Download Theoretical prediction of encapsulation and adsorption of platinum

Theoretical prediction of encapsulation and
adsorption of platinum-anticancer drugs
into single walled boron nitride and carbon
nanotubes
Zabiollah Mahdavifar & Rezvan
Moridzadeh
Journal of Inclusion Phenomena and
Macrocyclic Chemistry
and Macrocyclic Chemistry
ISSN 1388-3127
Volume 79
Combined 3-4
J Incl Phenom Macrocycl Chem (2014)
79:443-457
DOI 10.1007/s10847-013-0367-1
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J Incl Phenom Macrocycl Chem (2014) 79:443–457
DOI 10.1007/s10847-013-0367-1
ORIGINAL ARTICLE
Theoretical prediction of encapsulation and adsorption
of platinum-anticancer drugs into single walled boron nitride
and carbon nanotubes
Zabiollah Mahdavifar • Rezvan Moridzadeh
Received: 8 July 2013 / Accepted: 6 October 2013 / Published online: 13 October 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract In this research, the adsorption and encapsulation of cisplatin, nedplatin, oxaliplatin and carbaplatin as
Pt-anticancer drugs into the (7,7) boron nitride nanotube
(BNNT) and carbon nanotube (CNT) are investigated using
density functional theory. The different orientation modes
of drug molecules onto the outer and inner surfaces of
BNNT and CNT are studied. Analysis of the adsorption
energy reveals that the complex formation process is
favorable. The calculated adsorption energies indicate that
the encapsulation of drugs inside the nanotubes is more
favorable than the adsorption of drugs outside of the
nanotubes. On the other hand, the results show that the
BNNT/oxaliplatin(in) system is more stable than the others. The stabilization of nanotube/drug complexes results in
electronic and structural properties change in the nanotubes. The natural bond orbital calculations show that the
van der Waals forces, hydrogen bonding and electrostatic
interactions are the major factors contributed to the overall
stabilities of the complexes. The predicted electronic and
structural properties of BNNT compared to the CNT
towards Pt-anticancer drugs, suggest that BNNT can act as
drug delivery vehicles.
Keywords Pt-anticancer drug Encapsulation Adsorption BNNT DFT
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-013-0367-1) contains supplementary
material, which is available to authorized users.
Z. Mahdavifar (&) R. Moridzadeh
Computational Chemistry Group, Department of Chemistry,
Faculty of Science, Shahid Chamran University, Ahvaz, Iran
e-mail: [email protected]; [email protected]
Introduction
Medicinal application of metals can be traced back almost
5,000 years [1]. Metal centers, being positively charged,
favorably bind to negatively charged biomolecules; the
constituents of proteins and nucleic acids offer excellent
ligands for binding to metal ions [2]. The accidental discovery of the antitumor properties of cis-diamminedichloroplatinum (II) (cisplatin) are made by Rosenberg et al.
[3–5] while examining the influence of electric current on
bacterial growth. Cisplatin is the modern inorganic medical
chemistry that has been used as anticancer drug for three
decades [6–8]. Over the past 30 years, platinum-based
drugs, such as cisplatin, nedaplatin and oxaliplatin dominated the treatment of various solid tumors (such as lung,
ovary, testis, urinary bladder and neck cancers) [9]. The
success of cisplatin created the way for developing other
platinum (II) drugs, nedaplatin, including carbaplatin and
oxaliplatin [10]. All of platinum drug have similar structure, so, their mode of action is the same such as the prevention of DNA transcription and replication leading to
cellular apoptosis [11]. But there is a challenge, that,
cancer chemotherapeutic agents are cytotoxic and rarely
differentiate cancer cells from normal cells. They therefore,
affect both cancerous and normal cells, and may lead to the
destruction or impairment of vital organs [12]. In cancer
therapy, a major challenge is to deliver anticancer drug
molecules precisely to tumor sites for maximum treatment
efficacy while minimizing side effects to normal organs
[13, 14]. In recent years, advanced drug delivery systems
have been investigated that hold great promise for
improving cancer therapy outcomes [15–18]. Drug carrier
systems such as nanoparticles can be developed using
specific interactions between receptors on the cell surface
and targeting moieties conjugated to surface of drug
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carriers. In this way, therapeutic drugs conjugated to
therapeutic can be effectively transported to tumor cells. At
present, selectively goal drug delivery systems still face
challenges including improving specificity and stability,
regulating bioavailability, and developing targeting lower
toxicity carriers [19–23]. Therefore, it is important to
develop novel effective tumor-targeted drug delivery
systems.
One important application of nanotechnology is that of
drug delivery, and in particular the targeted delivery of
drugs using nanotubes. The use of nanomaterials in the
drug delivery is set to spread rapidly. Currently many
materials are under investigation for drug delivery and
more specifically for cancer therapy [24]. A suitable
understanding of the encapsulation behavior of drug molecules into nanotubes is fundamental for the development
of nanoscale drug delivery vehicles. Furthermore, there are
many other materials which may form single-walled
nanotubes, such as carbon, boron nitride and silicon [8],
and it is also important to understand their specific
advantages and disadvantages. Nanomaterials such as
nanotubes as a drug delivery system can protect the drugs
from degradation. Interestingly medical sciences are using
nanomaterials to reduce toxicity and side effects of drugs
and until recently, did not realize that carrier systems
themselves might impose risks to the patient [25].
Carbon nanotubes (CNTs) have shown great promise in
biomedical, environmental applications and as nanoscaled
vehicles for targeted drug delivery [26, 27]. A great number of literature studies indicate that single-walled carbon
nanotubes (SWCNTs) are potentially excellent delivery
agents for cancer fighting drugs [12, 28–30]. One of the
main advantages of the CNT is its ability to deliver drugs
directly to cancer cells [31, 32]. In comparison to CNTs,
boron nitride nanotubes (BNNTs) exhibit improved electronic properties, high chemical stability, improved biocompatibility, and high resistance to oxidation at high
temperatures [33]. In comparison, BNNTs have shown
superior water permeation properties compared to CNTs of
similar diameter and length [34]. BNNTs nontoxic to
health and environment due to their chemical inertness,
structural stability, and therefore they are more appropriate
for medical applications such as drug delivery [35]. To
date, biomedical applications of BNNTs remain largely
unexplored. Ciofani et al. [36–38] initiated the first biocompatibility tests on BNNTs. Chen et al. [39] used pristine BNNTs for in vitro tests although the authors formed
aggregates in the culture media. The experimental results
for BNNTs do not appear to inhibit cell growth or induce
apoptotic pathways in the HEK 293 cells. These studies
demonstrated relevant safety of BNNT, which may have
potential applications in the biological systems where the
toxicity of CNTs is a problem. Explorations of BNNTs’
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bio-applications have just been started, only a few works
have been reported [35].
Density functional theory (DFT) has been applied to
quantitatively predict chemical properties [40] such as
chemical potential (l) and hardness (g), in the study of
molecular systems. Parr et al. [41] interpreted l and g as
the first and second partial derivatives of electronic energy
(E) with respect to the number of electrons (N) at a fixed
external potential (t(r)), respectively. According to the
Janak’s approximation [42], their analytical and operational definitions are given as follows:
oE
ðeL þ eH Þ
l¼
ð1Þ
ffi
oN tðr~Þ; T
2
1 o2 E
ðeL eH Þ
g¼
ð2Þ
ffi
2 oN 2 tðr~Þ; T
2
where eH and eL are the obtained energies of the highest
occupied molecular orbital (HOMO) and the lowest
unoccupied molecular orbital (LUMO) from DFT
calculations, respectively. Parr et al. [43] have defined an
index for the global electrophilicity power of a system in
terms of the chemical potential and hardness as:
x¼
l2
2g
ð3Þ
which was proposed as a measure of the electrophilic
power of a molecule.
The objective of the present study is to examine the
properties of encapsulation and adsorption of Pt-anticancer
drugs into the armchair (7,7) BNNTs and CNTs using DFT
calculations. The stabilization energy, structural parameters and electronic properties of pristine components and
nanotube/drug systems are also investigated. The results
may provide new insights to the delivery agents for cancer
fighting drugs.
Computational method
The encapsulation and adsorption of Pt-anticancer drugs
into BNNT and CNT were investigated within the framework of density function theory. The calculations were
carried out without any symmetry constraints using the
spin-polarized generalized gradient approximation (GGA)
with the modified Perdew-Wang91 exchange [44] plus the
Perdew-Wang91 correlation (MPW1PW91) [45]. The
mixed basis set LANL2DZ [46] for Pt atom in conjunction
with the conventional 6-31G(d) basis set for all other atoms
were employed. Two metal armchair nanotubes (NT) with
comparable diameter (10 Å), length (about 15 Å) and
chirality, i.e., finite (7,7) BNNT and CNT which is depicted
in Fig. 1, are chosen. The two ends of BNNT and CNT are
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Fig. 1 Fully optimized
structures of: a BNNT, b CNT,
c Cisplatin, d Nedaplatin,
e Oxaliplatin and f carbaplatin
using MPW1PM91/6-31G
terminated with hydrogen atoms. Furthermore, the natural
bonding orbitals (NBO) calculations [47] are performed
using NBO 3.1 program as implemented in the G03
package [48] at the above-considered method. All the
calculations were performed with the G03 program
package.
The adsorption of drug molecules into the outer and
inner surfaces of BNNT and CNT was considered. The
parallel and perpendicular orientations of anticancer drugs
into the outer surface of nanotubes were investigated. The
cisplatin anticancer drug approaches to the outer surface of
CNT and BNNT through two different modes approach: (1)
with amine group and (2) with Cl group into the nanotube
surface. Therefore, the effect of amine and Cl groups of
cisplatin on the adsorption process was considered. For the
encapsulation of drug molecules into the inside of nanotubes, the best position of drug molecules was determined
by the Z coordinates of the nanotubes. The Z = 0 point
(centre of the Cartesian coordinates) was chosen in the
centre of nanotubes. The inclusion processes are simulated
by putting the drugs in one end of nanotube and then letting
it pass through the nanotube by steps. In every step, single
point calculations were used to obtain the heat of formation
of the nanotube/drug complexes. Based on our calculations, the potential energy surfaces (see Fig. S1 in Supplementary material) as well as the intermolecular
nanotube/drug distance were also obtained. Figure S1
shows the best position of the drug molecules into the
inside of the BNNT and CNT nanotubes.
In order to understand the nanotube/drug interactions,
the adsorption energy (Eads) of drug onto nanotubes is
defined as:
Eads ¼ Etubedrug ðEtube þ Edrug Þ
ð4Þ
where Etube/drug denotes the total energy of the adduct
BNNT and CNT with the corresponding drugs molecule
and Etube and Edrug are the total energies of the isolated
nanotube and drug molecules, respectively. According to
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Table 1 HOMO, LUMO, gap energy, D (eV), Hardness, g (eV), Electrophilicity, x (eV) and the difference between the energies of frontier
orbitals, DEF.O (eV) of pristine nanotubes and drugs
Type
HOMO
LUMO
D
g
x
DF.O (NTHOMO-drug
DF.O(drugHOMO-NTLUMO)
LUMO)
BNNT
CNT
BNNT
CNT
–
BNNT
-6.800
-0.033
6.767
6.767
0.862
–
–
–
CNT
-4.299
-3.140
1.159
1.159
5.967
–
–
–
–
Cisplatin
Nedaplatin
-6.470
-5.48
-1.317
-0.262
5.153
5.218
5.153
5.218
1.471
0.79
5.483
6.538
2.982
4.037
6.437
5.447
3.33
2.34
Oxaliplatin
-5.735
-0.377
5.358
5.358
0.872
6.423
3.922
5.702
2.595
Carbaplatin
-6.234
-0.551
5.683
5.683
1.013
6.249
3.748
6.201
3.094
Table 2 Adsorption energy (Eads), interaction energy (Eint), deformation energy (Edef) (kJ/mol) and nearest intermolecular distance, r(Å), of
drugs adsorption onto the BNNT and CNT
Type
Eads kj/mol)
Edef
Edef
NT
drug
Edef
Eint
Bond
re (Å)
BNNT/Cisplatin (in)
-34.309
10.874
2.724
13.599
-47.907
N3–H
2.713
BNNT/Cisplatin (N-vertical)
-26.853
3.573
0.958
4.531
-31.384
N3–H
2.332
BNNT/Cisplatin (Cl-vertical)
-26.062
3.635
1.557
5.192
-31.253
N3–H
2.377
BNNT/Cisplatin (horizontal)
-29.953
4.213
0.657
4.866
-34.819
N3–H
2.365
CNT/Cisplatin (in)
-61.417
1.354
2.377
3.732
-65.153
C1–H
2.606
CNT/Cisplatin (N-vertical)
-25.376
0.113
0.494
0.602
-25.978
C1–H
2.904
CNT/Cisplatin (Cl-vertical)
BNNT/Nedaplatin (in)
3.038
-63.885
0.008
7.883
0.000
3.711
0.008
11.594
3.025
-75.479
C1–Cl
N3–H
4.256
2.626
BNNT/Nedaplatin (vertical)
-21.292
42.191
11.744
53.936
-75.228
N3–H
2.450
BNNT/Nedaplatin (horizontal)
-27.794
3.548
1.607
5.151
-32.945
N3–H
2.455
CNT/Nedaplatin (in)
-64.455
2.121
5.297
7.418
-71.871
C3–H
2.690
CNT/Nedaplatin (out)
-22.640
-0.289
0.527
0.238
-22.878
C3–H
2.807
CNT/Nedaplatin (horizontal)
-21.118
0.234
0.496
0.730
-21.848
C3–H
2.664
BNNT/Oxaliplatin (in)
-98.111
10.025
1.845
11.874
-109.985
N3–H
2.606
BNNT/Oxaliplatin (I)
-42.815
5.272
1.004
6.276
-49.091
N3–H
2.597
BNNT/Oxaliplatin (G)
-40.966
8.565
1.121
9.686
-50.652
N3–H
2.500
BNNT/Carbaplatin (in)
-59.450
12.832
-8.703
4.13
-63.580
N3–H
2.457
CNT/Carbaplatin (I)
-40.622
0.134
-12.242
-12.108
-28.501
C7–H
2.785
CNT/Carbaplatin (G)
-30.506
0.226
-12.364
-12.138
-18.368
C7–H
2.610
the Eq. 4, a negative adsorption energy indicates that the
complex formed is stable and positive adsorption energy
belongs to the local minimum where the adsorption of drug
molecule onto the nanotubes is prevented by a barrier. The
adsorption energy encompasses both interaction (Eint) and
deformation (Edef) energy contributions, which both occur
during the adsorption process. The following equations are
applied to calculate these contributions
Eads ¼ Edef þ Eint
ð5Þ
Eint ¼ Etube=drug ðEtube in complex þ Edrug in complex Þ
ð6Þ
Edef ¼ Edef drug þ Edef tube
ð7Þ
where Etube in complex and Edrug in complex is the total energy
of tube and drug molecule in complexes respectively. Also,
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Edef tube and Edef drug is the deformation energy of tube and
drug molecule in complexes respectively
Results and discussion
The geometry optimization of pristine armchair (7,7)
BNNT and CNT is performed at MPW1PW91/631G(d) level of theory. The calculated average B–N and
C–C bond lengths of BNNT and CNT were 1.44 and
1.42 Å, respectively in good agreement with the data of
other works [49, 50]. In addition, to test the validity of our
calculations methods, the calculated structural and electronic properties of cisplatin were compared with results of
experimental [51] and theoretical [52] research works. The
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Fig. 2 Final optimized
geometries of cisplatin
adsorption onto the BNNT,
a outside and b inside of the
BNNT
structural and electronic properties of cisplatin are well
reproduced. The obtained electronic properties of each
component are listed in Table 1. The final optimization
geometries of pristine nanotubes and anticancer drugs are
presented in Fig. 1. To investigate the adsorption of anticancer drugs into the outer surface of nanotubes, different
orientations of drug including perpendicular and parallel
were considered. Furthermore, the encapsulation of anticancer drugs inside the nanotubes was investigated.
Molecular geometry and adsorption properties of Ptdrugs into nanotubes
First, the interaction of cisplatin with CNT and BNNT was
investigated. To test the adsorption properties of anticancer
drugs into the nanotubes, the adsorption energies were
calculated using Eq. 4. The calculated adsorption energies
and intermolecular distances of Pt-drug molecules and tube
walls are summarized in Table 2. The relaxed geometries
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Table 3 Compared selected
bond lengths (Å) of optimized
geometries of pristine drugs and
drug in complexes calculated by
MPW1PW91/6-31G(d) level of
theory (atom numbering is
according to Fig. 1)
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Type
Pt–N1
Pt–Cl1
Pt–O2
C2–O2
C3–C4
Cisplatin
2.089
2.324
–
–
–
BNNT/Cisplatin (in)
2.078
2.377
–
–
–
BNNT/Cisplatin (N-vertical)
2.081
2.328
–
–
–
BNNT/Cisplatin (Cl-Vertical)
2.089
2.324
–
–
–
BNNT/Cisplatin (horizontal)
2.085
2.329
–
–
–
CNT/Cisplatin (in)
2.076
2.336
–
–
–
CNT/Cisplatin (N-vertical)
2.081
2.330
–
–
–
CNT/Cisplatin (Cl-vertical)
2.089
2.324
–
–
–
Nedaplatin
2.089
–
1.976
1.331
–
BNNT/Nedaplatin (in)
2.072
–
1.993
1.321
–
BNNT/Nedaplatin (vertical)
BNNT/Nedaplatin (horizontal)
2.086
2.082
–
–
1.982
1.984
1.328
1.328
–
–
CNT/Nedaplatin (in)
2.070
–
1.989
1.317
–
CNT/Nedaplatin (vertical)
2.083
–
1.981
1.328
–
CNT/Nedaplatin (horizontal)
2.084
–
1.983
1.328
–
Oxaliplatin
2.089
–
1.983
1.325
–
BNNT/Oxaliplatin (in)
2.073
–
2.001
1.315
–
BNNT/Oxaliplatin (I)
2.084
–
1.992
1.319
–
BNNT/Oxaliplatin (II)
2.074
–
1.996
1.315
–
Carbaplatin
2.089
–
1.968
1.320
1.574
BNNT/Carbaplatin (in)
2.070
–
1.989
1.316
1.541
CNT/Carbaplatin (I)
2.080
–
1.984
1.321
1.541
CNT/Carbaplatin (II)
2.081
–
1.984
1.320
1.541
of the complexes formed are also depicted in Figs. 2 and 4.
As can be seen in Table 2, most of the calculated adsorption energies are negative, which means that the adsorption
process is favorable. In one case, the adsorption energy is
positive, which corresponds to the local minimum where
the adsorption of cisplatin onto the outer surface of CNT is
prevented by a barrier. Evaluations of adsorption energies
in different situations give some interesting information.
First, when the cisplatin vertically approaches to the outer
surface of CNT with amine group, the CNT/cisplatin system is more stable than if the Cl group of cisplatin
approaches to the outer surface of CNT (see Fig. S2).
These results suggest that the cisplatin can adsorb onto the
outer surface of CNT through amine group. In this situation, the Cl group of cisplatin is free and can replace a
water molecule if the adsorption process occur in the
solution phase [10, 53]. Second, the most negative
adsorption energy is related to the encapsulation of cisplatin inside of CNT with -61.417 kJ/mol, which means
that the cavity of CNT is favorable for encapsulation of
cisplatin. Furthermore, the CNT/cisplatin(in) complex is
more stable than those other systems. The second lowest
adsorption energy is relevant to the encapsulation of
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Bond length (Å)
cisplatin inside of BNNT with -34.309 kJ/mol. The
intermolecular distances between walls of CNT and BNNT
in two above considered complexes are 2.606 and 2.713 Å,
respectively (see Table 2).
The adsorption of cisplatin on the outer surface of
BNNT through two different orientations, vertically and
horizontally, was also considered. Furthermore, the effect
of the amine and Cl groups on the adsorption of cisplatin
into the BNNT surface was investigated. The final optimization geometry of BNNT/cisplatin systems indicate that
the vertical mode through amine or Cl groups approaches
to BNNT surface, converges to the horizontally mode,
which means the drug in the horizontally orientation can
more strongly interact with the BNNT surface. This result
is in agreement with the result of the adsorption energy.
The adsorption energy gained of horizontally orientation is
about -29.953 kJ/mol. The initial and final optimization
geometries of the BNNT/cisplatin are depicted in Fig. 2.
Here the hydrogen interaction between amine group of
drug and nitrogen atom of BNNT surface and the charge
transfer between nanotubes and cisplatin (will be discussed
in the NBO section) are the major factors contributed to the
overall stabilities of complexes formed. From the final
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optimization geometry of BNNT/cisplatin(in) system, it is
clear that the cisplatin is located in the entrance of the
nanotube because of high reactivity of two ends of the
nanotubes (see Fig. 2 and 2S). To investigate the geometry
of cisplatin, the structural parameters such as bond lengths
and bond angles of cispltin in considered complexes are
also investigated. These results are collected in Table 3 and
Table S1. As can be seen in Table 3, the bond lengths and
bond angles of cispltin in considered complexes is nearly
constant compared to free cisplatin. For example, the value
of Pt–N1 bond in pristine cisplatin and cisplatin in BNNT/
cisplatin(in) complex is 2.089 and 2.078 Å respectively. In
the case of CNT/cisplatin(in) complex, the Pt–N1 bond is
2.076 Å (see Table 3). Furthermore, the bond angles of
cisplatin such as Cl1–Pt–Cl2, N1–Pt–Cl1 and N1–Pt–N2
remained constant. Details of bond angles are summarized
in Table S1 in the Supplementary material section. These
results indicate that there is no significant changed is
observed in the geometry of cisplatin during the complex
formations.
Next, the adsorption and encapsulation of nedaplatin
anticancer drug into the CNT and BNNT was considered.
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Since the nedaplatin can act on the DNA with bidentate
ligand [54], the adsorption of nedaplatin through the amine
group approach to the nanotube walls was considered. The
calculated adsorption energy which is depicted in Table 2,
show the more negative values is related to the encapsulation of this drug into the CNT and BNNT. Note that the
vertically nedaplatin orientation changes to the horizontally
mode after full optimization of BNNT/nedaplatin systems.
Thus the horizontally mode is favorable for nedaplatin to
form a stable complex with BNNT surface (adsorption
energy of -23.640 kJ/mol). The adsorption energies of
nanotube/nedaplatin systems indicate that when the nedaplatin molecule encapsulated inside of considered
nanotubes, the complexes formed are more stable than the
nedaplatin adsorbed outside of CNT and BNNT. The
nearest intermolecular distances between drug atoms and
nanotube walls are about 2.6 Å (see Table 2). The formed
complexes are stabilized by the hydrogen interaction
between nedaplatin and nanotube walls. The final optimized geometries are shown in Figs. 3 and 4. In conclusion, the BNNT and CNT can act as drug carrier and
protected the drug from degradation, because no significant
Fig. 3 Final optimized
geometries of nedaplatin
adsorption onto the BNNT,
a vertical, b horizontal and
c inside of BNNT
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Fig. 4 Final optimized
geometries of nedaplatin
adsorption onto the a outside
b inside of the CNT and final
optimized geometries of
carbaplatin adsorption with two
different c horizontal and
d vertical modes onto the
outside of the CNT
change has been observed in the drug structure. Furthermore, according to the results of the Thable 3 and Table S1,
it can be seen that Similar to the cisplatin, there is no
significant changed occurred in the geometry of nedaplatin
drug during the complex formations.
The complex formation of oxaliplatin with BNNT in
three different drug orientations was also investigated. The
most negative adsorption energy gained belongs to BNNT/
oxaliplatin(in) system. The adsorption energy for this system is -98.111 kJ/mol (Table 2). The final optimization
geometries of BNNT/oxaliplatin(in) system indicate that
the drug is located at the end of the nanotube due to the
high reactivity of the two ends of nanotube. For the
adsorption of oxaliplatin on the outside of the BNNT, the
drug is oriented horizontally through two different modes
(I and II), which is depicted in Fig. 5. The final optimization structures reveal that the mode II converges to the
mode I. The calculated adsorption energies is about
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-41.5 kJ/mol for BNNT/oxaliplatin(in)system and the
shortest distances between drug and nanotube are about
2.56 Å (see Table 2).
The complex formation of carbaplatin anticancer with
BNNT and CNT was also examined. Oxaliplatin approaches the outer surface of the CNT with two different horizontally and vertically orientations, as shown in Fig. 4.
That the calculated adsorption energies which is depicted
in Table 2 are negative means the complexes formed are
more stable. In comparison, the adsorption energies of
carbaplatin drug encapsulate inside of BNNT and CNT
show that when the carbaplatin encapsulate inside of
BNNT, the formed complex is more stable than the carbaplatin encapsulate inside of CNT. The adsorption energy
gained for BNNT/carbaplatin(in) system is about
-59.451 kJ/mol. After full optimization, the relaxed
geometries indicate that carbaplatin is located at the
entrance to the nanotubes (see Figs. 4, 5). Considering the
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Fig. 5 Final optimized
geometries of oxaliplatin
adsorption onto the outside of
the BNNT a mode I, b mode II,
c inside of the BNNT and final
optimized geometries of
carbaplatin adsorption onto the
d inside of the BNNT
intermolecular distances between nanotubes and carbaplatin (Table 2), demonstrates that the shortest intermolecular
distance is related to the BNNT/carbaplatin. In addition,
the shortest intermolecular distance for in all complexes
belongs to the H atom of amine group of drugs and N or C
atoms of BNNT and CNT, respectively (see Figs. 2, 3, 4,
5). These results showed that the hydrogen bonding is the
major factor contributing to the overall stabilities of the
complexes.
The structural change in the BNNT, CNT and Pt-drugs
is an important factor contributing to the formation of
complexes in the adsorption or encapsulation processes of
Pt-drugs into the BNNT and CNT. Therefore, the deformation energy of nanotubes and drugs in the nanotube/drug
systems were studied. The adsorption energy encompasses
both interaction (Eint) and deformation (Edef) energy
contributions, since are both occur during the adsorption
process. The deformation and interaction energies of
nanotube/drug systems are calculated using Eqs. 6 and 7
(see Table 2). The results are interesting. First, the curvature in the structure of BNNT is more than the CNT.
Second, when the drug molecule is adsorbed on or
encapsulated in the BNNT or CNT, the deformation energy
of drugs in the BNNT/drug systems are less than the CNT/
drug systems, which means the curvature in the geometry
of drugs in the BNNT/drug systems is significantly smaller
than the CNT/drug systems. Thus, the BNNT can better
protect the geometries of drug compared to CNT. In other
words, the BNNT can act as good career for Pt-anticancer
drugs without significantly changing the geometry of
drugs. To compare the structural parameters of pristine
drugs and the drugs in formed complexes, the data are
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Table 4 Calculated partial
charges of Pt, Cl, N, O, and H
atoms of pristine anticancer
drugs and drug in complex
(atom numbering is according to
Fig. 1)
J Incl Phenom Macrocycl Chem (2014) 79:443–457
Type
Pt
Cl1
N1
O2
O3
H2
Cisplatin
0.241
-0.399
-1.029
–
–
0.428
BNNT/Cisplatin (in)
0.301
-0.423
-1.032
–
–
0.435
BNNT/Cisplatin (N-vertical)
0.244
-0.411
-1.024
–
–
0.436
BNNT/Cisplatin (horizontal)
0.243
-0.408
-1.025
–
–
0.436
CNT/Cisplatin (in)
0.266
-0.435
-1.019
–
–
0.431
CNT/Cisplatin (N-vertical)
0.250
-0.416
-1.022
–
–
0.430
CNT/Cisplatin (Cl-vertical)
0.241
-0.399
-1.029
–
–
0.428
Nedaplatin
0.511
–
-1.042
-0.700
-0.631
0.227
BNNT/Nedaplatin (in)
0.538
–
-1.028
-0.696
-0.659
0.222
BNNT/Nedaplatin (vertical)
0.512
–
-1.038
-0.701
-0.638
0.225
BNNT/Nedaplatin (horizontal)
0.527
–
-1.036
-0.698
-0.640
0.224
CNT/Nedaplatin (in)
0.530
–
-1.029
-0.696
-0.671
0.216
CNT/Nedaplatin (vertical)
0.514
–
-1.035
-0.701
-0.640
0.224
CNT/Nedaplatin (horizontal)
0.515
–
-1.035
-0.700
-0.641
0.222
Oxaliplatin
BNNT/Oxaliplatin (in)
0.547
0.675
–
–
-0.837
-0.856
-0.677
-0.730
-0.579
-0.600
0.449
0.450
BNNT/Oxaliplatin (I)
0.572
–
-0.836
-0.677
-0.593
0.447
BNNT/Oxaliplatin (II)
0.568
–
-0.832
-0.671
-0.586
0.457
Carbaplatin
0.562
–
-1.045
0.698
-0.638
0.259
BNNT/Carbaplatin (in)
0.711
–
-1.056
-0.745
-0.629
0.245
CNT/Carbaplatin (I)
0.563
–
-1.037
-0.704
-0.622
0.245
CNT/Carbaplatin (II)
0.563
–
-1.042
-0.706
-0.618
0.246
collected in Tables 3 and S1 (see Supplementary material
for Table S1). As can be seen in Tables 3 and S1, there is
no significant change observed in the structural parameters
of drugs in complexes compared to the pristine drugs.
These results indicate that the structural geometries of the
drugs remains nearly constant and these results are in well
agreement with the results of the small deformation energy
of drugs.
NBO analysis
Natural bond orbital (NBO) analysis provides an impressive method for studying intra- and intermolecular bonding
and interaction among bonds, and provides a suitable basis
for investigating charge transfer. Therefore, the electronic
properties of pristine components and nanotube/drug systems are considered. The electron population analysis
reveals that considerable charge transfer occurs during the
adsorption and encapsulation processes. During the interactions between anticancer drugs molecule and nanotubes,
charge transfer might occur from drugs to the nanotubes or
vice versa. One of the essential characteristics affecting the
possibility of interaction of drug and nanotubes is the
distribution of effective charges on the atoms. The partial
charges of Pt, Cl, N, O and H atoms of drugs derived from
123
the NBO calculations are summarized in Table 4. The
partial charges of drug atom, which is depicted in Table 4,
reveal that the Cl atom of cisplatin and O atom of other
anticancer drugs in complexes are more negative than those
in isolated molecules. On the other hand, the Pt, N and H
atoms of all considered drugs in complexes are more
positive than those in pristine molecules. These results
indicate that the charge distribution are changed when the
drug molecules interaction with nanotubes. So, when the
drug molecules is adsorbed or encapsulated into the BNNT
and CNT, there is a charge transfer from drug to the
nanotube producing a common chemical potential. This
trend is vice versa for nanotube/cisplatin complexes; the
electron density transfer was occurred from HOMO of
nanotubes to the LUMO of the cisplatin due to the energy
deference of jSWNT(HOMO) - Drug(LUMU)j. The most
important terms in this kind of interaction are contributed
from the partial charge transfer between the highest occupied molecular orbital (HOMO) of one component and the
lowest unoccupied molecular orbital (LUMO) of another.
The energies of HOMO, LUMO and HOMO–LUMO
(L–H) gaps of pristine components and formed complexes
are listed in Table 1. These results demonstrate that the
jDrug(HOMO) - SWNT(LUMU)j energy deference is considerably smaller than jSWNT(HOMO) - Drug(LUMU)j.
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453
Fig. 6 Typically contour plots
of the a HOMO and b LUMO of
BNNT/cisplatin(in), c HOMO
and d LUMO of BNNT/
ndaplatin(in), e HOMO and
f LUMO of BNNT/
nedaplatin(out)
Hence, based on the theory of frontier molecular orbitals,
nanotube/drug systems a significant overlap and electron
density transfer can be performed between the HOMO of
drugs and the LUMO of natotubes. These results agree with
the results of the partial charge transfer and the adsorption
energy. It can be concluded that a charge transfer, suggesting that stabilization of the bioconjugated complex is
mainly governed by electrostatic interactions, accompanies
the interaction between Pt-drugs and nanotubes. As can be
seen in Fig. 6, the HOMO orbital is distributed over the
cisplatin and the LUMO orbital is localized on the BNNT
in the BNNT/cisplatin(in) complex.
Many applications use the HOMO–LUMO gap as a
quantum descriptor to establish correlation in various
chemical and biochemical systems [55, 56]. The HOMO
and LUMO orbitals help to characterize the chemical
reactivity and kinetic stability of the molecule [57]. In
comparison, the electronic properties of nanotube/drug
systems such as HOMO–LUMO gap energy with pristine
nanotube demonstrate a considerable change has occurred
(see Tables 1 and 4). In the case of BNNT, the global
reactivity indices of nanotube/drug systems is significantly
changed compared to the pristine nanotube (see Tables 1
and 5) when the drug molecule interacted with BNNT
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J Incl Phenom Macrocycl Chem (2014) 79:443–457
Table 5 HOMO, LUMO, Gap D (eV) energy, electronic chemical potential (l) (eV), hardness (g) (eV), softness (S) (eV-1) and electrophilicity
(x) of BNNT/drug and CNT/drug systems
Type
HOMO
LUMO
Gap energy
l
g
S
x
BNNT/Cisplatin (in)
-6.588
-1.591
4.997
-4.089
4.997
0.200
1.673
BNNT/Cisplatin (N-Vertical)
-6.153
-0.917
5.236
-3.535
5.236
0.191
1.193
BNNT/Cisplatin (Cl-Vertical)
-6.230
-1.011
5.218
-3.620
5.218
0.192
1.256
BNNT/Cisplatin (Horizontal)
-6.274
-1.029
5.245
-3.651
5.245
0.191
1.269
CNT/Cisplatin (in)
-4.542
-3.385
1.157
-3.963
1.157
0.864
6.788
CNT/Cisplatin (N-Vertical)
-4.607
-3.456
1.152
-4.031
1.152
0.868
7.056
CNT/Cisplatin (Cl-Vertical)
BNNT/Nedaplatin (in)
-4.074
-5.921
-2.918
-0.548
1.156
5.373
-3.496
-3.234
1.156
5.373
0.865
0.186
5.286
0.976
BNNT/Nedaplatin (out)
-5.141
-0.214
4.928
-2.677
4.928
0.203
0.727
BNNT/Nedaplatin (horizontal)
-5.331
-0.198
5.133
-2.764
5.133
0.195
0.744
CNT/Nedaplatin (in)
-4.489
-3.334
1.154
-3.912
1.154
0.867
6.629
CNT/Nedaplatin (out)
-4.587
-3.426
1.160
-4.007
1.160
0.862
6.918
CNT/Nedaplatin (horizontal)
-4.466
-3.309
1.157
3.888
1.157
0.864
6.530
BNNT/Oxaliplatin (in)
-6.505
-0.797
5.708
-3.651
5.708
0.175
1.168
BNNT/Oxaliplatin (I)
-5.865
-0.350
5.514
-3.107
5.514
0.181
0.876
BNNT/Oxaliplatin (G)
-6.034
-0.523
5.511
-3.278
5.511
0.181
0.975
BNNT/Carbaplatin (in)
-6.678
-0.790
5.888
-3.734
5.888
0.170
1.184
CNT/Carbaplatin (I)
-4.637
-3.477
1.159
-4.057
1.159
0.862
7.097
CNT/Carbaplatin (G)
-4.326
-3.168
1.158
-3.747
1.158
0.863
6.060
surface. In addition, when the drug molecule adsorbs onto
the surface of nanotube, the hardness of the system is
slightly decreased and the electrophilicity of the system is
slightly increased, indicating that the reactivity of the
system is increased. In order to understand the effect of the
adsorption process of drug molecule into the BNNT and
CNT on the electronic properties of drug molecule, total
density of states (DOS) was calculated from the eigenvalue
generated by the MPWPW91 functional (see Figs. 7 and
S3). The density of states (DOS) of a system describes the
number of states per interval of energy at each energy level
that are available to be occupied by electrons. A high DOS
at a specific energy level means that there are many states
available for occupation. A DOS of zero means that no
states can be occupied at that energy level. In general, a
DOS is an average over the space and time domains
occupied by the system. According to our results, the DOS
plot for drug molecule in complexes formed compared to
the pristine component indicate that there is no significant
change in the characteristic features of the DOS is occurred. It means that the BNNT and CNT can carry the drug
molecule without significant change in electronic properties of entitled drugs.
The second order Fock matrix was carried out to evaluate the donor–acceptor (bond–antibond) interactions in
the NBO analysis. The interactions result is a loss of
occupancy from the localized NBO of the idealized Lewis
structure into an empty non-Lewis orbital. For each donor
123
(i) and acceptor (j), the stabilization energy could be estimated by 2nd-order perturbation theory as follow [58]:
_ 2
ri F rj
ð2Þ
DEi!j ¼ 2
ð8Þ
ej ei
_
where F is the effective orbital Hamiltonian and
D _ E
D _ E
ei ¼ ri F ri , ej ¼ rj F rj are the respective orbital
energies of donor and acceptor NBOs.
For each donor (i) and acceptor (j) NBOs, the stabilization energy E(2) associated with delocalization (2estabilization) is estimated. The larger E(2) value, the more
intensive is the interaction between electron donors and
electron acceptors, i.e. the more donating tendency from
electron donors to electron acceptors and the greater the
extent of conjugative interaction in the molecular system.
Delocalization of electron density between occupied (bond
or lone pair) and formally unoccupied (antibond and
Rydgberg) NBO orbitals correspond to a stabilizing donor–
acceptor interaction. The strongest interaction is in this
situation (adsorbed anticancer drugs onto the BNNT and
CNT) identified for the interaction of p–(B1–N3) localized
on BNNT as donor with the adjacent d*–(N1–H1) bond of
drug molecule as acceptor in the BNNT/cisplatin(out)
complex. The energy of this charge transfer is obtained
13.305 kJ/mol. Tables S2 and S3 show the donor- acceptor
(bond–antibond) interactions for the adsorption of Pt-drug
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J Incl Phenom Macrocycl Chem (2014) 79:443–457
455
Fig. 7 Comparison of
electronic density of states
(DOS) for pristine a oxaliplatin
and b oxaliplatin in BNNT/
oxaliplatin(in) complex, blue
lines represent virtual orbitals,
green lines represent occupied
orbitals, and the red line
represents DOS spectra. (Color
figure online)
molecule onto the BNNT and CNT surfaces. These results
are in accordance with partial charge distributions.
Conclusion
One of the important applications of nanotechnology is in drug
delivery in particular, the targeted delivery of drugs using
nanotubes. A proper understanding of encapsulation behavior
of drug molecules into nanotubes is vital for develop nanoscale drug delivery vehicles. In this work, the complex formation of Pt-anticancer drugs with single walled boron nitride
and CNTs has been investigated within the framework of
density function theory. The calculated adsorption energy
reveals that the formation of complexes is favorable. The
formation of complexes between CNT and BNNT with Ptanticancer drugs resulted in a structural change in the BNNT
and CNT with no significant change in the drug geometries.
Our computations indicated that the encapsulation of drugs
inside of the nanotubes is more favorable than that of the
adsorption of drugs outside of the nanotubes. Analysis of the
NBO calculations showed that the interaction between Ptdrugs and nanotubes is accompanied with charge transfer and
hydrogen bonding, which suggest that the stabilization of the
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456
bioconjugated complexes is mainly governed by the electrostatic interactions. A variation in the values of the adsorption
energy in these bioconjugated complexes suggests a higher
electronic sensitivity of semiconducting BNNT compared to
the metallic CNT, leading to the possible applications of
BNNT in the drug delivery.
J Incl Phenom Macrocycl Chem (2014) 79:443–457
18.
19.
Acknowledgments The authors should thank Shahid Chamran
University for their supports in this scientific research.
20.
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