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Application of C30B15N15 heterofullerene in the isoniazid drug delivery: DFT studies
Physica E 89 (2017) 72–76
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Application of C30B15N15 heterofullerene in the isoniazid drug delivery: DFT studies Mehrnoosh Khodam Hazratia, Zargham Bagherib, Ali Bodaghic, a b c
MARK
⁎
Department of Chemistry, Tarbiat Modares University, Tehran, Iran Department of Physics, College of Science, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran Department of Chemistry, Tuyserkan Branch, Islamic Azad University, Tuyserkan, Iran
A R T I C L E I N F O
A BS T RAC T
Keywords: C30B15N15 heterofullerene Isoniazid Drug delivery DFT
Using density functional theory, we have investigated the potential application of a C30B15N15 heterofullerene in anti-cancer isoniazid drug delivery. It was found that isoniazid prefers to attach via its –NH2 group to a boron atom of the C30B15N15 with releasing a large energy of about 21.91 kcal/mol. Our partial density of states analysis demonstrates that the boron atoms significantly contribute in generation of virtual orbitals of C30B15N15 fullerene, indicating that these atoms will be suitable for nucleophilic attack rather than carbon atoms. In addition to the large released energy, the electronic properties C30B15N15 are significantly sensitive to the isoniazid attachment which can recognize the drug trajectory by affecting the fluorescence emission properties. Unlike, different nanostructures whose structures need to be manipulated to be suitable for drug delivery, the C30B15N15 fullerene can be used in the pristine form. We proposed a drug release mechanism in cancer tissues, representing that in the low pH of the cancer cells the drug and C30B15N15 fullerene are considerably protonated, thereby separating the drug from the surface of the fullerene. The reaction mechanism of the drug with the fullerene is changed from covalence in natural environment to hydrogen bonding in acidic cancer cells.
1. Introduction Heterofullerenes which are made by substitutional doping in the fullerene shell and inorganic fullerenes have attracted great attention recently [1–15]. The most prominent heterofullerenes contain boron and nitrogen instead of carbon atoms. For B- and N-doped C60 fullerenes, the possible incorporation of dopants at several positions of the cage must be considered [16]. In 1991, Guo and coworkers stated that there should be no B-B or N-N bonds in the B- and N-doped C60 fullerene structures [17]. One year later, Xia et al. showed that B30N30 heterofullerenes are theoretically stable and they can be synthesized from borazine [18]. In 2004, Erkoç investigated C30B15N15 heterofullerenes by semi-empirical molecular orbital calculations [19]. They suggested a stable structure with a frontier molecular orbital energy gap value of about 1 eV [19]. Isoniazid molecule was prepared for the first time by Meyer and Mally in 1912, while they were entirely unaware of its potential for treating tuberculosis [20]. After 40 years of no attention to this compound, Bernstein et al. discovered that isoniazid is an antitubercular drug [21]. Despite the widely used and the efficient effects
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of isoniazid in tuberculosis treatment, it can cause severe side effects such as peripheral neuropathy and hepatotoxicity which confines the doses that can be used clinically [22,23]. Drug delivery systems offer some advantages including the possibility to target specifically the tumor cells and protect the drug from degradation [24]. Thus, it can enhance the therapeutic efficiency and reduce the toxicity of the drug. On the other hand, when bacteria are treated with antibiotics, the drug resistance increases and higher concentrations of antibiotic are needed for affecting on the bacteria. Hence, a system that facilities delivery of high doses of drug to the bacteria sites is highly desirable [24]. By advent of nanotechnology, different nanostructures have found promising applications in gas sensors, electronic, gas removal, drug delivery, etc [25–41]. Recently, much attention has been paid to delivery of anti-cancer drugs such isoniazid by nanostructures [42– 44]. Although, an effective carrier to reduce the side effects associating with isoniazid therapies is still lacking. B- and N-doped heterofullerenes have been already known as noncytotoxic nanostructures which can be functionalized with several molecules for biological applications [45,46]. Saikia et al. have studied the structure and electronic properties of the noncovalent functiona-
Corresponding author. E-mail address: [email protected] (A. Bodaghi).
http://dx.doi.org/10.1016/j.physe.2017.02.009 Received 8 January 2017; Received in revised form 21 January 2017; Accepted 8 February 2017 Available online 08 February 2017 1386-9477/ © 2017 Elsevier B.V. All rights reserved.
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lization of BN nanotubes with isoniazid [47]. Furthermore, Judge and coworkers have synthesized a C60/isoniazid conjugate and successfully tested it for antimycobacterial activity [48]. In this work, we investigate the potential utility of C30B15N15 heterofullerene as a drug carrier for isoniazid anti-tubercular drug by means of density functional theory (DFT) calculations. The adsorption and release mechanisms of the drug will be considered.
called A, B, and C and highlighted in Fig. 1 by red, green and orange circles, respectively. The MEP plot for the optimized structure of isoniazid with a formula C6H7N3O depicted in Fig. 1. It shows the most likely reaction sites of isoniazid which are a carbonyl oxygen, a nitrogen atom of hexagon and a −NH2 group as numbered from 1 to 3 in this work. Hence, there are 9 main interaction states between the isoniazid molecule and the C30B15N15 fullerene.
2. Computational details
3.2. The isoniazid adsorption on C30B15N15
The B3LYP exchange-correlation functional [49,50] and 6–31G (d) basis set were performed to study the interaction between the C30B15N15 fullerene and the isoniazid drug. The B3LYP is a commonly used density functional which frequently has been jointed with 6–31G (d) basis set to explore different properties of nanostructures [51–65]. Geometry optimizations, adsorption energies (Ead), molecular electrostatic potential (MEP), natural bond orbitals (NBO) and electronic properties such as the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and the HOMO-LUMO energy gaps (Eg) were carried out using GAMESS program package at the same level of theory [66]. GaussSum program [67] was used to draw density of states (DOS) plots. We have done vibrational frequency calculations to make sure that all optimized structures correspond to the global minima on the potential energy surface. The values of Ead for the optimized complexes were obtained by following equation:
The optimized structures of the 9 studied complexes of isoniazid and C30B15N15 are presented in Fig. 2. The bond lengths between the interaction sites are about 1.60, 1.64 and 1.65 Å for different involving heads of isoniazid. The distances are almost identical for all three types of boron atoms. The values of Ead and the BSSE corrected Ead are listed in Table 1, indicating that the adsorptions from −NH2 head group of isoniazid on the boron atoms are the most favorable interaction between isoniazid and C30B15N15 molecules. The nitrogen in −NH2 group has a lone pair and tends to react with boron atom as a Lewis base. The values of Ead as well as the bond lengths show that there is a negligible chemical difference between boron atoms in the C30B15N15. Therefore, we assumed that all boron atoms are identical and focused on the boron type C. The BSSE corrected Ead values are about −7.58, −17.70 and −21.91 kcal mol−1 for C1, C2 and C3 complexes, showing that there are relatively strong interactions between the reactants. Complex C3 with the most negative value of Ead is the most stable complex between all the studied complexes. Table 1 indicates that the effect of the BSSE correction on the weaker interaction is larger.
Ead = E(Isoniazid /C30 B15 N15) – E(Isoniazid) − E(C30 B15 N15) + BSSE (1) where E(Isoniazid /C30B15N15) is the energy of the complex between isoniazid and the C30B15N15 heterofullerene. The counterpoise method of Boys and Bernardi was used to calculate the basis set superposition error (BSSE) energy for all studied complexes [68]. Moreover, to predict the charge transfer between the isoniazid molecule and C30B15N15, we accomplished NBO analysis.
3.3. The electronic properties The results of DFT calculations reported in Table 1 and partial DOS plot in Fig. 3 show that C30B15N15 heterofullerene is a semiconductor with an Eg value about 0.96 eV in which the HOMO and LUMO energies are about −4.52 and −3.56 eV, respectively. This is in good agreement with the previously reported value [10]. Interestingly, PDOS plot demonstrates that the N atoms which are much more electronegative atoms with a lone pair (Lewis base) significantly contribute in the generation of occupied orbitals. While the electron deficient boron atoms are mainly responsible of virtual orbital creation which is in consistence their Lewis acid character. Carbon atoms with a moderate electronegativity contribute in both occupied and virtual orbitals. In complex C1, after the interaction, the HOMO level of the cage is slightly shifted to more positive value and the LUMO level is shifted from −3.56 to −4.03 eV. Thus, the Eg is decreased by about 11% from 0.96 to 0.88 eV. The changes in HOMO, LUMO and Eg in complex C2 are similar to those in the complex C1. For the complex C3, while HOMO level is slightly shifted to higher positive value, there is a
3. Results and discussion 3.1. Structure and properties of isoniazid and C30B15N15 The C30B15N15 heterofullerene consists of four types of hexagonal and three types of pentagonal rings which are shown as H1-H4 and P1P3 in Fig. 1. It is a polar molecule with a dipole moment about 3.39 D. The calculated equilibrium C–C bond lengths in C30B15N15 are about 1.42 Å, being comparable with those of C60 fullerene (~1.41 Å [69]). The average C–B, C–N and B–N bond lengths are about 1.54 Å, 1.44 Å and 1.47 Å, respectively. Depending on the position of atoms in the structure of C30B15N15 fullerene, there are three types of boron atoms
Fig. 1. (a) The optimized structure of C30B15N15 heterofullerene consists of four types of hexagonal (H1-H4) and three types of pentagonal (P1-P3) rings. Different types of boron atoms (A, B and C) are marked by red, green and orange circles. (b) The optimized structure of the isoniazid molecule and its MEP plot. Different active sites are determined by 1, 2 and 3. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).
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Fig. 2. The optimized structures of the studied complexes of C30B15N15 heterofullerene and isoniazid.
significant shift in the energy of the LUMO level (from −3.56 to −2.99 eV). Thus, in contrast to the complexes C1 and C2, the Eg in the complex C3 is increased by about 32% (from 0.96 to 1.27 eV). These changes in the Eg values will alter the fluorescence emission of the C30B15N15 after interaction with the drug and it can help to trace the drug trajectory by the spectrophotometers in the body. The HOMO and LUMO profiles, and the DOS plots for the complexes C1, C2 and C3 are shown in Fig. 1S (Supplementary materials). One can clearly see that in contrast to complex C3, the LUMO levels in complexes C1 and C2 are located on the drug. In complex C3, the electron lone pair of the −NH2 group is free enough to interact with the electron deficient boron atoms easily. While the electron lone pairs of oxygen and nitrogen atoms are much involved in the resonance, thus, the interactions between the drug and C30B15N15 are less favorable in complexes C1 and C2. The obtained values of adsorption energies also confirm these results. Therefore, the attachment from the −NH2 group to the boron site of C30B15N15 (complexes A3, B3 and C3) is the main mechanism of the drug adsorption. The length of newly formed B-N bonds in these complexes are about 1.65 Å.
Table 1 The calculated adsorption energy (Ead) and BSSE corrected Ead (EBSSE) in kcal mol−1, HOMO, LUMO energies, and HOMO-LUMO energy gap (Eg) of bare C30B15N15 cage and the isoniazid and C30B15N15 complexes in eV. System
Ead
EBSSE
HOMO
LUMO
Eg
%ΔEg
Q (e)
C30B15N15 A1 A2 A3 B1 B2 B3 C1 C2 C3
– −9.36 −20.82 −25.14 −12.95 −22.06 −26.12 −13.97 −21.95 −26.79
– −3.52 −16.61 −20.30 −6.89 −17.94 −21.85 −7.58 −17.70 −21.91
−4.52 −4.01 −4.02 −4.21 −4.08 −4.02 −4.32 −4.03 −4.02 −4.26
−3.56 −3.15 −3.22 −3.23 −3.09 −3.15 −3.19 −3.15 −3.19 −2.99
0.96 0.86 0.80 0.98 0.99 0.87 1.13 0.88 0.83 1.27
– −10.42 −16.67 2.08 3.12 −9.37 17.71 −11.11 −13.54 32.29
– 0.251 0.298 0.235 0.242 0.294 0.222 0.248 0.289 0.235
3.4. Quantum molecular description and population analysis The electrophilicity indices (ω) are computed as a descriptor of charge transfer direction. So that, the higher values of ω, the higher electrophilicity of the structure [70]. We have calculated ω by using the following equations:
μ = (EHOMO+ELUMO )/2
(2)
η = [−EHOMO−(−ELUMO )]/2
(3)
ω=μ2/2η
(4)
Fig. 3. The partial density of states (PDOS) plot for C30B15N15 heterofullerene.
where μ is electronic chemical potential and η chemical hardness of the 74
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potential application of this fullerene as a drug carrier. We showed that the most favorable state is the interaction of –NH2 group of the drug with the B atoms of the fullerene with adsorption energy of about −21.96 kcal/mol. The electronic properties of the fullerene show a high sensitivity toward the drug which can help one to detect the trajectory of the drug in the body because of the change of fluorescence emission properties of the cluster in the presence of the drug. An interaction mechanism change is predicted from covalent bonding in blood to hydrogen bonding in cancer tissue. This indicates that the isoniazid can be separated from the C30B15N15 carrier in the low pH of cancerous tissues by proton attack. The energy of the hydrogen bonding is predicted be very low about 11.30 kcal/mol.
Table 2 Quantum molecular descriptors (in eV) and the charge transfer for complexes C1, C2 and C3. System
μ
η
ω
QMulliken (e)
QNBO (e)
C1 C2 C3
−3.59 −3.60 −3.62
0.43 0.41 0.63
14.69 15.61 10.37
0.248 0.289 0.235
0.306 0.338 0.346
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Fig. 4. The optimized structure of protonated isoniazid (C6H8N3O+) and C30B15N15, showing separation from each other in the acidic environment. Distances are in Å.
ground state. The results are summarized in Table 2. A higher value for Eg indicates more stability and low reactivity of the complex [71]. In the complex C3 the electrophilicity of the complex (10.37) is less than that of the complexes C1 and C2 (14.69 and 15.61, respectively). Hence, in complex C3, the drug adsorption on the C30B15N15 heterofullerene decreases the electrophilicity and enhance the stability of the cage. Furthermore, NBO theory has been performed to analyze the characteristic of interactions at the active sites of isoniazid and C30B15N15. For all complexes, there is a charge transfer from the isoniazid drug to the C30B15N15 cage. Based on NBO analysis, in the complex C3, a charge about 0.346 e is transferred from the isoniazid to the cage which is larger than that which occurred in the case of complexes C1 and C2. 3.5. Drug release We showed that the C30B15N15 heterofullerene is somewhat suitable for the isoniazid drug adsorption which is the first and the most significant step in the drug delivery process. However, one of the most challenging steps in drug delivery is drug release from the carrier in the target cell. As a matter of fact, the pH of the tumor cells is less than the normal cells and therefore, the cancerous tissues have an acidic environment (~pH < 6) [72]. We examined the effect of pH on the most stable complex between the C30B15N15 heterofullerene and the isoniazid drug (complex C3). We assumed that H+ species will intensively tend to attach to the nucleophilic heads of the isoniazid drug and C30B15N15 cage. Therefore, we protonated the −NH2 group of isoniazid, and carried out the optimization calculations. As a result, the Ead in the acidic environment increases from −21.91 to −11.30 kcal mol−1 and the distance between the drug and the C30B15N15 heterofullerene increase to 3.72 Å. Also the nature of the interaction is changed from a covalent to the hydrogen bonding as shown in Fig. 4. Hence, the drug is separated from the carrier by proton attack as shown in Fig. 4. As a result, we have shown that in an acidic environment the drug cannot attach to the carrier and has to be released. 4. Conclusions Using DFT calculations, we have studied the isoniazid drug attachment and release to C30B15N15 heterofullerene to investigate the 75
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Physica E journal homepage: www.elsevier.com/locate/physe
Application of C30B15N15 heterofullerene in the isoniazid drug delivery: DFT studies Mehrnoosh Khodam Hazratia, Zargham Bagherib, Ali Bodaghic, a b c
MARK
⁎
Department of Chemistry, Tarbiat Modares University, Tehran, Iran Department of Physics, College of Science, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran Department of Chemistry, Tuyserkan Branch, Islamic Azad University, Tuyserkan, Iran
A R T I C L E I N F O
A BS T RAC T
Keywords: C30B15N15 heterofullerene Isoniazid Drug delivery DFT
Using density functional theory, we have investigated the potential application of a C30B15N15 heterofullerene in anti-cancer isoniazid drug delivery. It was found that isoniazid prefers to attach via its –NH2 group to a boron atom of the C30B15N15 with releasing a large energy of about 21.91 kcal/mol. Our partial density of states analysis demonstrates that the boron atoms significantly contribute in generation of virtual orbitals of C30B15N15 fullerene, indicating that these atoms will be suitable for nucleophilic attack rather than carbon atoms. In addition to the large released energy, the electronic properties C30B15N15 are significantly sensitive to the isoniazid attachment which can recognize the drug trajectory by affecting the fluorescence emission properties. Unlike, different nanostructures whose structures need to be manipulated to be suitable for drug delivery, the C30B15N15 fullerene can be used in the pristine form. We proposed a drug release mechanism in cancer tissues, representing that in the low pH of the cancer cells the drug and C30B15N15 fullerene are considerably protonated, thereby separating the drug from the surface of the fullerene. The reaction mechanism of the drug with the fullerene is changed from covalence in natural environment to hydrogen bonding in acidic cancer cells.
1. Introduction Heterofullerenes which are made by substitutional doping in the fullerene shell and inorganic fullerenes have attracted great attention recently [1–15]. The most prominent heterofullerenes contain boron and nitrogen instead of carbon atoms. For B- and N-doped C60 fullerenes, the possible incorporation of dopants at several positions of the cage must be considered [16]. In 1991, Guo and coworkers stated that there should be no B-B or N-N bonds in the B- and N-doped C60 fullerene structures [17]. One year later, Xia et al. showed that B30N30 heterofullerenes are theoretically stable and they can be synthesized from borazine [18]. In 2004, Erkoç investigated C30B15N15 heterofullerenes by semi-empirical molecular orbital calculations [19]. They suggested a stable structure with a frontier molecular orbital energy gap value of about 1 eV [19]. Isoniazid molecule was prepared for the first time by Meyer and Mally in 1912, while they were entirely unaware of its potential for treating tuberculosis [20]. After 40 years of no attention to this compound, Bernstein et al. discovered that isoniazid is an antitubercular drug [21]. Despite the widely used and the efficient effects
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of isoniazid in tuberculosis treatment, it can cause severe side effects such as peripheral neuropathy and hepatotoxicity which confines the doses that can be used clinically [22,23]. Drug delivery systems offer some advantages including the possibility to target specifically the tumor cells and protect the drug from degradation [24]. Thus, it can enhance the therapeutic efficiency and reduce the toxicity of the drug. On the other hand, when bacteria are treated with antibiotics, the drug resistance increases and higher concentrations of antibiotic are needed for affecting on the bacteria. Hence, a system that facilities delivery of high doses of drug to the bacteria sites is highly desirable [24]. By advent of nanotechnology, different nanostructures have found promising applications in gas sensors, electronic, gas removal, drug delivery, etc [25–41]. Recently, much attention has been paid to delivery of anti-cancer drugs such isoniazid by nanostructures [42– 44]. Although, an effective carrier to reduce the side effects associating with isoniazid therapies is still lacking. B- and N-doped heterofullerenes have been already known as noncytotoxic nanostructures which can be functionalized with several molecules for biological applications [45,46]. Saikia et al. have studied the structure and electronic properties of the noncovalent functiona-
Corresponding author. E-mail address: [email protected] (A. Bodaghi).
http://dx.doi.org/10.1016/j.physe.2017.02.009 Received 8 January 2017; Received in revised form 21 January 2017; Accepted 8 February 2017 Available online 08 February 2017 1386-9477/ © 2017 Elsevier B.V. All rights reserved.
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lization of BN nanotubes with isoniazid [47]. Furthermore, Judge and coworkers have synthesized a C60/isoniazid conjugate and successfully tested it for antimycobacterial activity [48]. In this work, we investigate the potential utility of C30B15N15 heterofullerene as a drug carrier for isoniazid anti-tubercular drug by means of density functional theory (DFT) calculations. The adsorption and release mechanisms of the drug will be considered.
called A, B, and C and highlighted in Fig. 1 by red, green and orange circles, respectively. The MEP plot for the optimized structure of isoniazid with a formula C6H7N3O depicted in Fig. 1. It shows the most likely reaction sites of isoniazid which are a carbonyl oxygen, a nitrogen atom of hexagon and a −NH2 group as numbered from 1 to 3 in this work. Hence, there are 9 main interaction states between the isoniazid molecule and the C30B15N15 fullerene.
2. Computational details
3.2. The isoniazid adsorption on C30B15N15
The B3LYP exchange-correlation functional [49,50] and 6–31G (d) basis set were performed to study the interaction between the C30B15N15 fullerene and the isoniazid drug. The B3LYP is a commonly used density functional which frequently has been jointed with 6–31G (d) basis set to explore different properties of nanostructures [51–65]. Geometry optimizations, adsorption energies (Ead), molecular electrostatic potential (MEP), natural bond orbitals (NBO) and electronic properties such as the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and the HOMO-LUMO energy gaps (Eg) were carried out using GAMESS program package at the same level of theory [66]. GaussSum program [67] was used to draw density of states (DOS) plots. We have done vibrational frequency calculations to make sure that all optimized structures correspond to the global minima on the potential energy surface. The values of Ead for the optimized complexes were obtained by following equation:
The optimized structures of the 9 studied complexes of isoniazid and C30B15N15 are presented in Fig. 2. The bond lengths between the interaction sites are about 1.60, 1.64 and 1.65 Å for different involving heads of isoniazid. The distances are almost identical for all three types of boron atoms. The values of Ead and the BSSE corrected Ead are listed in Table 1, indicating that the adsorptions from −NH2 head group of isoniazid on the boron atoms are the most favorable interaction between isoniazid and C30B15N15 molecules. The nitrogen in −NH2 group has a lone pair and tends to react with boron atom as a Lewis base. The values of Ead as well as the bond lengths show that there is a negligible chemical difference between boron atoms in the C30B15N15. Therefore, we assumed that all boron atoms are identical and focused on the boron type C. The BSSE corrected Ead values are about −7.58, −17.70 and −21.91 kcal mol−1 for C1, C2 and C3 complexes, showing that there are relatively strong interactions between the reactants. Complex C3 with the most negative value of Ead is the most stable complex between all the studied complexes. Table 1 indicates that the effect of the BSSE correction on the weaker interaction is larger.
Ead = E(Isoniazid /C30 B15 N15) – E(Isoniazid) − E(C30 B15 N15) + BSSE (1) where E(Isoniazid /C30B15N15) is the energy of the complex between isoniazid and the C30B15N15 heterofullerene. The counterpoise method of Boys and Bernardi was used to calculate the basis set superposition error (BSSE) energy for all studied complexes [68]. Moreover, to predict the charge transfer between the isoniazid molecule and C30B15N15, we accomplished NBO analysis.
3.3. The electronic properties The results of DFT calculations reported in Table 1 and partial DOS plot in Fig. 3 show that C30B15N15 heterofullerene is a semiconductor with an Eg value about 0.96 eV in which the HOMO and LUMO energies are about −4.52 and −3.56 eV, respectively. This is in good agreement with the previously reported value [10]. Interestingly, PDOS plot demonstrates that the N atoms which are much more electronegative atoms with a lone pair (Lewis base) significantly contribute in the generation of occupied orbitals. While the electron deficient boron atoms are mainly responsible of virtual orbital creation which is in consistence their Lewis acid character. Carbon atoms with a moderate electronegativity contribute in both occupied and virtual orbitals. In complex C1, after the interaction, the HOMO level of the cage is slightly shifted to more positive value and the LUMO level is shifted from −3.56 to −4.03 eV. Thus, the Eg is decreased by about 11% from 0.96 to 0.88 eV. The changes in HOMO, LUMO and Eg in complex C2 are similar to those in the complex C1. For the complex C3, while HOMO level is slightly shifted to higher positive value, there is a
3. Results and discussion 3.1. Structure and properties of isoniazid and C30B15N15 The C30B15N15 heterofullerene consists of four types of hexagonal and three types of pentagonal rings which are shown as H1-H4 and P1P3 in Fig. 1. It is a polar molecule with a dipole moment about 3.39 D. The calculated equilibrium C–C bond lengths in C30B15N15 are about 1.42 Å, being comparable with those of C60 fullerene (~1.41 Å [69]). The average C–B, C–N and B–N bond lengths are about 1.54 Å, 1.44 Å and 1.47 Å, respectively. Depending on the position of atoms in the structure of C30B15N15 fullerene, there are three types of boron atoms
Fig. 1. (a) The optimized structure of C30B15N15 heterofullerene consists of four types of hexagonal (H1-H4) and three types of pentagonal (P1-P3) rings. Different types of boron atoms (A, B and C) are marked by red, green and orange circles. (b) The optimized structure of the isoniazid molecule and its MEP plot. Different active sites are determined by 1, 2 and 3. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).
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Fig. 2. The optimized structures of the studied complexes of C30B15N15 heterofullerene and isoniazid.
significant shift in the energy of the LUMO level (from −3.56 to −2.99 eV). Thus, in contrast to the complexes C1 and C2, the Eg in the complex C3 is increased by about 32% (from 0.96 to 1.27 eV). These changes in the Eg values will alter the fluorescence emission of the C30B15N15 after interaction with the drug and it can help to trace the drug trajectory by the spectrophotometers in the body. The HOMO and LUMO profiles, and the DOS plots for the complexes C1, C2 and C3 are shown in Fig. 1S (Supplementary materials). One can clearly see that in contrast to complex C3, the LUMO levels in complexes C1 and C2 are located on the drug. In complex C3, the electron lone pair of the −NH2 group is free enough to interact with the electron deficient boron atoms easily. While the electron lone pairs of oxygen and nitrogen atoms are much involved in the resonance, thus, the interactions between the drug and C30B15N15 are less favorable in complexes C1 and C2. The obtained values of adsorption energies also confirm these results. Therefore, the attachment from the −NH2 group to the boron site of C30B15N15 (complexes A3, B3 and C3) is the main mechanism of the drug adsorption. The length of newly formed B-N bonds in these complexes are about 1.65 Å.
Table 1 The calculated adsorption energy (Ead) and BSSE corrected Ead (EBSSE) in kcal mol−1, HOMO, LUMO energies, and HOMO-LUMO energy gap (Eg) of bare C30B15N15 cage and the isoniazid and C30B15N15 complexes in eV. System
Ead
EBSSE
HOMO
LUMO
Eg
%ΔEg
Q (e)
C30B15N15 A1 A2 A3 B1 B2 B3 C1 C2 C3
– −9.36 −20.82 −25.14 −12.95 −22.06 −26.12 −13.97 −21.95 −26.79
– −3.52 −16.61 −20.30 −6.89 −17.94 −21.85 −7.58 −17.70 −21.91
−4.52 −4.01 −4.02 −4.21 −4.08 −4.02 −4.32 −4.03 −4.02 −4.26
−3.56 −3.15 −3.22 −3.23 −3.09 −3.15 −3.19 −3.15 −3.19 −2.99
0.96 0.86 0.80 0.98 0.99 0.87 1.13 0.88 0.83 1.27
– −10.42 −16.67 2.08 3.12 −9.37 17.71 −11.11 −13.54 32.29
– 0.251 0.298 0.235 0.242 0.294 0.222 0.248 0.289 0.235
3.4. Quantum molecular description and population analysis The electrophilicity indices (ω) are computed as a descriptor of charge transfer direction. So that, the higher values of ω, the higher electrophilicity of the structure [70]. We have calculated ω by using the following equations:
μ = (EHOMO+ELUMO )/2
(2)
η = [−EHOMO−(−ELUMO )]/2
(3)
ω=μ2/2η
(4)
Fig. 3. The partial density of states (PDOS) plot for C30B15N15 heterofullerene.
where μ is electronic chemical potential and η chemical hardness of the 74
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potential application of this fullerene as a drug carrier. We showed that the most favorable state is the interaction of –NH2 group of the drug with the B atoms of the fullerene with adsorption energy of about −21.96 kcal/mol. The electronic properties of the fullerene show a high sensitivity toward the drug which can help one to detect the trajectory of the drug in the body because of the change of fluorescence emission properties of the cluster in the presence of the drug. An interaction mechanism change is predicted from covalent bonding in blood to hydrogen bonding in cancer tissue. This indicates that the isoniazid can be separated from the C30B15N15 carrier in the low pH of cancerous tissues by proton attack. The energy of the hydrogen bonding is predicted be very low about 11.30 kcal/mol.
Table 2 Quantum molecular descriptors (in eV) and the charge transfer for complexes C1, C2 and C3. System
μ
η
ω
QMulliken (e)
QNBO (e)
C1 C2 C3
−3.59 −3.60 −3.62
0.43 0.41 0.63
14.69 15.61 10.37
0.248 0.289 0.235
0.306 0.338 0.346
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Fig. 4. The optimized structure of protonated isoniazid (C6H8N3O+) and C30B15N15, showing separation from each other in the acidic environment. Distances are in Å.
ground state. The results are summarized in Table 2. A higher value for Eg indicates more stability and low reactivity of the complex [71]. In the complex C3 the electrophilicity of the complex (10.37) is less than that of the complexes C1 and C2 (14.69 and 15.61, respectively). Hence, in complex C3, the drug adsorption on the C30B15N15 heterofullerene decreases the electrophilicity and enhance the stability of the cage. Furthermore, NBO theory has been performed to analyze the characteristic of interactions at the active sites of isoniazid and C30B15N15. For all complexes, there is a charge transfer from the isoniazid drug to the C30B15N15 cage. Based on NBO analysis, in the complex C3, a charge about 0.346 e is transferred from the isoniazid to the cage which is larger than that which occurred in the case of complexes C1 and C2. 3.5. Drug release We showed that the C30B15N15 heterofullerene is somewhat suitable for the isoniazid drug adsorption which is the first and the most significant step in the drug delivery process. However, one of the most challenging steps in drug delivery is drug release from the carrier in the target cell. As a matter of fact, the pH of the tumor cells is less than the normal cells and therefore, the cancerous tissues have an acidic environment (~pH < 6) [72]. We examined the effect of pH on the most stable complex between the C30B15N15 heterofullerene and the isoniazid drug (complex C3). We assumed that H+ species will intensively tend to attach to the nucleophilic heads of the isoniazid drug and C30B15N15 cage. Therefore, we protonated the −NH2 group of isoniazid, and carried out the optimization calculations. As a result, the Ead in the acidic environment increases from −21.91 to −11.30 kcal mol−1 and the distance between the drug and the C30B15N15 heterofullerene increase to 3.72 Å. Also the nature of the interaction is changed from a covalent to the hydrogen bonding as shown in Fig. 4. Hence, the drug is separated from the carrier by proton attack as shown in Fig. 4. As a result, we have shown that in an acidic environment the drug cannot attach to the carrier and has to be released. 4. Conclusions Using DFT calculations, we have studied the isoniazid drug attachment and release to C30B15N15 heterofullerene to investigate the 75
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