronic structure (Eq. 2). Decrease incauses a decrease in the reactivity and an increase in stability.

Table 2 presents the quantum molecular descriptors for CAP, MNP and MNP/CAP1-4 in both phases. In this table,E(gap of energy between LUMO and HOMO) was also calculated.Enotably determines a more stable configuration.

According to the data in Table 2,andErelated to the CAP drug are higher than those of MNP/CAP1-4, showing the reactivity of CAP increases in the presence of MNP.of CAP increases in the pre- sence of MNP, showing that CAP acts as an electron acceptor.

Table 2. Quantum Molecular Descriptors (eV) and Binding Energies (kJ×mol-1) of CAP, MNP and MNP/CAP1-4

3.2 Covalent functionalization

First we considered MNP/CAP1-2 configurations for the investigation of covalent functionalization in solution phase. In these cases, hydroxyl and amino groups in MNP/CAP1-2 attack the Fe atom to transfer its proton to the surface OH group of MNP. Scheme 1 shows the mechanism for the formation of covalent bond between CAP and MNP. In these mechanisms, reactants MNP/CAP1-2 are converted into the products MNPCAP1-2/H2O by losing H2O.

Scheme 1.1and2mechanisms

According to Scheme 1, in these mechanisms surface OH group from Fe6(OH)18(H2O)6is sub- stituted by N (O) from drug CAP to give product MNPCAP1(2)/H2O. The optimized structures of products MNPCAP1-2/H2O are shown in Fig. 3.

Using reactant MNP/CAP1 and product MNPCAP1/H2O, the transition state ofkstep was optimized which we call TS1(Fig. 4). The calcu- lated bond lengths for all mechanisms are shown in Figs. 2～4.

The other reaction for the covalent functionali- zation of CAP onto MNT is shown in Scheme 2. In this mechanism H2O from Fe6(OH)18(H2O)6is substituted by C=O and F groups from CAP to give products MNPCAP3/H2O and MNPCAP4/H2O, respectively. The optimized structures of products MNPCAP3/H2O and MNPCAP4/H2O are shown in Fig. 3.

Fig. 3. Optimized structures of MNPCAP1-4/H2O

Fig. 4. Optimized structures of TSk1-TSk4

Table 3. Relative Energies (kJ×mol-1) for Different Species in k1-k4 Mechanisms

Scheme 2.3and4mechanisms

The activation energyfor3mechanism is lower than1,2and4mechanisms by 83.44, 44.13and 7.34kJ×mol-1, respectively. On the other hand, products MNPCAP1-2/H2O (1and2mechanisms) are more stable than MNPCAP3-4/H2O (3and4mechanisms), so products MNPCAP1-2/H2O (high activation energies) and MNPCAP3-4/H2O (low activation energies) are thermodynamic and kinetic products, respectively.

In other words, thermodynamic and kinetic controls act opposite each other. The high energy barriers of1and2mechanisms are related to the proton transfer from OH and NH of drug to OH of the cluster. Different techniques such as using ultrasonic irradiation help to increase the contribution of1and2mechanisms and are in favor of thermodynamic control.

4 CONCLUSION

Four configurations of noncovalent interaction of drug capecitabine (CAP) onto-Fe2O3nanoparticles (MNP) were investigated in gas and solution phases. MNPs were modeled using Fe6(OH)18(H2O)6ring clusters. The binding energies for two configurations in gas and solution phases are negative, so these interactions are energetically favorable. The global hardness and HOMO-LUMO energy gap of CAP are higher than MNP/CAP1-4, showing the reactivity of the CAP increases in the presence of-Fe2O3nanoparticles.

Four mechanisms of covalent functionalization of drug CAP onto MNP thorough OH(1mechanism), NH (2mechanism), C=O (3mechanism) and F (4mechanism) groups have been studied in detail. The activation parameters related to1,2and4mechanisms are higher than the3mechanism. The products of1and2mechanisms are more stable, but the products of3and4mechanisms are formed faster and therefore MNPCAP3/H2O and MNPCAP4/H2O are kinetic products.

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6 July 2017;

25 December 2017

① We thank the Research Center for Animal Development Applied Biology for allocation of computer time

. E-mails: almorsali@yahoo.com and morsali@mshdiau.ac.ir

10.14102/j.cnki.0254-5861.2011-1775