Introduction

Lomustine drug is an alkylating nitrosourea utilized to treat different kinds of cancer [1]. However, its clinical utility is limited by dose-dependent toxicity, such as pulmonary and hematologic toxicity [2, 3]. Furthermore, since lomustine has a hydrophobic structure, intravenous injection is associated with significant side effects like blood respiratory system failure and vessels embolization [4]. Therefore, a rapid and reliable lomustine detection technique is essential.

Chromatographic and spectrophotometric techniques are generally time-consuming, expensive, and more complicated. Besides these, it has been specified that chemical sensors based on nanostructures can detect various materials at low concentrations because of the high surface/volume ratio [5-7]. The utilization of sensors has many advantages, such as easy construction against the easy analytical instrument, short reply time, small size, and low cost [8]. Various nanomaterials like nanocone, nanotubes, nanowires, nanosheets, and nanoclusters have been widely used for chemical sensors [9-17].

Among various nanostructures, fullerenes are known as suitable candidates for chemical sensors of different compounds regarding their appropriate properties such as unique spherical structure, highly symmetrical nature, and hydrophobic characteristics [18-22]. Kroto et al. introduced fullerene (C₆₀) in 1985 [23]. After introducing fullerene C₆₀, the stability and structure of nanoclusters (fullerenes) with less than 60 carbon atoms have attracted considerable attention [24-26]. Different sizes of fullerenes such as C₆, C₁₂, C₂₄, and C₄₈ were common resources for chemical sensors and diverse medical applications [27, 28]. Among various sizes of fullerenes studied, the C₄₈ nanocluster has gained special attention due to its possible structure flexibility [29, 30]. Therefore, in the current work, the interaction of lomustine with the C₄₈ nanocluster was initially investigated using density functional theory (DFT) calculations. Moreover, we inserted Al, Si, Ge, and Ga atoms instead of a C atom in the C₄₈ (Al-, Si-, Ge-, and Ga-doped C₄₇) to find an efficient sensor for lomustine detection.

Computational Method

Adsorption of lomustine onto the pure C₄₈ and Si-, Al-, Ge-, and Ga-doped C₄₇ nanoclusters surface was calculated using DFT. All calculations were done with the GAMESS software [31] with the B3PW91/6-311G(d, p) level of theory [32, 33]. The previous studies were reported that the B3PW91 method is one of the best methods [34, 35], and 6-311G(d, p) basis set known as convenient for nanocarrier systems [36, 37]. The adsorption energies (E_ad) of lomustine onto the pure and doped carbon nanoclusters were obtained with the following equations:

E_ad = E(lomustine/C₄₈) – E(C₄₈) – E(lomustine) (1)

E_ad = E(lomustine/Si-doped C₄₇) – E(Si-doped C₄₇) – E(lomustine)                          (2)

E_ad = E(lomustine/Al-doped C₄₇) – E(Al-doped C₄₇) – E(lomustine)                         (3)

E_ad = E(lomustine/Ge-doped C₄₇) – E(Ge-doped C₄₇) – E(lomustine)                       (4)

E_ad = E(lomustine/Ga-doped C₄₇) – E(Ga-doped C₄₇) – E(lomustine)                       (5)

Where E(lomustine/C₄₈), E(lomustine/Si-doped C₄₇), E(lomustine/Al-doped C₄₇), E(lomustine/Ge-doped C₄₇), and E(lomustine/Ga-doped C₄₇) are the total energies of the C₄₈, Si-, Al-, Ge-, and Ga-doped C₄₇ interacted with lomustine, and E(lomustine), E(C₄₈), E(Si-doped C₄₇), E(Al-doped C₄₇), E(Ge-doped C₄₇), and E(Ga-doped C₄₇)  are the total energy of the lone lomustine, C₄₈, Si-, Al-, Ge-, and Ga-doped C₄₇, respectively. Thermodynamic parameters (enthalpy (ΔH), entropy (ΔS), and Gibbs free energy (ΔG)) were further investigated at the same method to check the validity of the optimization. Moreover, the density of states (DOS), molecular electrostatic potential (MEP), natural bond orbital (NBO), and all energy calculations analyses were reviewed.

Results and Discussion

Adsorption of lomustine onto the C₄₈

The lomustine optimized structure and molecular electrostatic potential (MEP) plot were indicated in Figure 1. As indicated in the MEP plot of lomustine, the negative charges are mainly localized at the 10 and 20 atoms (red color), which can be adsorbed on the electron-withdrawing parts of the nanoclusters [38].

Figure 1: Optimized structure and MEP plots of the letrozole drug and C₄₇ and the most stable complexes in states A and B

The optimized nanocluster of C₄₈ includes four 4-membered (4-R), four 6-membered (6-R), and two 8-membered (8-R) rings displayed in Figure 1. The angles in C-C-C bounds for octagons is 134.99, for hexagons is 120.01 and for tetragons is 90.01. The C₄₈ nanocluster structural properties indicated that three C-C bonds with a bond distance of 1.46, 1.36, and 1.50 Å are correlated to the 6R-4R, 6R-8R, and 4R-8R mutual bonds, respectively, which completely agrees with the previous work [39]. First, the C₄₈ nanocluster was selected to investigate the adsorption of lomustine. The reactivity of lomustine with C₄₈ was reviewed in diverse adsorption sites (Figure 1). After relaxation, two main orientations were found judging from the values of the thermodynamic calculation and E_ad (10 and 20 atoms of lomustine and C atom of C₄₇ which their names is states A and B), as indicated in Figure 2. The E_ad of lomustine with the C₄₈ in states A and B were obtained to be -3.05 and -2.99 kcal mol^-1 with equilibrium distances of 3.41 and 3.69 Å, respectively (Table 1). Thus, the adsorption of the lomustine (from its 10 orientation) on the C₄₈ nanocluster (state A) is the most stable complex since E_ad values were indicated in state A are more negative than that of state B, and equilibrium distance is shorter than the state B. The E_ad of lomustine with the B₂₄N₂₄ nanocluster was calculated -10.73 kcal mol^-1 [38]. Therefore, the E_ad values indicated appropriate binding in the B₂₄N₂₄ nanocluster compared with the C₄₈ nanocluster. The natural bond orbital (NBO) calculations were depicted charge transfers from the lomustine to the C₄₈ in states A and B to be 0.007 and 0.006 e, respectively. Positive values of the NBO charge of lomustine illustrated that the charge transferred from the drug to C₄₈. After lomustine adsorption on the C₄₈ nanocluster, the ΔH parameters were investigated about 6.92 and 8.42 kcal mol^-1, and the ΔG values were calculated 21.92 and 27.51 kcal mol^-1 in state A and B, respectively. These results confirmed the E_ad values that the lomustine adsorption is stronger in state A.

Figure 2: Optimized structures and MEP plots for the Si-, Al-, Ge-, and Ga-doped C₄₇

Adsorption of lomustine onto the Si-, Al-, Ge-, and Ga-doped C₄₇

The E_ad of lomustine with C₄₈ showed a weak interaction. Thus, a Carbon (C) atom of C₄₈ was altered with Silicon (Si), Aluminum (Al), Gallium (Ga), or Germanium (Ge) atom (Si-, Al-, Ga, and Ge-doped C₄₇) for lomustine adsorption. The MEP plots and most stable structures of Si-, Al-, Ga-, and Ge-doped C₄₇ are depicted in Figure 2. MEPs of doped nanoclusters revealed Si, Al, Ge, and Ga atoms have more metallic characteristics than the C atoms. The bond length in Si-, Al-, Ge, and Ga-doped C₄₇ nanoclusters for doped atoms-C are longer than the corresponding C-C bonds in the C₄₈. The most stable structures of lomustine/ Si-, Al-, Ge, and Ga-doped C₄₇ complexes in the two states are demonstrated in Figures 3 and 4. After lomustine adsorption on nanoclusters, the calculated E_ad of lomustine/Si-doped C₄₇ in states C and D are -67.32 and -24.21 kcal mol^-1, and for lomustine/Ge-doped C₄₇ in states E and F are -45.88 and -27.17 kcal mol^-1, respectively. Similar to the C₄₈, the lomustine adsorption from its 1O atom with Si-doped C₄₇ and Ge-doped C₄₇ (states C and E) are the most stable states. When lomustine interacts from its 10 atom with Si and Ge atoms of nanocluster in states C and E (the most stable states), the N-O atoms (2O and 18N) of lomustine are transferred to the carbon atom of the nanoclusters (Figure 3). This decomposition process of the lomustine can destroy drug efficiency. The E_ad of lomustine/Al-doped C₄₇ and lomustine/Ga-doped C₄₇ complexes in states G, H, I, and J was calculated to be -45.00, -32.81, -29.76, and -23.06 kcal mol^-1, respectively (Table 1). The equilibrium distances in states G, H, I, and J were determined at 1.93, 1.92, 2.00, and 2.05 Å. The NBO calculation indicated charge transfer from the lomustine to Al- and Ga-doped C₄₇ nanoclusters, and values revealed charge transfer in the Al- and Ga-doped C₄₇ are more than the pure C₄₈. The ΔH and ΔG values in Al-doped C₄₇ and Ga-doped C₄₇ nanoclusters were obtained negative values. Thus, negative values indicated that the adsorption of lomustine on the Al-doped C₄₇ and Ga-doped C₄₇ is exothermic, and the lomustine's adsorption is spontaneous. The E_ad calculated values are more negative than the ΔG values, indicating ΔS reduction.

Figure 3: Optimized structures for the Si-doped C₄₇ and Ga-doped C₄₇ complexes in different states

Table 1: Calculated adsorption energy (Ead/kcal mol-1), bond distance between lomustine and nanoclusters (D/Å), NBO charge on the lomustine in complexes (QNBO/e), HOMO energies (E(HOMO)/eV), LUMO energies (E(LUMO)/eV), energy gap (Eg/eV), and %ΔEg change in electrical conductivity after the lomustine adsorption, dipole moment (DM/Debye), enthalpy (ΔH/kcal mol-1), Gibbs free energy (ΔG/kcal mol-1) and entropy (ΔS/kcal K-1 mol-1), in gas phase

Evaluation of the electrical properties of lomustine on the nanoclusters

Electronic properties of nanoclusters after and before interaction of the lomustine drug were reviewed in Table 1. In the C₄₈ nanocluster, the HOMO and LUMO energies are about -5.59 and -4.48 eV, respectively. Therefore, the E_g (LUMO-HOMO) was calculated at 1.11 eV. Likewise, Kamali et al. calculated the E_g of C₄₈ 1.11 eV at the same level of theory of the current work [39]. The HOMO and LUMO values changed in the doped nanoclusters. The HOMO energies for Si-, Ge-, Al-, and Ga-doped C₄₇ were calculated -5.61, -5.59, -5.69, and -5.79 eV, respectively. Furthermore, LUMO values of Si-, Ge-, Al, and Ga-doped C₄₇ were calculated -4.59, -4.58, -3.89, and -3.94 eV, respectively. These results demonstrated that replacing the Si or Ge atoms instead of the C atom stabilizes the HOMO and LUMO levels, and replacing the Al or Ga atoms stabilizes the HOMO and destabilizes the LUMO levels. Therefore, in the Si-, Ge-, Al, and Ga-doped C₄₇ nanoclusters, the E_g values were changed 8.11%, 8.11%, -62.16%, and -60.36% compared with the C₄₈ nanocluster. After lomustine adsorption, in the most stable complex of the lomustine/C₄₈ (state A), the E_g value was not sensibly changed (10.81%). The LUMO and HOMO values in the Si-, Ge-, and Ga-doped C₄₇ were altered to higher values after adsorption of lomustine and destabilized the LUMO and HOMO levels. However, in the Al-doped C₄₇, the LUMO value is stabilized by altering from -3.89 to –4.34 eV, and the HOMO value is destabilized by about 0.60 eV. Thus, in the most stable Si-, Ge-, Al- and Ga-doped C₄₇ complexes (states C, E, G, and I), the E_g changed about 12.75%, 16.67%, -58.33%, and -12.92%. The E_g values indicate sensitivity and reactivity. The lower levels indicate higher electrical conductivity, sensitivity, and reactivity since the changing in E_g values corresponds to the population of conduction elections, as stated by Equation 6 [40, 41].

σ=AT^3/2exp(-E_g/2KT)              (6)

Where K, A, and T are a constant in Boltzmann’s constant, electrons/m³.K^3/2, and temperature, respectively. Taking Equation 6 into account, the population of electrical conductivity exponentially increases as E_g decreases, which is changed into an electrical signal. Thus, it is clear that the Al-doped C₄₇ is more sensitive than other nanoclusters. Reduce the E_g through the interaction of lomustine revealed the Al-doped C₄₇ can sense the lomustine drug. DOS diagram plays a substantial role in the adsorption characteristics of lomustine with the nanoclusters [41-43], as displayed in Figure 5.

Figure 4: Optimized structures for the Al-doped C₄₇ and Ge-doped C₄₇ complexes in different states

After the adsorption of lomustine on the Al-doped C₄₇, the DOS plot of the Al-doped C₄₇ was changed in the LUMO, HOMO and E_g region. The MEP plots of lomustine/Al-doped C₄₇ in the state G (the most stable state) in Figure 5 demonstrate a considerable change after adsorption in the electrostatic potential. The MEP plot was revealed that the lomustine drug is more positive after interaction with nanocluster (blue and green colors). Therefore, this result indicated charge transfers from lomustine to the Al-doped C₄₇, and it could be corroborated the result of NBO charge transfers.

Recovery time

The kind of recovery time and interaction is significant for sensor development. Since strong interactions often cause long recovery times, which are not suitable for the detection process. The recovery time is recognized experimentally by exposure to the UV light or heating the adsorbent to higher temperatures [44]. Hence, the recovery time was calculated with the following equations:

τ = υ₀^-1 exp (-ΔG/KT)                                                (7)

Where T, K, and ν₀ are the temperature, Boltzmann’s constant, and attempt frequency, respectively. If UV of 10¹⁸ s^-1 (ν ~10¹⁸ s^-1) is used for attempt frequency to extract the lomustine attached to Al-doped C₄₇ nanocluster, the recovery time for the lomustine/Al-doped C₄₇ will be about 2.58 s at 298 K. These results revealed that the Al-doped C₄₇ has an ideal short recovery time. Therefore, the Al-doped C₄₇ nanocluster is an appropriate candidate for sensing the lomustine drug.

Figure 5: DOS and MEP plots of lomustine/Al-doped C₄₇ (state G)

Adsorption of lomustine in the solvent phase

To review the solvent effect on the adsorption process of lomustine on the Al-doped C₄₇ nanocluster, the pure nanocluster and most stable complex optimized with taking water as a solvent by using the B3PW91/6-311G(d, p) level of theory. The calculated ΔE_solv (total energy in aqua phase - total energy in gas phase) was -11.19 and 20.48 kcal mol^-1 in the pure and complex form of Al-doped C₄₇, respectively. Therefore, the stability of the structures in the solution phase is significantly enhanced, and the high solvation energies exert their applicability as sensors in biological fluids. The E_ad values in the solvent phase were revealed no significant alterations in comparison with the gas phase.

Conclusion

In this work, the adsorption of lomustine on the pure C₄₈ and Si-, Al-, Ge-, and Ga-doped C₄₇ nanoclusters was reviewed to find a new system for detecting lomustine. The E_ad values between lomustine and pure C₄₈ nanocluster showed a weak interaction. Lomustine adsorption on the Si- and Ge-doped C₄₇ nanoclusters indicated strong interaction, which can decompose the drug. The investigations indicated the appropriate E_ad after lomustine adsorbed on the Al-doped C₄₇ nanoclusters. In addition, the DOS plots and electrical conductivity indicated that the Al-doped C₄₇ nanocluster has excellent sensitivity to the lomustine compared with the Si-, Ge-, Ga-doped C₄₇ nanocluster. Furthermore, the Al-doped C₄₇ nanocluster indicated an appropriate short recovery time. Thus, the results of this study determined that the Al-doped C₄₇ nanocluster can selectively identify the lomustine drug.

Acknowledgements

This article was derived from PhD degree thesis in the Islamic Azad University-Ardabil branch.

Funding

This research did not receive any specific grant from fundig agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.

Conflict of Interest

There are no conflicts of interest in this study.

ORCID:

Farshid Salimi

https://www.orcid.org/0000-0003-0715-7388

HOW TO CITE THIS ARTICLE

Elnaz Golipour-Chobara, Farshid Salimi, Gholamreza Ebrahimzadeh-Rajaei. Sensing of Lomustine Drug by Pure and Doped C48 Nanoclusters: DFT Calculation. Chem. Methodol., 2022, 6(10) 790-800

https://doi.org/10.22034/CHEMM.2022.344895.1555

URL: http://www.chemmethod.com/article_154163.html