Delivery of Cisplatin Anti-Cancer Drug from Carbon, Boron Nitride

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Delivery of Cisplatin Anti-Cancer Drug from Carbon, Boron Nitride, and Silicon Carbide Nanotubes Forced by AgNanowire: A Comprehensive Molecular Dynamics Study Esmat Mehrjouei, Hamed Akbarzadeh, Amir Nasser Shamkhali, Mohsen Abbaspour, Sirous Salemi, and Pooya Abdi Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 08 Jun 2017 Downloaded from http://pubs.acs.org on June 10, 2017

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Molecular Pharmaceutics

Delivery of Cisplatin Anti-Cancer Drug from Carbon, Boron Nitride, and Silicon Carbide Nanotubes Forced by Ag-Nanowire: A Comprehensive Molecular Dynamics Study Esmat Mehrjoueia, Hamed Akbarzadeh*a, Amir Nasser Shamkhalib, Mohsen Abbaspoura, Sirous Salemia, Pooya Abdic a) Department of Chemistry, Faculty of Basic Sciences, Hakim Sabzevari University, 96179- 76487 Sabzevar, Iran b) Department of Chemistry, Faculty of Science, University of Mohaghegh Ardabili, 56199-11367 Ardabil, Iran c) Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, 14395 -1561, Tehran, Iran

* Email: [email protected] Tel.: +98 915 3008670 Fax: +98 571 400332 **Email: [email protected] Tel: +98 45 33514702 Fax: +98 45 33514701 1 ACS Paragon Plus Environment


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Abstract In this work, liberation of cisplatin molecules from interior of a nanotube due to entrance of an Ag-nanowire inside it was simulated by classical molecular dynamics method. The aim of this simulation was investigation on the effects of diameter, chirality, and composition of the nanotube, as well as the influence of temperature on this process. For this purpose, single walled carbon, boron nitride, and silicon carbide nanotube were considered. In order to more concise comparison of the results, a new parameter namely efficiency of drug release, was introduced. The results demonstrated that the efficiency of drug release is sensitive to its adsorption on outer surface of the nanotube. Moreover, this efficiency is also sensitive to the nanotube composition and its diameter. For the effect of nanotube composition, the results indicated that silicon carbide nanotube has the least efficiency for drug release, due to its strong drug-nanotube. Also, the most important acting forces on drug delivery are van der Waals interactions. Finally, the kinetic of drug release is fast and is not related to the structural parameters of the nanotube and temperature, significantly.

Keywords: Nanotube; Nanowire; Drug Delivery; MD Simulation; Adsorption;

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Introduction Carbon nanotubes (CNTs) have been target of many experimental and theoretical researches due to their unique electrical 1, thermal 2, mechanical

3

and optical

4

properties. At recent years,

various applications of CNTs have been investigated such as biosensors 5, electronics 6, nanoinjectors 7, energy and gas storage devices 8, variety of composites

9-10

and especially

biomedical goals11-12 . The application of CNTs for drug delivery aims is one of the important research areas of biochemistry and medicinal chemistry

13-15

. Because, many studies have

confirmed that functionalized CNTs (ƒ-CNTs) are biocompatible and can be decomposed by oxidative enzymes. Hence they can be removed from the living body16-17. This finding has opened the door to the application of CNTs for drug delivery purposes. Moreover, CNTs have some intrinsic properties which combination of these characteristics makes them as ideal nanoscale carriers for drug delivery to the target cells. For instance, CNTs with a flexible structure, needle like shape, hydrophobic property and high length-to-diameter ratio are able to penetrate and cross through the cell membrane like a needle or even enter the cell nuclei 18-21. It has been discovered that CNTs are capable to carry different kinds of drugs with high capacity and deliver them to the target cells due to their large inner volume and specific surface area 21. In principle, the drug molecules can be encapsulated in the inert inner wall or attached to the reactive outer surface and open ends of a CNT by covalent bonds or various non-covalent interactions

22

. The outer CNT surface also can be functionalized by the attachment of various

functional groups for specific targeting and release of drug in the target cells 23. On one hand, the pharmacological activities and loss bioactivity of the drug can be occurred due to covalent interactions on the outer CNT surface. On the other hand, the morphology of the hollow cavity of inner wall in CNTs protect drug from external destroying agents during their delivering to the target area

24

. Hence, encapsulation of drug in inner wall of CNT is more favorable than

attaching on its outer surface and is a better method for drug loading. Many experimental and theoretical investigations have been performed in order to study encapsulation behaviors of various molecules inside CNTs including gas molecules, fullerene (C60), water, and therapeutic molecules, ranging from small molecules such as anticancer drugs to biomacromolecules such as protein, peptide and DNA

25-42

. Hilder and Hill theoretically investigated the effect of the CNT

diameter on the encapsulation of the well-known anticancer drug molecule, cisplatin (CisPt), into 3 ACS Paragon Plus Environment


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CNT. They resulted that the required CNT radius for maximum absorption of CisPt molecules is 5.3 Å, and minimum CNT radius which accepts a CisPt molecule is 4.785 Å

26

. Chen et al.

investigated the encapsulation of the Zadaxin drug inside CNT using molecular dynamics (MD) and steered MD (SMD) simulations from the energetic point of view. They found that the van der Waals (vdw) interactions between the drug and the CNT act as the driving force for the drug encapsulation. Also, they concluded that the length and diameter of nanotubes play the key role in this process 27. Rungnim et al. investigated encapsulation of various amounts of the anticancer drug, gemcitabine, inside SWCNT using classical MD simulation. Their results indicated that at low drug concentrations π−π stacking interaction between the gemcitabine molecules and the nanotube wall are dominant, whereas at high drug concentrations the molecules have tendency to have electrostatic interactions with the tube wall 28. As mentioned above, the interactions between CNTs and various molecules play an important role for encapsulation and filling process. The molecules can overcome on small potential barrier at the open ends of a CNT and spontaneously be encapsulated inside it. Due to the deep potential well inside hollow cavity of a CNT, the encapsulated drug molecules are usually stable. Furthermore, the release process from the nanotube needs to harmless triggers and driving mechanisms at the target site. There are many experimental studies including test-tube experiments including in vitro and in vivo circumstances in which drug release from the interior of a CNT is reported using different mechanisms (NIR) irradiation as a heating source fields (RF) irradiation

32

functionalized fullerenes

30

. These mechanisms are near-infrared

, dialysis tube diffusion technique

, decrease of PH 35

30-35

33

, electrical stimulation

34

31

, radiofrequency

, using dimethylamino-

, and etc. In addition to the mentioned experimental researches,

several theoretical studies have been performed to investigate the different ways for release of molecules from CNTs

36-42

. Using MD method, Panczyk et al. simulated CisPt release from

MWCNTs capped by magnetic nanoparticles (MNPs) with a cobalt-core/silica-shell structure called nanocontainers (NC). By applying an external magnetic field, they observed uncapping of the NC and CisPt release

36

. The same group also investigated the role of collisions and

interactions between NCs in the release process by MD study

37

. A molecular dynamics study

was carried out to investigate the effect of domino wave of a CNT on the molecules release by Xue et al

38

. Then, Xue et al. in another investigation used MD simulation in order to study

release of DNA and water encapsulated molecules inside SWCNTs by C60 molecule and Ag4 ACS Paragon Plus Environment

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nanowire as fillers 39. They concluded that stronger SWCNT-filler van der Waals interactions are driving forces for the release of encapsulated molecules. Cheng et al. via MD simulation reported that a peptide encapsulated inside a large CNT can be fully released by a small CNT through a competitive replacement process 40. Saikia et al. studied the role of temperature on the release of the anti-tubercular drug pyrazinamide (PZA) from SWCNTs using fullerene, as external filler, by MD simulation technique. They obtained that release of PZA molecules from nanotubes with small diameter increases with temperature, while PZA release from carbon nanotubes with larger diameter is temperature-independent and spontaneous

41

. Using MD simulation Chaban et al.

studied the effects of temperature and concentration on the diffusion coefficient of antibiotic drug, ciprofloxacine (CIP), inside CNTs. They reported that for release of drug molecules temperature dependency of diffusion coefficient is more important than its concentration dependency

42

. Chaban and Prezhdo using classical MD simulation proposed that high vapor

pressures produced inside CNT caused by boiling of a confined solvent can be used to pull out drug molecules

43

. As an overall result, in addition to the temperature and heating techniques,

any particle which strongly interacts and be absorbed in CNTs, can be used as a release agent for encapsulated drugs if it is not harmful for human health. Nowadays, duo to increasing the number of cancer cases worldwide, and in order to overcome some of challenges in the treatment of cancer, such as poor intracellular penetration, non-selectivity in transportation to tumor tissue, toxic effects for healthy cells, and limited stability of free anticancer drugs, applications of CNTs in cancer therapy is increasing considerably

20,23

. However, some questions can be proposed

here: Can nanowires of noble metals such as Ag, Au, and Pt be used for release of drugs encapsulated in CNTs? What about the other nanotubes such as boron nitride nanotube (BNNT)44-47 and silicon carbide nanotube (SiCNT)48 ? Also, for single-walled carbon nanotubes (SWCNTs), what are the diameter and chirality effects on this drug releasing process? It has not been performed a comprehensive theoretical study which includes clear answers to these questions. The antibacterial activities of Ag-nanoclusters (AgNCs) are well known at recent years. It seems that functionalization of these materials with other biocompatible molecules and agents can change activity of AgNCs and also decrease risks for using them in human body. Therefore, using AgNCs for other biological purposes in human body is still a challenging area of biochemistry and biomedical research 49-53.



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Cisplatin (CisPt) is a platinum based chemotherapy drug which is widely used against several types of cancer cases such as head, neck, testis, bladder, breast, ovary, and lung cancer. It has also some damaging side effects such as: kidney and nerve damage, hearing loss, anaphylactic reactions, nausea and vomiting 54. In this study, cisplatin (cis-diammine dichloro platinum (II)) with chemical formula Pt(NH3)2Cl2 is selected as a model drug and encapsulated inside SWNTs, BNNT, and SiCNT. Then, the new idea of using Ag nanowire as an external release agent is studied by MD simulation. Also, the effects of temperature, chirality and diameter of the CNTs will be investigated.

Simulation Method All of the MD simulations were performed by DL_POLY classic software

55

using isothermal-

isobaric ensemble (NPT) at 1.0 atm pressure and 0.1 ps relaxation time for thermostat and barostat. The simulation steps of this work are described as following: 1) At the first step, each nanotube was located in a orthorhombic cell with (100 Å × 50 Å × 50 Å) dimensions containing 1876 CisPt molecules and periodic boundary conditions were applied in three dimensions. The dangling bonds at two ends of each nanotube were saturated by H groups due to satisfy more realistic conditions. Then the system was simulated in isothermalisobaric ensemble for 1 ns in order to fill the nanotube by CisPt molecules. Finally, the filled nanotube was taken for the next step. 2) At the second step, the filled nanotube accompanied by a Ag-nanowire with 8.67 Å diameter and 200 Ag atoms were located in a orthorhombic box with (100 Å × 50 Å × 50 Å) dimensions containing 12321 water molecules and appropriate concentrations of Na+, K+, Cl¯, and HCO3¯ ions in order to better simulate extracellular fluid

56

. Then the system was simulated in

isothermal-isobaric ensemble up to 50 ns in order to give sufficient opportunity for Ag-nanowire diffusion into the nanotube and release of encapsulated CisPt molecules. In order to study the effect of nanotube diameter, (9,9), (12,12), and (15,15)-SWCNTs were selected. Also, in order to study of chirality effect, (21,0), (16,8), and (12,12)-SWCNTs with the same diameters were considered. Moreover, (12,12)-BNNT, (9,9)-SiCNT, and (12,12)-SWCNT 6 ACS Paragon Plus Environment

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with the same diameters were selected to study the effect of nanotube composition. Finally, (12,12)-SWCNT was used in order to study temperature effect at 298, 310, 330, and 337 K. The cutoff radius for all simulations was 12 Å and equations of motion were integrated by Verletleapfrog algorithm

57

. Also, time step for all simulations was 1fs and temperature of the system

was controlled by Nosé-Hoover thermostat field was used

60

58-59

. For SWCNT and BNNT, DREIDING force

. Also, for SiCNT GROMOS96 force field was selected

61

. The square-planar

geometry and Coulomb charges of the cisplatin molecule was provided by the works of Hilder et al.62 and Lopes et al63. It has been reported that DREIDING force field give appropriate results for BNNTs

64-65

and GROMOS96 force field give better results for SiCNTs

66

. It is noticeable

that there is not the same force field for all of mentioned nanotubes. Also, the quantum SuttonChen (QSC) many-body potential was utilized for Ag-Ag interactions force filed was applied for water molecules

69

67-68

. Moreover, TIP3P

. For the rest interactions (CisPt/Ag-nanowire,

CisPt/nanotube, and nanowire/nanotube interactions) Lennard-Jones (LJ) 12−6 potentials with Lorentz-Berthelot combination rules were applied

61

. Also, in order to obtain self diffusion

coefficients, velocity autocorrelation functions were calculated

70

. Snapshots of final structures

of systems after 50 ns containing (12,12)-SWCNT with water molecules, (9,9)-SiCNT, and (12,12)-BNNT are illustrated in Figure 1. Also, the snapshots for initial states of simulation steps including first step (filling of the nanotube with CisPt) and second step (addition of Agnanowire) are presented in Figure S1 of supporting information. The snapshots of all simulated systems at beginning, 25 ps, 50 ps, 75 ps, 100 ps, 200 ps, 5 ns, 10 ns, and 50 ns were shown in Figures S2 to S11 of supporting information. It is noticeable that in order to clear illustration of CisPt releasing process, water molecules are removed from all of the snapshots. Also, supporting information contains videos of simulated drug release process for the systems containing (12,12)-BNNT, (9,9)-SiCNT, (9,9)-SWCNT, (12,12)-SWCNT, and (15,15)-SWCNT. Moreover, density of water near the nanotubes after 50 ns were calculated and listed in Table 1 in comparison with experimental data 71. The results of this table represent small differences which can confirm the accuracy of simulations.



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Results and Discussion Effect of nanotube diameter: The center of mass distances (COMs) between CisPt molecules and (9,9), (12,12), and (15,15)SWCNTs and also between Ag nanowire and (9,9), (12,12), and (15,15)-SWCNTs versus simulation time at 310 K are plotted in Figure 2. Also, total energy (Etot), its configuration part (Ecfg), intermolecular potential energy (Evdw), and columbic energy (Ecol) of the simulation boxes for (9,9), (12,12), and (15,15)-SWCNTs versus simulation time at 310 K are plotted in Figure 3. In order to better understand COM figures, it should be noted that origin of Cartesian coordinates was selected at the center of simulation box. Therefore, as nanowire starts to enter into the nanotube and CisPt molecules exit from its internal space, COMs of nanowire and CisPt should be changed to smaller distances, until their COM distances reach an approximately constant value which means that to the extent which Ag-nanowire enters into the tube space, CisPt molecules exit from it. As it is obvious from Figure 2, Ag nanowire is rapidly diffuses into the nanotube and remains inside it. Instead, CisPt molecules are pulled out from the nanotube and remain out of it. This result is in consistent with that of the Figure 3. As it is shown in this figure, Etot and its mentioned contributions reach to a constant value after 500 ps for all of the considered nanotube diameters which mean that CisPt molecules are replaced by Ag-nanowire, quickly. This is an interesting result, due to the fact that time required for release of encapsulated CisPt molecules are faster than encapsulated DNA and water driven by Ag-nanowire in the work of Xue et al

39

(500 ps compared to 1500 ps). For all of (9,9), (12,12) and (15,15)

nanotubes, this substitution is happened near to 500 ps. However, in the case of (12,12) and (15,15) nanotubes, after reaching of complete release of CisPt molecules at 500 ps, COM distances of CisPt and Ag-nanowire become more closer together which is not the case for (9,9) nanotube. Considering Figures S2 to S4 of supporting information, after 5 ns, some of released CisPt molecules are adsorbed on the outer surface of SWCNT. In order to better representation of this adsorption of released drug molecules, total number of initial encapsulated CisPt molecules, Ntot and number of them adsorbed on the outer wall of the nanotube (adsorbed group) at a long time after their release (50 ns), Nads are given in Table 2 for the mentioned nanotubes. The Nads/Ntot ratio for (9,9), (12,12), and (15,15) nanotubes are 0.50, 0.63, and 0.82, respectively. Therefore, the most Nads/Ntot ratio is obtained for (15,15) nanotube. Moreover, by considering 8 ACS Paragon Plus Environment

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Figures S2 to S4, one can observe that for (12,12), and (15,15) nanotubes, the adsorbed CisPt molecules are distributed along with total length of nanotube, but this is not the case for (9,9) one. This can be the reason for difference between COM plots of (9,9)-SWCNT with the other ones in Figure 2. This different pattern of adsorption on (9,9) nanotube can be related to its less Ntot value in comparison with the other tubes. Therefore, small number of adsorbates leads to local distribution of them near that tube end which drug molecules have been released from it earlier. The difference of Etot, Ecfg, Evdw, and Ecol of the simulation boxes for (9,9), (12,12), and (15,15)-SWCNTs between 25 and 1000 ps at 310 K are given in Table 2. In this table percent of difference in energy (%∆E) is defined as:

%∆E =

E (25 ps) − E (1000 ps) ×100 E(25 ps)

(1)

The first result of Table 2 is the importance of Ecfg and its essential part, Evdw. By definition, configurational energy is the non-kinetic part of the total energy. As it is obvious from Table 2, for all of the considered nanotube diameters, contribution of Ecfg and its main part, Evdw in the total energy difference between release of CisPt molecules from SWCNT and entering of Agnanowire inside it, is more than other contributions. This is in good agreement with the results of previous studies

39

which means that non-bonded interactions are driving forces for delivery of

drug molecules encapsulated inside SWCNTs. This efficient drug release is due to the strong interaction of SWCNTs with transition metal nanowires which leads to irreversible encapsulation of them

72-73

. Moreover, %∆Etot is decreased by increase of tube diameter which is reasonable

because entering of Ag-nanowire into the larger nanotube is easier due to the smaller repulsive interactions in larger distances. Also, the small value of ∆Etot in comparison with ∆Ecfg and ∆Evdw can be related to the large number of water molecules in the simulation box due to the strong interactions between water molecules and their large heat capacity. The variations of %∆Evdw and %∆Ecol do not obey a simple trend like %∆Etot. From (9,9) to (12,12) nanotubes, %∆Evdw is increased, then decreased for (15,15) nanotube. As mentioned earlier, the interaction of Ag-nanowire with carbon nanotube is strong. Therefore, the main contribution of %∆Evdw is Ag-nanowire/SWCNT interaction. As it is obvious from Figures S2 to S4, Ag-nanowire undergoes a thinning before complete entering into the nanotube. Therefore, the mean distance of the nanowire from the tube wall can be the key parameter in the nanowire-nanotube 9 ACS Paragon Plus Environment


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interaction. For (9,9)-SWCNT this distance corresponds with the repulsion region of Ag-C potential. Instead, for (12,12)-SWCNT this distance is located near the minimum point of Ag-C potential. Hence, from (9,9) to (12,12) system, %∆Evdw is increased. Whereas, for (15,15)SWCNT the mean distance of Ag-nanowire from the tube wall lays in attraction branch of Ag-C LJ potential. This leads to smaller %∆Evdw of this system in comparison with (12,12) one. The trend for %∆Ecol is different in such a way that it is decreased from (9,9) to (15,15) nanotube. This trend of %∆Ecol can be described by Figures S2 to S6 of supporting information. The initial state for %∆Ecol can be considered as Figures S2(b), S3(b), and S4(b) for which the nanowire starts to enter into the nanotube and CisPt molecules are displaced and become closer together. In the other words, CisPt molecules in this initial state exhibit resistance against exiting force exerted by the nanowire. The final state for %∆Ecol can also be considered as Figures S2(f), S3(f), and S4(f) for which all of drug molecules have been released. This final state is similar to all of the systems. However, the initial state for %∆Ecol is not the same for (9,9), (12,12), and (15,15)-SWCNTs. For narrower nanotubes, the remaining space for CisPt molecules inside the nanotube is smaller and Columbic forces among them are stronger. Instead, for thicker nanotubes this space for drug molecules is wider and Columbic forces among them are weaker. Therefore, %∆Ecol should be reduced with increase of nanotube diameter. Also, radial distribution function (RDF) plots of Pt-C pair potential for (9,9), (12,12), and (15,15) SWCNTs at 310 K from 25 ps to 50 ns are shown in Figure 4. These RDF plots for each SWCNT can be divided into two groups: The first group is RDF of Pt-C pair potential for 25 to 200 ps time interval (namely releasing RDF group) in which height of first peak (HFP) is reduced by increase of simulation time, because from 25 to 200 ps CisPt molecules are released from the nanotube. The second group is RDF plots of Pt-C pair for 5, 10, and 50 ns (namely adsorption RDF group) for which HFP is increased by simulation time, because some of CisPt molecules are adsorbed on the outer surface of SWCNT. This is in good agreement with the previous results. The HFPs for RDF of (15,15) system at 50 ns is considerably more than other nanotubes, because Nads/Ntot ratio is the highest for it. Also, patterns of releasing and adsorption RDF groups are different which implies that this drug release is irreversible due to the fact that after drug release, different sites of SWCNT are occupied by adsorbed CisPt molecules. Finally, diffusion coefficient (D) of CisPt versus simulation time for simulation boxes containing (9,9), (12,12), and (15,15) SWCNTs at 310 K is plotted in Figure 5. As it is obvious from this figure, 10 ACS Paragon Plus Environment

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the pattern of fluctuations of D values for the system containing (15,15)-SWCNT is different from those containing (9,9) and (12,12) ones. The systems containing (9,9) and (12,12) nanotubes, exhibit a large maximum of D from 25 to 100 ps, however this large maximum value is not seen for (15,15) one. This maximum of D can be related to he mentioned resistance of CisPt molecules against the exiting force exerted by Ag-nanowire. For (9,9) and (12,12) systems, the remaining space inside the nanotube during nanowire entering is not large which leads to more stress inside the nanotube. Therefore, when nanowire entering continues, this large stress leads to sadden exiting of drug molecules with large D value. However, this is not the case for (15,15) nanotube and larger space inside it reduces the stress before release of drug molecules. As an overall result, one can define efficiency of drug release (EDR) or its percent (%EDR) for a fixed time interval as follows:  N % EDR =  1 − ads N tot 

  × 100 

(2)

where Nads and Ntot have been introduced, earlier. Using Table 2 values, %EDR for (9,9), (12,12), and (15,15) SWCNTs are obtained 50%, 37%, and 18%, respectively which emphasizes on the more efficient drug release of (9,9) nanotube. Therefore, diameter of the nanotube can affect efficiency of drug release, significantly.

Effect of nanotube chirality: COM values between CisPt molecules and (21,0)-zigzag, (16,8)-chiral, and (12,12)-armchair SWCNTs and also between Ag nanowire and (21,0)-zigzag, (16,8)-chiral, and (12,12)-armchair SWCNTs versus simulation time at 310 K are plotted in Figure 6. It is noticeable that diameters of mentioned nanotubes are the same. As shown in this figure, CisPt and Ag-nanowire COM plots for (16,8)-chiral nanotube exhibit different pattern compared to the other two nanotubes with armchair and zigzag structure. This different behavior of (16,8)-chiral nanotube can also be seen from Etot, Ecfg, Evdw, and Ecol of the simulation boxes versus simulation time which are shown in Figure 7. After 500 ps Etot, Ecfg, and Evdw become constant, however Ecol exhibits some fluctuations. By comparing the scale of these fluctuations with order of magnitude of Etot, Ecfg, and Evdw one can conclude that these variations in Ecol is not important and role of van der Waals 11 ACS Paragon Plus Environment


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interactions is dominant in drug release process. By considering these plots, it is clear that Etot, Ecfg, and Evdw, and Ecol variations for the system containing (16,8)-chiral nanotube are different than the others in such a way that these variations for (21,0), and (12,12) systems are very similar together. In order to interpret the different behavior of chiral nanotube, Ntot, Nads (50 ns), the difference of Etot, Ecfg, Evdw, and Ecol accompanied with their percents for the simulation boxes containing (21,0), and (16,8)-SWCNTs from 25 to 1000 ps at 310 K are given in Table 2. The Nads/Ntot ratios for systems containing (21,0), and (16,8)-SWCNTs are obtained 0.65, and 0.86, respectively. This means that released CisPt molecules have more tendencies to adsorb on the chiral nanotube and near Nads/Ntot ratios for (21,0), and (12,12) systems is in good agreement with their similar trends in Figure 7. Also, ∆Etot, ∆Ecfg, ∆Evdw, and also their percents do not indicate considerable sensitivity to the chirality of the nanotube. This is also a reasonable result, because diameters of these nanotubes are the same and therefore average intermolecular distances are not considerably changed with chirality of the nanotube. Therefore, differences between van der Waals energies during drug release process are not sensitive to the chirality of the nanotube. However, comparison between energy plots of (16,8)-SWCNT and those of the zigzag and armchair ones, exhibits less thermodynamic stability of chiral nanotube. This is in agreement with the results of previous studies which emphasized on the more thermodynamic instability of chiral nanotube in comparison with armchair and zigzag structures

74

. Hence, The

more tendencies of drug molecules to adsorb on the outer surface of (16,8) chiral nanotube can be related to its lower thermodynamic stability which leads to the less difference between initial and final states of drug release process for the system containing chiral nanotube. As a result, more Nads value for this system is responsible for more similarity of the initial and final states. The mean square displacement (MSD) plots of CisPt for simulation boxes containing (21,0), (16,8), and (12,12)-SWCNTs at 310 K are illustrated in Figure 8. As it is obvious from this figure, fluctuations of MSD for (16,8) system is less than the others which means that existence of more localized (adsorbed) CisPt molecules in this system. It is noticeable that existing of some fluctuations in MSD plots at higher simulation times indicates that complete dispersion of CisPt molecules through the water medium needs more times than 50 ns due to the heavy mass of drug molecules. Moreover, RDF plots of Pt-C pair potential for (21,0), (16,8), and (12,12) SWCNTs at 310 K from 25 ps to 50 ns are shown in Figure 9. It is noticeable that more adsorption of released CisPt molecules on the outer wall of (16,8) nanotube can be distinguished from RDF 12 ACS Paragon Plus Environment

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plots, because HFP of Pt-C pair for (16,8) system at 50 ns is considerably more than 5 and 10 ns which can be interpreted as more Nads value in this system. However, this is not the case for systems containing zigzag and armchair nanotubes. In the following, D values of CisPt for (21,0), (16,8), and (12,12) systems versus simulation time at 310 K are given in Figure 10. As expected, variation pattern of CisPt diffusion coefficient for (16,8) nanotube is different than the others, specially at 900 ps which reaches to a large maximum. This time is corresponding with a complete separation of released drug molecules into two groups in such a way that one of them is far from the nanotube end, see Figure S6(g) of the supporting information. As an overall result, using data of Table 2, %EDR values for (21,0), and (16,8), systems are obtained 35%, and 14%, respectively. Therefore, armchair nanotubes are more efficient for drug release. By considering these results one can conclude that chirality of the SWCNT can affect efficiency of this process by a thermodynamic stability mechanism.

Effect of nanotube composition: COM values between CisPt molecules and (12,12)-BNNT, (9,9)-SiCNT, and (12,12)-SWCNT and also between Ag nanowire and BNNT, SiCNT, and (12,12)-SWCNT versus simulation time at 310 K are plotted in Figure S12 of supporting information. Like the previous sections, the rate of drug release is not changed considerably by change of nanotube composition. Also Etot, Ecfg, Evdw, and Ecol of the simulation boxes contaning (12,12)-BNNT, (9,9)-SiCNT, and (12,12)SWCNT versus simulation time at 310 K are shown in Figure S13 of supporting information. Again, similar to previous sections, after 500 ps, the encapsulated CisPt molecules are completely released from nanotube internal space and Evdw plays the main role in ths process. However, energy plots for SiCNT system shows its considerable thermodynamic instability in comparison with the other structures. Also, Ntot, Nads(50 ns), the difference of Etot, Ecfg, Evdw, and Ecol accompanied with their percents for the simulation boxes containing (12,12)-BNNT, (9,9)SiCNT, and (12,12)-SWCNT from 25 to 1000 ps at 310 K are listed in Table 2. This table indicates that %∆Etot, %∆Ecfg, and %∆Evdw values for (9,9)-SiCNT is more than the others which means that Nads/Ntot ratio for this system is higher. It is noticeable that although different force fields were used for different nanotubes, however ∆E differences can be compared among 13 ACS Paragon Plus Environment


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different compositions. Because, in one hand the main part of ∆E values is ∆Evdw which is related to intermolecular interactions. On the other hand, as mentioned earlier, the main part of ∆Evdw is due to Ag-nanowire/nanotube interactions which have been modeled by LJ(12,6) and columbic potential using Lorentz-Berthelot combination rules. Moreover, ∆Evdw values are too larger than common errors in energetic values of mentioned force fields 60-61. Also, as mentioned earlier there is not a common force field for all of studied nanotubes. The Nads/Ntot ratios for (12,12)-BNNT, and (9,9)-SiCNT are obtained 0.16, and 0.82, respectively. This result implies that CisPt molecules have stronger interaction with the surface of SiCNT due to its less thermodynamic stability. This leads to a different MSD plot of CisPt for this nanotube. The MSD plots of CisPt for simulation boxes containing (12,12)-BNNT, (9,9)-SiCNT, and (12,12)SWCNT at 310 K are illustrated in Figure 11. As it is obvious from this figure, MSD of CisPt for (9,9)-SiCNT exhibits a different pattern at simulation times more than 10 ns, in comparison with (12,12)-BNNT. This phenomenon indicates stronger CisPt-nanotube interactions for this system which leads to existence of strongly adsorbed drug molecules localized on the outer surface of the nanotube. Also, RDF plots of important pair potentials for (12,12)-BNNT, (9,9)-SiCNT, and (12,12)-SWCNT systems at 310 K are shown in Figure S14 of supporting information. The strong adsorption of released CisPt molecules on the outer surface of (9,9)-SiCNT can be understood from the very similar RDF plots of Pt-C and Pt-Si pairs at 5, 10, and 50 ns. Whereas, RDF plots for Pt-B and Pt-N pairs for (12,12)-BNNT have negligible HFPs at the mentioned simulation times which indicates small number of adsorbed CisPt molecules on its surface. Finally, D values of CisPt in (12,12)-BNNT, (9,9)-SiCNT, and (12,12)-SWCNT systems at 310 K as a function of simulation time are demonstrated in Figure S15 of supporting information. As it is obvious from this figure, D values of CisPt in (12,12)-BNNT system is more than the other systems at all of the simulation times which means that more mobility of drug molecules in this system and small number of localized drug molecules on the tube surface. Using data of Table 2 %EDR values for (12,12)-BNNT, and (9,9)-SiCNT systems are obtained 84%, and 18%, respectively. As an overall result, composition of the nanotube has significant effect on the efficiency of drug release process.

Effect of temperature: 14 ACS Paragon Plus Environment

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COM values between CisPt molecules and (12,12)-SWCNT and also between Ag nanowire and (12,12)-SWCNT versus simulation time at 298K, 310 K, 330 K, and 337 K are given in Figure S16 of supporting information. As it is obvious from this figure, temperature changing within 298K to 337 K range, has not considerable effect on the rate of drug release, because at the mentioned temperatures, all of the encapsulated drug molecules have been completely released after 500 ps, see Figures S9(e), S10(e), and S11(e) of supporting information. Also Etot, Ecfg, Evdw, and Ecol of the simulation boxes containing (12,12)- SWCNT versus simulation time at 298 K, 310 K, 330 K, and 337 K are shown in Figure S17 of supporting information. As it is clear from this figure, variations of Etot, Ecfg, Evdw, and Ecol at different temperatures are similar and do not show considerable differences. Also Ntot, Nads(50 ns), the difference of Etot, Ecfg, Evdw, and Ecol accompanied with their percents for the simulation boxes containing (12,12)- SWCNT from 25 to 1000 ps at 298 K, 330 K, and 337K are listed in Table 3. The ∆E values and their percents do not demonstrate considerable differences. The Nads /Ntot ratios at 298, 330, and 337 K are obtained 0.47, 0.58, and 0.68, respectively. The smaller value for Nads /Ntot ratios at 298 K can be related to the lower kinetic energy of CisPt molecules at this temperature. The molecular weight of CisPt is considerably more than water molecule. Therefore, at lower temperatures, drug molecules do not have enough opportunity to diffuse and adsorb on the outer surface of nanotube. Also, RDF plots of Pt-C pair potentials for (12,12)-SWCNT system at 298, 310, 330, and 337 K are shown in Figure S18 of supporting information. As shown in this figure, Pt-C RDF plots at different temperatures do not exhibit significant differences. However, as temperature increases, HFPs at 50 ns is increased due to more adsorption of drug molecules on the outer surface of the nanotube. In the following, D values of CisPt in (12,12)-SWCNT system at 298, 310, 330, and 337 K versus simulation time are given in Figure S19 of supporting information. As expected, D values of CisPt at higher temperatures are increased. However, variations of D values by simulation time at mentioned temperatures do not exhibit considerable differences. Because, unlike the previous sections (effects of diameter, chirality and composition), the differences of Nads at different temperature does not depend on the drug-nanotube interactions, rather depends on the kinetic energy of released CisPt molecules. Using data of Table 3, %EDR values at 298, 330, and 337 K are obtained 53%, 42%, and 32%, respectively. Therefore, one can conclude that



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temperature cannot be an essential parameter for drug release process if this process is mainly driven by van der Waals interactions.

Conclusion In this work, release of encapsulated cisplatin drug from a nanotube caused by Ag-nanowire diffusion into the nanotube was simulated by MD method. The effects of nanotube structural properties (its diameter, chirality, and composition) accompanied by temperature effect on the release process were studied. The results indicated that nanotube composition and diameter are more important than its chirality and temperature of the system. Also, it was appeared that the main phenomenon which controls the efficiency of drug release is adsorption of drug molecules on the outer surface of the nanotube. Therefore, the drug release process driven by Ag-nanowire diffusion into the nanotube, is not kinetically controlled rather it is mainly thermodynamically controlled. This thermodynamic control is more involved in adsorption of released drug molecules on the nanotube surface. These results can be helpful for future experimental studies. Because, these results can help experimental scientists in order to concentrate on those parameters which affect the efficiency of this process, more significantly. Also, one can deactivate outer surface of the nanotube by its functionalization with appropriate molecules or ions. Therefore the aim of this work was introducing a new idea for encapsulated drug release using Ag-nanowire. However clinical treatment of this process needs many experimental and theoretical future studies because these statements are not completely mature comments and many studies are required in this field due to the complexity of these studies in a real living system such as human body.

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Captions Table caption: Table 1: Water densities near the nanotube for different simulation boxes at 310 K in comparison with 0.99333 g/cm3 as experimental value 68 for pure water at this temperature and pressure of 1 atm. Nanotube

Water density (g/cm3)

(9,9)-SWCNT

0.981

(12,12)-SWCNT

0.979

(15,15)-SWCNT

0.975

(12,12)-BNNT

0.982

(9,9)-SiCNT

0.984

Table 2: Difference of Etot, Ecfg, Evdw, and Ecol of the simulation boxes and their percent for (9,9), (12,12), (15,15), (21,0), and (16,8)-SWCNTs, and also BNNT and SiCNT between 25 and 1000 ps accompanied with Ntot, and Nads(50 ns) at 310 K. All energy units are reported in kcal/mol. Nads

Nanotube

-∆Etot

% ∆Etot

-∆Ecfg

% ∆Ecfg

-∆Evdw

% ∆Evdw

-∆Ecol

% ∆Ecol

Ntot

(9,9)

37

0.61

1658

21.21

1554

16.44

63

92.87

10

5

(12,12)

74

0.60

2919

20.72

2712

17.20

76

43.82

19

12

(15,15)

97

0.50

3465

15.66

3384

14.17

124

39.57

33

27

(21,0)

72

0.56

2894

20.61

2780

17.83

70

33.58

20

13

(16,8)

72

0.61

2824

20.61

2637

17.01

54

24.70

21

18

BNNT

62

0.49

2403

15.59

2282

13.62

55

33.31

19

3

SiCNT

2881

28.92

2571

24.48

2615

21.81

45

20.52

17

14

Table 3: Same as Table 1 for (12,12)-SWCNT at different temperatures. T (K) -∆Etot % ∆Etot -∆Ecfg % ∆Ecfg -∆Evdw % ∆Evdw -∆Ecol % ∆Ecol Ntot Nads (50 ns) 298

73

0.59

2831

20.03

2640

16.73

99

56.67

19

9

330

74

0.62

2879

20.53

2663

18.89

82

47.00

19

11

337

75

0.63

2897

20.67

2710

17.19

57

31.70

19

13


(50 ns)

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Figure Caption: Figure 1: Snapshots of final structures of systems containing (12,12)-SWCNT with water molecules (a), (9,9)-SiCNT without water molecules (b), and (12,12)-BNNT without water molecules (c). Water molecules were removed in order to clarity of the snapshots. Figure 2: : COMs between CisPt molecules and (9,9), (12,12), and (15,15)-SWCNTs and also between Ag nanowire and (9,9), (12,12), and (15,15)-SWCNTs versus simulation time at 310 K. Figure 3: Etot, Ecfg, Evdw, and Ecol of the simulation boxes for (9,9), (12,12), and (15,15)-SWCNTs versus simulation time at 310 K. Figure 4: RDF plots of Pt-C pair potential for (9,9), (12,12), and (15,15) SWCNTs at 310 K from 25 ps to 50 ns. Figure 5: D values of CisPt versus simulation time for simulation boxes containing (9,9), (12,12), and (15,15) SWCNTs at 310 K. Figure 6: The same as Figure 2 for SWNTs with the same diameter and (21,0), (16,8), and (12,12) chiralities. Figure 7: The same as Figure 3 for for simulation boxes containing (21,0), (16,8), and (12,12) SWCNTs. Figure 8: MSD plots of CisPt for simulation boxes containing (21,0), (16,8), and (12,12) nanotubes. Figure 9: The same as Figure 4 for SWNTs with the same diameter and (21,0), (16,8), and (12,12) SWCNTs. Figure 10: The same as Figure 5 for SWNTs with the same diameter and (21,0), (16,8), and (12,12) chiralities from 25 ps to 50 ns. Figure 11: MSD plots of CisPt for simulation boxes containing (12,12)-BNNT, (9,9)-SiCNT, and (12,12)-SWCNT.



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Figure 1:

(a)

(b)


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(c)



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Figure 2:


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Figure 3:



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Figure 4:


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Figure 5:



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Figure 6:


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Figure 7:



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Figure 8:


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Figure 9:



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Figure 10:


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Figure 11:



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Page 38 of 38

Delivery of Cisplatin Anti-Cancer Drug from Carbon, Boron Nitride

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