Quantum Mechanical Study on the Adsorption of Drug Gentamicin onto γ-Fe₂O₃ nanoparticles

 Introduction

Gentamicin is a commonly used antibiotic which prevents bacterial infection around the implant. It is an aminoglycoside antibiotic, and can treat many types of bacterial infections, particularly Gram-negative infection. It is also one of the few heat-stable antibiotics that remains active even after autoclaving, and this makes it particularly useful in the preparation of certain microbiological growth media¹.

Regarding the increasing use of nanotechnology in today’s life, understanding of the functional mechanism of  nanoparticles is of great importance. The rapid development of  nanoscience has opened new ways in timely and prompt diagnosing of diseases and drug delivery. The use of nanoparticles in drug delivery is a new field which is rapidly developing^2-5.

Jayarathne et al. presented a model for γ-Fe₂O₃ nanoparticles on the basis of  Fe₆(OH)₁₈(H₂O)₆ ring cluster which is in good consistency with the experimental data including vibration frequencies and bond lengths⁶. The huge surface, easy separation and low cost are the reasons to use γ-Fe₂O₃ nanoparticles as the strong adsorbent materials.

In spite of extensive use of magnetic nanoparticles, so far, molecular mechanism of adsorption of drugs in water by these nanoparticles has not been investigated. In this work, using quantum mechanical methods, the noncovalent adsorption of gentamicin onto γ-Fe₂O₃ nanoparticles was studied.

Computational Details

All of the present calculations have been performed with the B3LYP^7-9  hybrid density functional level using the GAUSSIAN 03 package¹⁰. The 6-31G(d,p) basis sets were employed except for Fe where the LANL2DZ basis set was used with effective core potential (ECP) functions.

The solvent has an important role in chemical reactions explicitly  or implicitly^11-15. The implicit effects of the solvent was considered by using the polarized continuum model (PCM)¹⁶. In the PCM method, the molecular cavity is made up of the union of interlocking atomic spheres. All degrees of freedom for all geometries were optimized in solution (water).

Results and Disscussion

The properties of γ-Fe₂O₃ nanoparticles were modeled using Fe₆(OH)₁₈(H₂O)₆ ring clusters of six edge sharing octahedra joining via 12 OH groups. The 6 water molecules and 6 surface OH groups were expected to form a network of H-bonded interactions (Fig. 1). The optimized geometries of gentamicin (GEN), Fe₆(OH)₁₈(H₂O)₆ or γ-Fe₂O₃ nanoparticle (NP) in solution phase are shown in Fig. 1. Gentamicin is a non-planar molecule with the amino and hydroxyl groups protruding out of the molecular plane as shown in Fig. 1.

Figure1: Optimized structure of Fe6(OH)18(H2O)6 or γ-Fe2O3 nanoparticle (NP) and gentamicin (GEN).  Click here to View figure

 

Three  possible modes of noncovalent interaction of Gentamicin onto γ-Fe₂O₃  nanoparticles were studied. Figures 2-4 present these configurations in solution phase, namely, GEN/NP1-GEN/NP3. Gentamicin may interact with γ-Fe₂O₃  nanoparticles through amino ( GEN/NP1 ) and hyroxyl (GEN/NP2) groups to form hydrogen bonds. In GEN/NP3 parallel orientation was considered.

Figure 2: Optimized structure of GEN/NP1.  Click here to View figure

 

Figure 3: Optimized structure of GEN/NP2.  Click here to View figure

 

Figure 4: Optimized structure of GEN/NP3.  Click here to View figure

 

The binding energies (E_b) of gentamicin whit γ-Fe₂O₃  nanoparticles are calculated using the following equation and presented in Table 1:

E_b = E_GEN|_NP – (E_NP– E_GEN)                     (1)

Using the calculated binding energies of  GEN/NP1-GEN/NP3 in Table 1, these energies are negative in solution phase indicating gentamicin is stabilized by γ-Fe₂O₃  nanoparticles surface. Among the 3 configurations in the solution phase, the configuration 2, in which the drug interacts with γ-Fe₂O₃  nanoparticles through hyroxyl (GEN/NP2) group, is the most stable configuration.

In describing stability and chemical reactivity of different systems, quantum molecular descriptors have been used like the chemical potential,  the global hardness, the electrophilicity index and etc.

The chemical potential (μ) which shows escape tendency of an electron from equilibrium, is defined as follows:

where  is the ionization potential and is the electron affinity of the molecule.

The global hardness (μ) shows the resistance of one chemical species against the change in its electronic structure (Equation (3)). Increase η in  causes an increase in the stability and a decrease in reactivity.

η = (I-A)/2                   (3)

Electrophilicity index (ω) was defined by Parr as follows¹⁷:

ω = μ² |2η                  (4)

Tabels 1 represents the values of the quantum molecular descriptors calculated for GEN, NP and GEN/NP1-3 in solution phases. In this table, besides quantum molecular descriptors, E_g (HOMO-LUMO energy gap) was also presented. E_g notably  shows a more stable system.

Table 1: Bonding energies (kJ/mol) quantum molecular descriptors (eV) for optimized geometries. 

Species	Eb	EHOMO	ELUMO	Eg	I	A
GEN	–	-5.95	-1.85	4.11	5.95	1.85	-3.90	2.05	3.70
NP	–	-5.58	-4.48	1.10	5.58	4.48	-5.03	0.55	22.95
GEN/NP1	-74.61	-5.93	-4.33	1.60	5.93	4.33	-5.13	0.80	16.39
GEN/NP2	-94.35	-6.09	-3.30	2.79	6.09	3.30	-4.69	1.40	7.88
GEN/NP3	-86.82	-5.94	-3.27	2.67	5.94	3.27	-4.60	1.33	7.94

 

According to the data in Table 1, , I, and E_g related to the gentamicin drug are higher than GEN/NP1-3, showing the stability of the gentamicin decreases in the presence of γ-Fe₂O₃ nanoparticles and its reactivity increases. Also, in confirmation of the previous issue, it is observed that  of the gentamicin becomes more negative in the presence of γ-Fe₂O₃ nanoparticles. of the gentamicin increases in the presence of γ-Fe₂O₃ nanoparticles, showing that the gentamicin acts as electron acceptor.

Six H₂O molecules, due to weaker bond relative to OH, are proper choices which leave the cluster and are replaced by gentamicin.  Scheme 1 shows the mechanism of covalent adsorption of GEN onto γ-Fe₂O₃ nanoparticles where  and  are equilibrium constants and  is rate constant (using GEN/NP2 as reactant).

Scheme 1  Click here to View scheme

 

species GEN/NP2 is initially formed with equilibrium constant K₁ , following which the species GEN/NPC and product are formed in k₁ and K´₁ paths. The optimized structures of GEN/NPC has been shown in Fig. 5 (covalent adsorption). GEN/NPC is more stable than GEN/NP2 by 49.31 kJ/mol, so GEN/NPC is thermodynamic product.

Figure 5: Optimized structure of GEN/NPC.  Click here to View figure

 

Conclusion

Using density functional theory, the effects of the adsorption of gentamicin onto γ-Fe₂O₃ nanoparticles have been studied in detail in solvent environment. Three  possible modes of noncovalent interaction of Gentamicin onto γ-Fe₂O₃ nanoparticles were investigated. Besides parallel interaction (GEN/NP3), there are two possibilities for the formation of hydrogen bonds between gentamicin  and γ-Fe₂O₃ nanoparticles, for the first possibility, gentamicin is interacted with  γ-Fe₂O₃ nanoparticles through amino groups (GEN/NP1) and for the second one through hydroxyl groups (GEN/NP2). The product of second possibility is more stable.

Acknowledgment

We thank the theoretical research group in research center for animal development applied biology for allocation of computer time.

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