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releasing of doxorubicin using single-walled carbon nanotube and multi-walled carbon nanotube: A molecular dynamics study
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pH-Sensitive Loading/Releasing of Doxorubicin Using Single-Walled Carbon Nanotube and Multi-Walled Carbon Nanotube: A Molecular Dynamics Study Reza Maleki , Hamid Hassanzadeh Afrouzi , Mirollah Hosseini , Davood Toghraie , Anahita Piranfar , Sara Rostami PII: DOI: Reference:
S0169-2607(19)31776-6 https://doi.org/10.1016/j.cmpb.2019.105210 COMM 105210
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Computer Methods and Programs in Biomedicine
Received date: Revised date: Accepted date:
11 October 2019 11 November 2019 12 November 2019
Please cite this article as: Reza Maleki , Hamid Hassanzadeh Afrouzi , Mirollah Hosseini , Davood Toghraie , Anahita Piranfar , Sara Rostami , pH-Sensitive Loading/Releasing of Doxorubicin Using Single-Walled Carbon Nanotube and Multi-Walled Carbon Nanotube: A Molecular Dynamics Study, Computer Methods and Programs in Biomedicine (2019), doi: https://doi.org/10.1016/j.cmpb.2019.105210
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Highlights
Adsorption and release of anti-cancer drug, DOXORUBICIN, through carbon nanotubes.
This study was done by molecular dynamics simulation.
DOX adsorption on SWNT and MWNT in neutral pH was stronger than it was in acidic pH.
Blood pH is suitable for DOX loading on CNT and CNT-DOX linkage remained stable at this pH;
pH-Sensitive Loading/Releasing of Doxorubicin Using Single-Walled Carbon Nanotube and Multi-Walled Carbon Nanotube: A Molecular Dynamics Study Reza Maleki1, Hamid Hassanzadeh Afrouzi2, Mirollah Hosseini3, Davood Toghraie4, Anahita Piranfar5, Sara Rostami6, 7*
1
Department of Chemical Engineering, Shiraz University, Shiraz, Iran
2
3
Babol Noshirvani University of Technology, Babol, Islamic Republic of Iran
Department of Mechanical Engineering, Islamic Azad University, Qaemshahr Branch, Qaemshahr, Mazandaran, Iran 4
Department of Mechanical Engineering, Khomeinishahr Branch, Islamic Azad University, Khomeinishahr, Iran
5
Biomechanic Department, Biomedical Engineering Faculty, Mashhad Branch, Islamic Azad University, Mashhad, Iran
6
Laboratory of Magnetism and Magnetic Materials, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam 7
Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
*Corresponding author: Email: [email protected]
Abstract 2
• Background and objective: Doxorubicin is one of the drugs used to treat cancer, and many studies have been conducted to control its release. In this study, carbon nanotubes have been proposed as a doxorubicin carrier, and the effect of carboxyl functional group on the controlled release of doxorubicin has been studied. • Methods: This study has been done by molecular dynamics simulation and was based on changing the pH as a mechanism controller. • Results: This work is intended to test the efficacy of this drug carrier for the release of doxorubicin. A comparison was also made between single-walled and double-walled carbon nanotubes to answer the question of which one can be a better carrier for doxorubicin. The study of DOXORUBICIN adsorption and release showed that the DOXORUBICIN adsorption on single-walled carbon nanotube and multi-walled carbon nanotube in neutral pH was stronger than it was in acidic pH, which could be due to the electrostatic interactions between the carboxyl group of nanotubes and DOXORUBICIN. Based on this and according to the investigation of hydrogen bonds, diffusion coefficients, and other results it was clear that the drug release in acidic pH was appropriate for body conditions. Since cancer tissues pH is acidic, this shows the suitability of carbon nanotube in drug delivery and DOXORUBICIN release in cancer tissues. In addition, it was shown that the blood pH (pH=7) is suitable for DOXORUBICIN loading on the carbon nanotube and carbon nanotube-DOXORUBICIN linkage remained stable at this pH; accordingly, the carbon nanotube could deliver DOXORUBICIN in blood quite well and release it in cancerous tissues. This suggests the carbon nanotubes as a promising drug carrier in the cancer therapy which can be also investigated in experiments. • Conclusion It was revealed that the bonds between multi-walled carbon nanotube and DOXORUBICIN was stronger and this complex had a slower release in the cancer tissues compared to the single-walled carbon nanotube; this can be regarded as an advantage over the single-walled carbon nanotube in the DOXORUBICIN delivery and release.
Keywords: Doxorubicin; Molecular dynamics; Carbon nanotube; Cancer; Drug release; Drug Loading; Diffusion. 3
1. Introduction
With the brand name of Adriamycin, DOXORUBICIN (DOX) is an anti-cancer drug preventing the growth of cancer cells by disrupting the bodily function. The DOX has been used for different types of cancers including breast cancer, bladder, thyroid, stomach, lung, bone, neural tissue, muscle, joints, and soft tissue. The DOX has also been applied in Hodgkin's disease and particular types of blood cancer[1]. By disrupting the production of necessary proteins for cancer cells growth, this drug blocks their growth and proliferation. It seems that this drug works in connection with DNA and inhibits the nucleic acid production by disturbing the molecular building and forming the steric hindrance. One of the severe side-effects of this drug is its probable damage to the cells around cancer tumors which may stop their growth[2]. Targeted drug-delivery can minimize these damages on non-cancerous cells and maximize the therapeutic response of the drug [3-8]. Nanotechnology-based drug-delivery systems have improved the pharmaceutical methods by controlling and slowing down the drug release, protecting pharmaceutical molecules, creating particle size smaller than cell, which can pass biological barriers and deliver drug to the target, increasing the drug durability in the bloodstream and biocompatibility[9]. All these features are realized through the targeted drug transport by nanostructures. Therefore, nanostructures can decrease the DOX side effects [10-14]. There has been a great deal of research into the targeted delivery of doxorubicin, and several carriers have been used to control it is released[15, 16]. Various polymer-carriers 4
such as chitosan, polyethylene glycol, and isopropyl acrylamide have been used for this purpose. Different composite carriers ĵhave also been used for this controlled release of doxorubicin[17-19].One of the promising carriers which have been recently highlighted in DOX drug-delivery are carbon nanostructures. Their size, shape and surface characteristics have made them suitable for drug-delivery [20-26]. The SWNTs and fullerenes have a diameter of 1 nm. Due to their high surface area, enable the surface engineering and functionalization can be performed precisely on these structures [27-30]. Due to the attractive properties of carbon structures, many studies have beenor conducted on their use in drug delivery systems[31, 32]. In such studies, graphene, graphene oxide, fullerenes, and other carbon structures have been used for drug delivery. Many researchers have investigated the use of carbon nanotubes for drug delivery[33]. Nanotubes type and size, as well as many other properties of the nanotubes, have been studied[34]. Carbon nanotubes have been used for targeted release of many drugs, including curcumin, doxorubicin, and others. Carbon nanotubes can have both a drug carrier and a sensor role[34-36]. For better solvability and biocompatibility as well as various substances delivery, the surface of these nanostructures is merged with different compounds. These particles can be loaded on the surface or inside these structures [37, 38]. Targeting and simultaneous delivery of two or more compounds are among the other essential characteristics of these particles. CNTs have an extraordinary capacity in diagnosis and destroying the cancer cells inside the body [3943]. Studies have shown that CNTs enter the cells vertically through the endocytosis
process. Moreover, due to the needle-like shape and sharp tips of CNTs, they can pierce into and pass the membranes without damaging cell membranes. Studies revealed that in comparison with MWNTs, the smaller SWNTs could diffuse in cell and nucleus cytoplasm and pass cell membranes more easily. Drug encapsulation inside the CNT can protect it during its transport within the body. After being delivered at the target place, encapsulating 5
substances will erode and disappear. The CNT-encapsulated drug should be proportional to the CNT size and diameter. CNTs have a considerable ability in diagnosing and destroying the cancer cells inside the body [44-46]. Considering the increasing trend of applying carbon nanotubes in drug delivery, it has been considered as a drug carrier too which can be efficiently tuned by functionalizing. Various type of simulation approaches can be used to tackle the problem in the field of biomedical engineering [47, 48] and biomedicine development [49] like traditional CFD [50, 51], Lattice Boltzmann method [52, 53], molecular dynamics [54] and dissipative particle dynamics [55-57]. The molecular dynamics (MD) is a powerful tool in providing qualitative and quantitative data on the interactions and the physical-chemical mechanisms of pharmaceutical systems[14, 58-62]. Regarding the problems and high cost of experimental tests, nowadays many studies are conducted based on comutational approach to simulate the drug-delivery systems in cancer therapy [63-66]. Some limited molecular dynamic studies also have addressed the DOX delivery [67-71]. For example, molecular dynamics tools have been employed to study the DOX release from Graphene carriers and Graphene oxide [70, 72, 73]. In these studies, the effects of pH, molecular bonds, carrier size, and functional groups were investigated. However, no molecular dynamics study has been carried out on the DOX adsorption mechanism, diffusion and release from the MWNT in comparison to SWNT. In this work the unique comparison between MWNT and SWNT for the DOX delivery has been done. An attractive study of nanotubes functionalized with carboxyl group has been suggested for use as a drug doxorubicin. The adsorption and release of doxorubicin on this carrier have been investigated. All studies have been performed using powerful molecular dynamics tools. The interactions between drugs and carriers have been studied under different conditions, and the results have been analyzed. This work considered CNTs as a proper carriers for the drug release, and compared the 6
adsorption, diffusion, and release of the DOX from the SWNT with those of the MWNT, and introduced CNTs as a proper carriers for the DOX delivery.
2. Materials and methods 2.1 Molecular dynamics The base of molecular dynamics of numerical integration from Newton's motion equations is for all available particles in the system. By enacting Newton’s motion equations, a set of consecutive atomic positions are achieved. By using the molecular dynamics, properties of the system for each upcoming moment can be predicted based on its existing properties. Molecular dynamics includes the three following stages [74-76]: 1. Receiving the primary configuration of the particles. 2. Calculating the list of neighbors. 3. Calculating the force input to each atom according to the configuration and primary conditions. In each step, the force input to atoms is calculated and merged with the present situations and velocities in order to achieve the upcoming positions and velocities in a short time forward. It is supposed that the enacting force on each atom is stable during this time step.
2.2. Force fields The potential energy is a set of interaction energies that changes with the change of distances among the particles. Eq. 1 shows the potential function [77]. Eq. 2 shows that by the derivation from potential function, force function can be achieved for each i atom in a N atom system. Equations are solved simultaneously during the short steps of time. On the
7
other hand, by means of the Eq. 3, the force can be related to the place and time of the atoms [82-85]:
U U (r )
(1)
Fi dv dri
(2)
d 2ri m i 2 Fi dt
(3)
i 1,..., N
In this model, the particles move on the straight lines at a steady speed. Collisions are quite elastic and occur at times when the distance between couples of spheres is equal to the total of their radii. After a collision, the new velocities of the colliding sphere are calculated according to the principle of conservation of linear motion size. Employing a hard-sphere model, quite useful results were achieved. In the Van der Waals potential, the force between two atoms or molecules changes continuously with their distances. While, there is no force among the particles in the hard-sphere model, unless, they collide with each other. These parameters are usually determined with fit laboratory data or through exact calculations in the quantum chemistry. The r is the distance between two atoms and V is the potential between two atoms [78, 79, 86-92].
V 4 r r 12
6
(4)
Eqs. 5 and 6 were used to calculate the drug diffusion coefficient. For calculation of the drug diffusion coefficient, the mean-square displacement (MSD) was calculated,
8
t MSD [r (t ) r (0)]2 1 [r (t ) r (0)] 2 t t t 0
(5) (6)
D 1 lim MSD 6 t t
The simulation was performed using GROMACS software. Because it is open-source and popular for the drug simulation. The GROMACS has got a variety of packages for molecular dynamics calculation, which has been used for many advanced drugs and molecular experiments. Utilizing the Newton’s motion equations, GROMACS predicts the behavior of 100 to 1000000 particles. GROMACS was first developed for biomolecules such as proteins, lipids, and nucleic acids, which have a lot of complex transplant interactions [80, 81].
2.3. System preparation To model the SWNT and MWNT molecules, TubeGen Online was used; carbon dioxide molecules were added to the CNTs surface in two protonated and deprotonated modes. In the protonated conditions, hydrogen atoms were added to the carboxyl group groups on the surface of the nanotube, but the surface of the nanotube could not be protonated. The protonated state is a condition at which the functional groups on the nanotube surface gained positive charge by getting hydrogen. However, the nanotube itself did not change in the protonated and deprotonated state. The carbon atom surface charge in these nanostructures was considered 0 based on using the available structure of naphthalene in the oplsaa force field. The GROMACS 5.1 software was used for molecular dynamics simulation. The input structures were prepared with oplsaa force field. To get the molecule parameters, which 9
were changed to the script format, all molecules were put in the box and the tip3p water model was used as the solvent. The energy minimization was conducted on all simulation systems with 50000 steps, and the steepest descent method was employed to delete the Van der Waals interactions and form hydrogen bonds between water molecules and the others. In the next stage, the system temperature was increased gradually. Then, it was balanced at a constant pressure for 200 ps. The Parrinello-Rahman algorithm was used to balance the system pressure. The MD simulation was carried out at 37 °C temperature for 50 ns. The cut-off distance was considered to be 1.2. To calculate the electrostatic force, the particle mesh Ewald (pme) was used. LINCS (Linear constraint solver) algorithm was also applied to maintain the length of all bonds. To accelerate the calculations, SHAKE algorithm was utilized to limit the bonds engaged in hydrogen atom.
3. Results 3.1. Interaction energies In Fig. 1, the interaction energy of the DOX molecule with MWNT and SWNT is illustrated. As it clearly shows, in neutral pH, the electrostatic energy had the main contribution in the total interaction. While in the acidic pH, the electrostatic tended to zero, and Van Der Waals energy contributed in the total interaction. The direct relationship of molecules charge increase with electrostatic energy can be observed in this diagram. This is because the carboxyl group had negative charge and more electrostatic interactions in neutral pH and no charge in acidic pH. The increase in the electrostatic energy in neutral pH shows the strong adsorption of drug on the CNT surface. The MWNT was a stronger adsorbent than the SWNT for DOX in this pH range. The interaction means that the energy difference became stronger in MWNT; because as CNT size got larger, the surface area, interactions, and drug molecules were increased. 10
Fig. 2.a shows the water density along with the simulating box. As can be seen, the water density was increased inside the SWNT. In the neutral mode, the density was lower which indicates the presence of DOX molecules around the CNT. Lower SWNT density in neutral pH reflects the higher drug adsorption on the SWNT surface in neutral pH compared to the acidic pH. The acidic pH showed higher water density compared to the neutral pH which is a sign of drug release from the CNT surface. It is seen in the figure that the drug adsorption on SWNT was better in neutral pH since the drug release from SWNT was better in acidic pH. Fig. 2.b illustrates water density along the simulating box, where, the decrease in the density is a sign of MWNT; therefore according to the previous analysis and the figure, it is clear that the drug to acidic pH, the density changes were more extensive in MWNT at neutral mode, as the MWNT possessed higher density the adsorption on MWNT was better in neutral pH as its drug release was better in acidic pH. Compared to the acidic pH, density changes were larger in MWNT at neutral mode, as the MWNT possessed higher density than the SWNT.
3.2. Kinetics of drug adsorption and mass transfer parameters The Fig. 3a demonstrates the energy diagram of the SWNT in terms of drug interaction time in neutral pH (pH=7). The DOX molecule diffused toward SWNT and was finally adsorbed on SWNT surface after 3000 ps. At the time of surface adsorption, the sudden changes of total energy indicate the drug-SWNT interaction. In Fig.3b, the same diagram is shown for acidic pH (pH=5). As can be seen, changes in the total interaction energy were more in neutral pH as compared with acidic pH, suggesting the stronger bonding between drug and CNT in the neutral pH than acidic pH. Changes of interaction energy by passing of time are depicted in Fig. 4a for the MWNT at neutral pH. Accordingly, the drug surface adsorption on the MWNT in this pH took 1600 ps. Interaction energy for MWNT was 11
higher than the SWNT which shows more close interaction and stronger drug adsorption on this carrier. Fig. 4b represents the drug adsorption on the MWNT in acidic pH. As it is clear, the total interaction energy in neutral pH was more than in the acidic pH indicating a stronger bond between the drug and MWNT in the neutral pH compared to the acidic pH. Table 1 lists the average number of hydrogen bonds of drug-nanocarrier, drug-water, and water-nanocarrier. The number of nanocarrier bonds at different pH is also presented. In this study, the criterion of hydrogen bond formation was considered as the maximum hydrogen acceptor distance equal to 3 . In addition, the minimum hydrogen acceptor angle was considered to be 90⁰. As can be seen, by increase in the pH, the average hydrogen bonds of nanocarriers was increased and reached a maximum value in neutral pH. This shows higher drug adsorption in neutral pH. Therefore, in neutral pH there is a maximum adsorption compared to the acidic pH. So, for drug adsorption, it is better to have a neutral environment, while the acidic environment is preferred for the drug release. This analysis explains the superiority of pH mechanism for the drug release and adsorption. Furthermore, regarding the abundance of water molecules over the drug molecules, a great number of hydrogen bonds between water and nanocarrier were created.
In Table 2, the mean diffusion coefficient of the drug molecule in water presented. The diffusion coefficients were calculated for SWNT and MWNT in neutral and acidic pH. As can be seen, the diffusion coefficients in the neutral environment were low which can be due to the increase in interactions as the result of hydrogen bonds between water and drug or water and CNT. Because the increase in interactions leads to the steric hindrance and accordingly due to the increase in the number of hydrogen bonds in neutral pH, the diffusion coefficient was decreased. Moreover, the drug diffusion coefficient was low in
12
MWNT, which can be attributed to the more interactions of the MWNT compared to the SWNT.
3.3. DOX adsorption and release on SWNT Fig. 5 schematically shows the drug adsorption on the SWNT surface. As it can be seen in the right picture, drugs had Van der Waals interactions among their aromatic rings. As it is evident, the drug molecules from different parts (both aromatic and amino parts) interacted with the nanotube surface. In this part, the interactions included hydrogen bonds, Van der Waals, and electrostatic interactions. Closer view of the interaction between the drug and nanotube in Fig. 6 reveals that the drugs interacted with the nanotube and other drugs on different parts. The aromatic-aromatic interactions between the drug-nanotube and drug-drug are observable. In this simulation, the carboxylic functional groups were protonated, and the nanotube surface charge was zero. In the protonated state, the carboxyl groups on the CNT surface gained positive charge by getting hydrogen and the drug surface charge was still positive. Fig. 7 shows the Van der Waals energy, electrostatic, and total energy (total of Van der Waals and electrostatic) during the simulation process. Electrostatic energy played the most crucial role in the drug-nanotube interaction in neutral pH, and the negative charge of carboxyl group in this pH resulted in an electrostatic interaction enhancement (compared to the acidic pH). The Van der Waals energy was mostly assigned to the aromatic-aromatic interactions between the drug and nanotube. The vertical axis in Fig. 8 shows the number of hydrogen bonds in neutral pH and the adsorption time. As it can be noticed in the figure, most black points were between 2 and 3 indicating that the average number of hydrogen bonds between the drug and carrier was approximately between 2 and 3. However the average number of hydrogen bonds in acidic pH was less than 1. This suggests a stronger 13
connection between the drug and CNT in neutral pH. Therefore, the acidic pH had better conditions for the drug release. Fig. 9 shows the energy vs. time plot for the acidic pH. Considering the zero charge of the carboxyl group in this pH, it can be stated that the electrostatic energy was shallow and almost zero, compared to that in neutral pH, and the total interaction energy was mostly due to the Van der Waals interactions. The vertical axis in Fig. 10 shows the number of hydrogen bonds in acidic pH and the release time, while the horizontal one shows the simulation time. It can be seen in this figure that most black points were between 0 and 1 indicating that the average number of hydrogen bonds between drug and carrier was less than 1. However, the average number of hydrogen bonds in neutral pH was about 2.4 suggesting the stronger connection between the drug and CNT in neutral pH. Therefore, the acidic pH had better conditions for drug release.
3.4. Drug release and adsorption based on MWNT Fig. 11 schematically shows the DOX release and adsorption on drug carrier of MWNT with carboxyl functional group. Fig. 12 shows the interaction energy vs. time for the DOX adsorption in neutral pH and drug release from the CNT in acidic pH. At the time of drug adsorption, the Van der Waals energy contribution was minor, while the electrostatic energy share formed the central part of total interaction energy. This is can be attributed to the presence of the carboxyl group, because this functional group has negative charge in neutral pH and has no charge in acidic pH. During the drug release, electrostatic energy was very negligible, and almost zero; and Van der Waals energy constituted the central part of total interaction energy. Furthermore, total interaction energy in neutral pH (drug adsorption) was much higher than the total interaction energy in acidic pH (drug release) reflecting that the drug tended to be released and separated from CNT. 14
Fig. 13 presents the number of hydrogen bonds at the time of the DOX adsorption and release from MWNT. As it is apparent in the figure, the average number of hydrogen bonds at the time of adsorption was much more than the hydrogen bonds at the time of drug release. The decrease of hydrogen bonds number shows the drug tendency to be released from MWNT in acidic pH. Fig. 14 shows the MSD diagram of the DOX. The local slope of plot is the diffusion coefficient in the corresponding time. A comparison of slopes shows that the average diffusion coefficient at the adsorption time was less than its value during the drug release which can be due to the steric hindrance of hydrogen bonds, which slowed down the drug molecule diffusion.
3.5. pH based stability The Root-mean-square deviation (RMSD) of the system is one of the critical parameters in molecular dynamics simulation. The RMSD shows the deviation of the particles position relative to their reference position at each time. The RMSD indicates the model stability, where, the slopes near to 0 show higher stability of the simulated model. The gradual increase in the slope or sharp fluctuations show the instability. Fig. 15 shows the RMSD for the neutral and acidic pH for MWNT and SWNT. At the beginning of the simulation, the system was instable, and after 300 ps the slope approached zero and the simulated system reached stability; in other words, a stable complex was created. This system reached a stable mode in a quick time which can be due to the small size of the molecules and the fast and robust interactions of molecules with each other. In order to assess the stability of each molecule, the data related to the interaction energy can be used. In Fig. 1, it is shown that the interaction energy between the CNT and DOX in neutral pH is
15
too high, which is an indicative of the high stability of the bonding between the drug and CNT. 4. Conclusion
Doxorubicin is one of the most common anticancer drugs that has been studied extensively for targeted drug delivery. In this study, carbon nanotubes have been proposed and studied as carriers of this drug. The results of this study showed that carbon nanotubes could be suitable carriers for the adsorption, transport, and release of doxorubicin. Carbon nanotubes have attractive drug delivery properties such as high diffusion coefficient and small size and many other features. This study sought to improve the properties of the nanotubes for doxorubicin release. The interesting point of this study was the use of carboxyl functional groups to improve the properties of the nanotubes. The surface charge of the carboxyl group changes based on environmental acidity. This key feature of carboxyl functional groups has enabled them to control drug release. Carboxyl functional groups are also hydrophilic and reinforce the hydrophilicity of carbon nanotubes. These also prevent aggregation of nanotubes into the bloodstream. This characteristic of carboxyl functional groups in hydrogen bonding diagrams is quite clear. These groups increase hydrophilicity by increasing hydrogen bonds. Thus, this study showed that using these functional groups can improve the properties of nanotubes for drug release. Also, in this study, multilayer and single wall nanotubes were compared, and it was found that multilayer nanotubes have better properties for the transfer and release of doxorubicin. As a recommendation for further studies, nanotubes can be used as drug carriers along with other compounds, such as polymers. It is necessary to take further steps to improve the properties of carbon nanotubes so that they can be used on a commercial scale. This study was performed using molecular
16
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Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
26
Fig. 1. The total interaction energy (total), Van der Waals and electrostatic energy between the DOX and SWNT and between the DOX and MWNT in acidic pH and neutral pH
8000
Interaction Energy (KJ/mol)
7000 6000 5000 4000 3000 2000 1000 0 Neutral-SWNT
Acid-SWNT
Van der waals
Neutral-MWNT Electrostatic
27
Acid-MWNT Total
Fig. 2.a. The water density vs. distance of simulation box for SWNT in acidic pH and neutral pH
Partial density 1100 CNT-mono-Neutral CNT-mono-Acid
Density (kg m-3)
1050
1000
950
900
850
800 0
1
2
3
Coordinate (nm)
28
4
5
6
Fig. 2.b. The water density vs. distance of simulation box for MWNT (Multi) in acidic pH and neutral pH
29
Fig. 3a. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT in neutral pH
30
Fig.3.b. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT
31
Fig. 4.a. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT in acidic pH
32
Fig. 4.b. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and MWNT in acidic pH
33
Fig. 5. The schematic illustration of the DOX adsorption on SWNT
34
Fig. 6. The schematic illustration of the DOX adsorption on SWNT (closer view)
35
Fig. 7. Total interaction energy (Total), Van der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT in neutral pH (loading)
0 VDW Elec Total
Energy (KJ/mol)
-1000
-2000
-3000
-4000
-5000 0
10000
20000
30000
Time (ps)
36
40000
50000
Fig. 8. Hydrogen bonds between the SWNT and DOX in neutral pH (adsorption)
7 Hydrogen bonds
Number of Hbonds
6 5 4 3 2 1 0 0
10000
20000
30000
Time (ps)
37
40000
50000
Fig. 9. Total interaction energy (Total), Van der Waals (VDW) and electrostatic energy (Elec) between DOX and SWNT in acidic pH (release)
0 VDW Elec Total
Energy (KJ/mol)
-100 -200 -300 -400 -500 -600 -700 -800 0
10000
20000
30000
Time (ps)
38
40000
50000
Fig. 10. Number of hydrogen bonds between SWNT and DOX in acidic pH (release)
4
Number of Hbonds
3
2
1
0 0
10000
20000
30000
Time (ps)
39
40000
50000
Fig. 11. The DOX loading and release based on MWNT
Uptake
Release
40
Fig. 12.a. Total interaction energy (Total), van der Waals (VDW) and electrostatic energy (Elec) between DOX and SWNT in acidic pH(release) and neutral pH (uptake)
0
Uptake
-1000
VDW Elec Total
Energy (KJ/mol)
-2000 -3000 -4000 -5000 -6000 -7000 -8000 0
10000
20000
30000
Time (ps)
41
40000
50000
Fig. 12.b. Total interaction energy (Total), van der Waals (VDW) and electrostatic energy (Elec) between DOX and SWNT in acidic pH(release) and neutral pH (uptake)
0
Energy (KJ/mol)
-100
VDW Elec Total
-200 -300 -400 -500 -600 -700 -800 0
10000
20000
30000
Time (ps)
42
40000
50000
Fig. 13.a. The hydrogen bonds between the MWNT and neutral pH (uptake)
8
Uptake
7
Number of Hbonds
6 5 4 3 2 1 0 0
10000
20000
30000
Time (ps)
43
40000
50000
Fig. 13.b. The hydrogen bonds between the MWNT and DOX in acidic pH (release(
6
Release
Number of Hbonds
5
4
3
2
1
0 0
10000
20000
30000
Time (ps)
44
40000
50000
Fig. 14.a. MSD of DOX in neutral pH (loading)
2
MSD (nm2)
Uptake
1
0 0
10000
20000
Time (ps)
45
30000
40000
Fig. 14.b. MSD of DOX in acidic pH (release)
15 14 13
Release
12
MSD (nm2)
11 10 9 8 7 6 5 4 3 2 1 0 0
10000
20000
Time (ps)
46
30000
40000
Fig. 15. The root-mean-squared deviation (RMSD) of the system as a function of time
16 14
RMSD(0A)
12 SWNT-Neutral pH SWNT-Acidic pH MWNT-Neutral pH MWNT-Acidic pH
10 8 6 4 2 0
10000
20000
30000
Time (ps)
47
40000
50000
60000
Table 1: number of hydrogen bonds between DOX-Nanocarrier, DOX-Water and Water-Nanocarrier Average Number of H-bond System DOXWaterDOX-Water Nanocarrier Nanocarrier SWNT 0.5 19 93 Acidic pH SWNT 2.4 18 224 Neutral pH MWNT 1.46 18 160 Acidic pH MWNT 2.24 18 372 Neutral pH
48
Table 2: diffusion coefficient of SWNT and MWNT in acidic pH and neutral pH D (105 System Average Adsorption Time (ps) cm2/s) SWNT 1.7 2100 Acidic pH SWNT 0.7 4200 Neutral pH MWNT 1.13 1600 Acidic pH MWNT 0.87 18000 Neutral pH
49
pH-Sensitive Loading/Releasing of Doxorubicin Using Single-Walled Carbon Nanotube and Multi-Walled Carbon Nanotube: A Molecular Dynamics Study Reza Maleki , Hamid Hassanzadeh Afrouzi , Mirollah Hosseini , Davood Toghraie , Anahita Piranfar , Sara Rostami PII: DOI: Reference:
S0169-2607(19)31776-6 https://doi.org/10.1016/j.cmpb.2019.105210 COMM 105210
To appear in:
Computer Methods and Programs in Biomedicine
Received date: Revised date: Accepted date:
11 October 2019 11 November 2019 12 November 2019
Please cite this article as: Reza Maleki , Hamid Hassanzadeh Afrouzi , Mirollah Hosseini , Davood Toghraie , Anahita Piranfar , Sara Rostami , pH-Sensitive Loading/Releasing of Doxorubicin Using Single-Walled Carbon Nanotube and Multi-Walled Carbon Nanotube: A Molecular Dynamics Study, Computer Methods and Programs in Biomedicine (2019), doi: https://doi.org/10.1016/j.cmpb.2019.105210
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Highlights
Adsorption and release of anti-cancer drug, DOXORUBICIN, through carbon nanotubes.
This study was done by molecular dynamics simulation.
DOX adsorption on SWNT and MWNT in neutral pH was stronger than it was in acidic pH.
Blood pH is suitable for DOX loading on CNT and CNT-DOX linkage remained stable at this pH;
pH-Sensitive Loading/Releasing of Doxorubicin Using Single-Walled Carbon Nanotube and Multi-Walled Carbon Nanotube: A Molecular Dynamics Study Reza Maleki1, Hamid Hassanzadeh Afrouzi2, Mirollah Hosseini3, Davood Toghraie4, Anahita Piranfar5, Sara Rostami6, 7*
1
Department of Chemical Engineering, Shiraz University, Shiraz, Iran
2
3
Babol Noshirvani University of Technology, Babol, Islamic Republic of Iran
Department of Mechanical Engineering, Islamic Azad University, Qaemshahr Branch, Qaemshahr, Mazandaran, Iran 4
Department of Mechanical Engineering, Khomeinishahr Branch, Islamic Azad University, Khomeinishahr, Iran
5
Biomechanic Department, Biomedical Engineering Faculty, Mashhad Branch, Islamic Azad University, Mashhad, Iran
6
Laboratory of Magnetism and Magnetic Materials, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam 7
Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
*Corresponding author: Email: [email protected]
Abstract 2
• Background and objective: Doxorubicin is one of the drugs used to treat cancer, and many studies have been conducted to control its release. In this study, carbon nanotubes have been proposed as a doxorubicin carrier, and the effect of carboxyl functional group on the controlled release of doxorubicin has been studied. • Methods: This study has been done by molecular dynamics simulation and was based on changing the pH as a mechanism controller. • Results: This work is intended to test the efficacy of this drug carrier for the release of doxorubicin. A comparison was also made between single-walled and double-walled carbon nanotubes to answer the question of which one can be a better carrier for doxorubicin. The study of DOXORUBICIN adsorption and release showed that the DOXORUBICIN adsorption on single-walled carbon nanotube and multi-walled carbon nanotube in neutral pH was stronger than it was in acidic pH, which could be due to the electrostatic interactions between the carboxyl group of nanotubes and DOXORUBICIN. Based on this and according to the investigation of hydrogen bonds, diffusion coefficients, and other results it was clear that the drug release in acidic pH was appropriate for body conditions. Since cancer tissues pH is acidic, this shows the suitability of carbon nanotube in drug delivery and DOXORUBICIN release in cancer tissues. In addition, it was shown that the blood pH (pH=7) is suitable for DOXORUBICIN loading on the carbon nanotube and carbon nanotube-DOXORUBICIN linkage remained stable at this pH; accordingly, the carbon nanotube could deliver DOXORUBICIN in blood quite well and release it in cancerous tissues. This suggests the carbon nanotubes as a promising drug carrier in the cancer therapy which can be also investigated in experiments. • Conclusion It was revealed that the bonds between multi-walled carbon nanotube and DOXORUBICIN was stronger and this complex had a slower release in the cancer tissues compared to the single-walled carbon nanotube; this can be regarded as an advantage over the single-walled carbon nanotube in the DOXORUBICIN delivery and release.
Keywords: Doxorubicin; Molecular dynamics; Carbon nanotube; Cancer; Drug release; Drug Loading; Diffusion. 3
1. Introduction
With the brand name of Adriamycin, DOXORUBICIN (DOX) is an anti-cancer drug preventing the growth of cancer cells by disrupting the bodily function. The DOX has been used for different types of cancers including breast cancer, bladder, thyroid, stomach, lung, bone, neural tissue, muscle, joints, and soft tissue. The DOX has also been applied in Hodgkin's disease and particular types of blood cancer[1]. By disrupting the production of necessary proteins for cancer cells growth, this drug blocks their growth and proliferation. It seems that this drug works in connection with DNA and inhibits the nucleic acid production by disturbing the molecular building and forming the steric hindrance. One of the severe side-effects of this drug is its probable damage to the cells around cancer tumors which may stop their growth[2]. Targeted drug-delivery can minimize these damages on non-cancerous cells and maximize the therapeutic response of the drug [3-8]. Nanotechnology-based drug-delivery systems have improved the pharmaceutical methods by controlling and slowing down the drug release, protecting pharmaceutical molecules, creating particle size smaller than cell, which can pass biological barriers and deliver drug to the target, increasing the drug durability in the bloodstream and biocompatibility[9]. All these features are realized through the targeted drug transport by nanostructures. Therefore, nanostructures can decrease the DOX side effects [10-14]. There has been a great deal of research into the targeted delivery of doxorubicin, and several carriers have been used to control it is released[15, 16]. Various polymer-carriers 4
such as chitosan, polyethylene glycol, and isopropyl acrylamide have been used for this purpose. Different composite carriers ĵhave also been used for this controlled release of doxorubicin[17-19].One of the promising carriers which have been recently highlighted in DOX drug-delivery are carbon nanostructures. Their size, shape and surface characteristics have made them suitable for drug-delivery [20-26]. The SWNTs and fullerenes have a diameter of 1 nm. Due to their high surface area, enable the surface engineering and functionalization can be performed precisely on these structures [27-30]. Due to the attractive properties of carbon structures, many studies have beenor conducted on their use in drug delivery systems[31, 32]. In such studies, graphene, graphene oxide, fullerenes, and other carbon structures have been used for drug delivery. Many researchers have investigated the use of carbon nanotubes for drug delivery[33]. Nanotubes type and size, as well as many other properties of the nanotubes, have been studied[34]. Carbon nanotubes have been used for targeted release of many drugs, including curcumin, doxorubicin, and others. Carbon nanotubes can have both a drug carrier and a sensor role[34-36]. For better solvability and biocompatibility as well as various substances delivery, the surface of these nanostructures is merged with different compounds. These particles can be loaded on the surface or inside these structures [37, 38]. Targeting and simultaneous delivery of two or more compounds are among the other essential characteristics of these particles. CNTs have an extraordinary capacity in diagnosis and destroying the cancer cells inside the body [3943]. Studies have shown that CNTs enter the cells vertically through the endocytosis
process. Moreover, due to the needle-like shape and sharp tips of CNTs, they can pierce into and pass the membranes without damaging cell membranes. Studies revealed that in comparison with MWNTs, the smaller SWNTs could diffuse in cell and nucleus cytoplasm and pass cell membranes more easily. Drug encapsulation inside the CNT can protect it during its transport within the body. After being delivered at the target place, encapsulating 5
substances will erode and disappear. The CNT-encapsulated drug should be proportional to the CNT size and diameter. CNTs have a considerable ability in diagnosing and destroying the cancer cells inside the body [44-46]. Considering the increasing trend of applying carbon nanotubes in drug delivery, it has been considered as a drug carrier too which can be efficiently tuned by functionalizing. Various type of simulation approaches can be used to tackle the problem in the field of biomedical engineering [47, 48] and biomedicine development [49] like traditional CFD [50, 51], Lattice Boltzmann method [52, 53], molecular dynamics [54] and dissipative particle dynamics [55-57]. The molecular dynamics (MD) is a powerful tool in providing qualitative and quantitative data on the interactions and the physical-chemical mechanisms of pharmaceutical systems[14, 58-62]. Regarding the problems and high cost of experimental tests, nowadays many studies are conducted based on comutational approach to simulate the drug-delivery systems in cancer therapy [63-66]. Some limited molecular dynamic studies also have addressed the DOX delivery [67-71]. For example, molecular dynamics tools have been employed to study the DOX release from Graphene carriers and Graphene oxide [70, 72, 73]. In these studies, the effects of pH, molecular bonds, carrier size, and functional groups were investigated. However, no molecular dynamics study has been carried out on the DOX adsorption mechanism, diffusion and release from the MWNT in comparison to SWNT. In this work the unique comparison between MWNT and SWNT for the DOX delivery has been done. An attractive study of nanotubes functionalized with carboxyl group has been suggested for use as a drug doxorubicin. The adsorption and release of doxorubicin on this carrier have been investigated. All studies have been performed using powerful molecular dynamics tools. The interactions between drugs and carriers have been studied under different conditions, and the results have been analyzed. This work considered CNTs as a proper carriers for the drug release, and compared the 6
adsorption, diffusion, and release of the DOX from the SWNT with those of the MWNT, and introduced CNTs as a proper carriers for the DOX delivery.
2. Materials and methods 2.1 Molecular dynamics The base of molecular dynamics of numerical integration from Newton's motion equations is for all available particles in the system. By enacting Newton’s motion equations, a set of consecutive atomic positions are achieved. By using the molecular dynamics, properties of the system for each upcoming moment can be predicted based on its existing properties. Molecular dynamics includes the three following stages [74-76]: 1. Receiving the primary configuration of the particles. 2. Calculating the list of neighbors. 3. Calculating the force input to each atom according to the configuration and primary conditions. In each step, the force input to atoms is calculated and merged with the present situations and velocities in order to achieve the upcoming positions and velocities in a short time forward. It is supposed that the enacting force on each atom is stable during this time step.
2.2. Force fields The potential energy is a set of interaction energies that changes with the change of distances among the particles. Eq. 1 shows the potential function [77]. Eq. 2 shows that by the derivation from potential function, force function can be achieved for each i atom in a N atom system. Equations are solved simultaneously during the short steps of time. On the
7
other hand, by means of the Eq. 3, the force can be related to the place and time of the atoms [82-85]:
U U (r )
(1)
Fi dv dri
(2)
d 2ri m i 2 Fi dt
(3)
i 1,..., N
In this model, the particles move on the straight lines at a steady speed. Collisions are quite elastic and occur at times when the distance between couples of spheres is equal to the total of their radii. After a collision, the new velocities of the colliding sphere are calculated according to the principle of conservation of linear motion size. Employing a hard-sphere model, quite useful results were achieved. In the Van der Waals potential, the force between two atoms or molecules changes continuously with their distances. While, there is no force among the particles in the hard-sphere model, unless, they collide with each other. These parameters are usually determined with fit laboratory data or through exact calculations in the quantum chemistry. The r is the distance between two atoms and V is the potential between two atoms [78, 79, 86-92].
V 4 r r 12
6
(4)
Eqs. 5 and 6 were used to calculate the drug diffusion coefficient. For calculation of the drug diffusion coefficient, the mean-square displacement (MSD) was calculated,
8
t MSD [r (t ) r (0)]2 1 [r (t ) r (0)] 2 t t t 0
(5) (6)
D 1 lim MSD 6 t t
The simulation was performed using GROMACS software. Because it is open-source and popular for the drug simulation. The GROMACS has got a variety of packages for molecular dynamics calculation, which has been used for many advanced drugs and molecular experiments. Utilizing the Newton’s motion equations, GROMACS predicts the behavior of 100 to 1000000 particles. GROMACS was first developed for biomolecules such as proteins, lipids, and nucleic acids, which have a lot of complex transplant interactions [80, 81].
2.3. System preparation To model the SWNT and MWNT molecules, TubeGen Online was used; carbon dioxide molecules were added to the CNTs surface in two protonated and deprotonated modes. In the protonated conditions, hydrogen atoms were added to the carboxyl group groups on the surface of the nanotube, but the surface of the nanotube could not be protonated. The protonated state is a condition at which the functional groups on the nanotube surface gained positive charge by getting hydrogen. However, the nanotube itself did not change in the protonated and deprotonated state. The carbon atom surface charge in these nanostructures was considered 0 based on using the available structure of naphthalene in the oplsaa force field. The GROMACS 5.1 software was used for molecular dynamics simulation. The input structures were prepared with oplsaa force field. To get the molecule parameters, which 9
were changed to the script format, all molecules were put in the box and the tip3p water model was used as the solvent. The energy minimization was conducted on all simulation systems with 50000 steps, and the steepest descent method was employed to delete the Van der Waals interactions and form hydrogen bonds between water molecules and the others. In the next stage, the system temperature was increased gradually. Then, it was balanced at a constant pressure for 200 ps. The Parrinello-Rahman algorithm was used to balance the system pressure. The MD simulation was carried out at 37 °C temperature for 50 ns. The cut-off distance was considered to be 1.2. To calculate the electrostatic force, the particle mesh Ewald (pme) was used. LINCS (Linear constraint solver) algorithm was also applied to maintain the length of all bonds. To accelerate the calculations, SHAKE algorithm was utilized to limit the bonds engaged in hydrogen atom.
3. Results 3.1. Interaction energies In Fig. 1, the interaction energy of the DOX molecule with MWNT and SWNT is illustrated. As it clearly shows, in neutral pH, the electrostatic energy had the main contribution in the total interaction. While in the acidic pH, the electrostatic tended to zero, and Van Der Waals energy contributed in the total interaction. The direct relationship of molecules charge increase with electrostatic energy can be observed in this diagram. This is because the carboxyl group had negative charge and more electrostatic interactions in neutral pH and no charge in acidic pH. The increase in the electrostatic energy in neutral pH shows the strong adsorption of drug on the CNT surface. The MWNT was a stronger adsorbent than the SWNT for DOX in this pH range. The interaction means that the energy difference became stronger in MWNT; because as CNT size got larger, the surface area, interactions, and drug molecules were increased. 10
Fig. 2.a shows the water density along with the simulating box. As can be seen, the water density was increased inside the SWNT. In the neutral mode, the density was lower which indicates the presence of DOX molecules around the CNT. Lower SWNT density in neutral pH reflects the higher drug adsorption on the SWNT surface in neutral pH compared to the acidic pH. The acidic pH showed higher water density compared to the neutral pH which is a sign of drug release from the CNT surface. It is seen in the figure that the drug adsorption on SWNT was better in neutral pH since the drug release from SWNT was better in acidic pH. Fig. 2.b illustrates water density along the simulating box, where, the decrease in the density is a sign of MWNT; therefore according to the previous analysis and the figure, it is clear that the drug to acidic pH, the density changes were more extensive in MWNT at neutral mode, as the MWNT possessed higher density the adsorption on MWNT was better in neutral pH as its drug release was better in acidic pH. Compared to the acidic pH, density changes were larger in MWNT at neutral mode, as the MWNT possessed higher density than the SWNT.
3.2. Kinetics of drug adsorption and mass transfer parameters The Fig. 3a demonstrates the energy diagram of the SWNT in terms of drug interaction time in neutral pH (pH=7). The DOX molecule diffused toward SWNT and was finally adsorbed on SWNT surface after 3000 ps. At the time of surface adsorption, the sudden changes of total energy indicate the drug-SWNT interaction. In Fig.3b, the same diagram is shown for acidic pH (pH=5). As can be seen, changes in the total interaction energy were more in neutral pH as compared with acidic pH, suggesting the stronger bonding between drug and CNT in the neutral pH than acidic pH. Changes of interaction energy by passing of time are depicted in Fig. 4a for the MWNT at neutral pH. Accordingly, the drug surface adsorption on the MWNT in this pH took 1600 ps. Interaction energy for MWNT was 11
higher than the SWNT which shows more close interaction and stronger drug adsorption on this carrier. Fig. 4b represents the drug adsorption on the MWNT in acidic pH. As it is clear, the total interaction energy in neutral pH was more than in the acidic pH indicating a stronger bond between the drug and MWNT in the neutral pH compared to the acidic pH. Table 1 lists the average number of hydrogen bonds of drug-nanocarrier, drug-water, and water-nanocarrier. The number of nanocarrier bonds at different pH is also presented. In this study, the criterion of hydrogen bond formation was considered as the maximum hydrogen acceptor distance equal to 3 . In addition, the minimum hydrogen acceptor angle was considered to be 90⁰. As can be seen, by increase in the pH, the average hydrogen bonds of nanocarriers was increased and reached a maximum value in neutral pH. This shows higher drug adsorption in neutral pH. Therefore, in neutral pH there is a maximum adsorption compared to the acidic pH. So, for drug adsorption, it is better to have a neutral environment, while the acidic environment is preferred for the drug release. This analysis explains the superiority of pH mechanism for the drug release and adsorption. Furthermore, regarding the abundance of water molecules over the drug molecules, a great number of hydrogen bonds between water and nanocarrier were created.
In Table 2, the mean diffusion coefficient of the drug molecule in water presented. The diffusion coefficients were calculated for SWNT and MWNT in neutral and acidic pH. As can be seen, the diffusion coefficients in the neutral environment were low which can be due to the increase in interactions as the result of hydrogen bonds between water and drug or water and CNT. Because the increase in interactions leads to the steric hindrance and accordingly due to the increase in the number of hydrogen bonds in neutral pH, the diffusion coefficient was decreased. Moreover, the drug diffusion coefficient was low in
12
MWNT, which can be attributed to the more interactions of the MWNT compared to the SWNT.
3.3. DOX adsorption and release on SWNT Fig. 5 schematically shows the drug adsorption on the SWNT surface. As it can be seen in the right picture, drugs had Van der Waals interactions among their aromatic rings. As it is evident, the drug molecules from different parts (both aromatic and amino parts) interacted with the nanotube surface. In this part, the interactions included hydrogen bonds, Van der Waals, and electrostatic interactions. Closer view of the interaction between the drug and nanotube in Fig. 6 reveals that the drugs interacted with the nanotube and other drugs on different parts. The aromatic-aromatic interactions between the drug-nanotube and drug-drug are observable. In this simulation, the carboxylic functional groups were protonated, and the nanotube surface charge was zero. In the protonated state, the carboxyl groups on the CNT surface gained positive charge by getting hydrogen and the drug surface charge was still positive. Fig. 7 shows the Van der Waals energy, electrostatic, and total energy (total of Van der Waals and electrostatic) during the simulation process. Electrostatic energy played the most crucial role in the drug-nanotube interaction in neutral pH, and the negative charge of carboxyl group in this pH resulted in an electrostatic interaction enhancement (compared to the acidic pH). The Van der Waals energy was mostly assigned to the aromatic-aromatic interactions between the drug and nanotube. The vertical axis in Fig. 8 shows the number of hydrogen bonds in neutral pH and the adsorption time. As it can be noticed in the figure, most black points were between 2 and 3 indicating that the average number of hydrogen bonds between the drug and carrier was approximately between 2 and 3. However the average number of hydrogen bonds in acidic pH was less than 1. This suggests a stronger 13
connection between the drug and CNT in neutral pH. Therefore, the acidic pH had better conditions for the drug release. Fig. 9 shows the energy vs. time plot for the acidic pH. Considering the zero charge of the carboxyl group in this pH, it can be stated that the electrostatic energy was shallow and almost zero, compared to that in neutral pH, and the total interaction energy was mostly due to the Van der Waals interactions. The vertical axis in Fig. 10 shows the number of hydrogen bonds in acidic pH and the release time, while the horizontal one shows the simulation time. It can be seen in this figure that most black points were between 0 and 1 indicating that the average number of hydrogen bonds between drug and carrier was less than 1. However, the average number of hydrogen bonds in neutral pH was about 2.4 suggesting the stronger connection between the drug and CNT in neutral pH. Therefore, the acidic pH had better conditions for drug release.
3.4. Drug release and adsorption based on MWNT Fig. 11 schematically shows the DOX release and adsorption on drug carrier of MWNT with carboxyl functional group. Fig. 12 shows the interaction energy vs. time for the DOX adsorption in neutral pH and drug release from the CNT in acidic pH. At the time of drug adsorption, the Van der Waals energy contribution was minor, while the electrostatic energy share formed the central part of total interaction energy. This is can be attributed to the presence of the carboxyl group, because this functional group has negative charge in neutral pH and has no charge in acidic pH. During the drug release, electrostatic energy was very negligible, and almost zero; and Van der Waals energy constituted the central part of total interaction energy. Furthermore, total interaction energy in neutral pH (drug adsorption) was much higher than the total interaction energy in acidic pH (drug release) reflecting that the drug tended to be released and separated from CNT. 14
Fig. 13 presents the number of hydrogen bonds at the time of the DOX adsorption and release from MWNT. As it is apparent in the figure, the average number of hydrogen bonds at the time of adsorption was much more than the hydrogen bonds at the time of drug release. The decrease of hydrogen bonds number shows the drug tendency to be released from MWNT in acidic pH. Fig. 14 shows the MSD diagram of the DOX. The local slope of plot is the diffusion coefficient in the corresponding time. A comparison of slopes shows that the average diffusion coefficient at the adsorption time was less than its value during the drug release which can be due to the steric hindrance of hydrogen bonds, which slowed down the drug molecule diffusion.
3.5. pH based stability The Root-mean-square deviation (RMSD) of the system is one of the critical parameters in molecular dynamics simulation. The RMSD shows the deviation of the particles position relative to their reference position at each time. The RMSD indicates the model stability, where, the slopes near to 0 show higher stability of the simulated model. The gradual increase in the slope or sharp fluctuations show the instability. Fig. 15 shows the RMSD for the neutral and acidic pH for MWNT and SWNT. At the beginning of the simulation, the system was instable, and after 300 ps the slope approached zero and the simulated system reached stability; in other words, a stable complex was created. This system reached a stable mode in a quick time which can be due to the small size of the molecules and the fast and robust interactions of molecules with each other. In order to assess the stability of each molecule, the data related to the interaction energy can be used. In Fig. 1, it is shown that the interaction energy between the CNT and DOX in neutral pH is
15
too high, which is an indicative of the high stability of the bonding between the drug and CNT. 4. Conclusion
Doxorubicin is one of the most common anticancer drugs that has been studied extensively for targeted drug delivery. In this study, carbon nanotubes have been proposed and studied as carriers of this drug. The results of this study showed that carbon nanotubes could be suitable carriers for the adsorption, transport, and release of doxorubicin. Carbon nanotubes have attractive drug delivery properties such as high diffusion coefficient and small size and many other features. This study sought to improve the properties of the nanotubes for doxorubicin release. The interesting point of this study was the use of carboxyl functional groups to improve the properties of the nanotubes. The surface charge of the carboxyl group changes based on environmental acidity. This key feature of carboxyl functional groups has enabled them to control drug release. Carboxyl functional groups are also hydrophilic and reinforce the hydrophilicity of carbon nanotubes. These also prevent aggregation of nanotubes into the bloodstream. This characteristic of carboxyl functional groups in hydrogen bonding diagrams is quite clear. These groups increase hydrophilicity by increasing hydrogen bonds. Thus, this study showed that using these functional groups can improve the properties of nanotubes for drug release. Also, in this study, multilayer and single wall nanotubes were compared, and it was found that multilayer nanotubes have better properties for the transfer and release of doxorubicin. As a recommendation for further studies, nanotubes can be used as drug carriers along with other compounds, such as polymers. It is necessary to take further steps to improve the properties of carbon nanotubes so that they can be used on a commercial scale. This study was performed using molecular
16
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Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
26
Fig. 1. The total interaction energy (total), Van der Waals and electrostatic energy between the DOX and SWNT and between the DOX and MWNT in acidic pH and neutral pH
8000
Interaction Energy (KJ/mol)
7000 6000 5000 4000 3000 2000 1000 0 Neutral-SWNT
Acid-SWNT
Van der waals
Neutral-MWNT Electrostatic
27
Acid-MWNT Total
Fig. 2.a. The water density vs. distance of simulation box for SWNT in acidic pH and neutral pH
Partial density 1100 CNT-mono-Neutral CNT-mono-Acid
Density (kg m-3)
1050
1000
950
900
850
800 0
1
2
3
Coordinate (nm)
28
4
5
6
Fig. 2.b. The water density vs. distance of simulation box for MWNT (Multi) in acidic pH and neutral pH
29
Fig. 3a. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT in neutral pH
30
Fig.3.b. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT
31
Fig. 4.a. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT in acidic pH
32
Fig. 4.b. The total interaction energy (Total), Van Der Waals (VDW) and electrostatic energy (Elec) between the DOX and MWNT in acidic pH
33
Fig. 5. The schematic illustration of the DOX adsorption on SWNT
34
Fig. 6. The schematic illustration of the DOX adsorption on SWNT (closer view)
35
Fig. 7. Total interaction energy (Total), Van der Waals (VDW) and electrostatic energy (Elec) between the DOX and SWNT in neutral pH (loading)
0 VDW Elec Total
Energy (KJ/mol)
-1000
-2000
-3000
-4000
-5000 0
10000
20000
30000
Time (ps)
36
40000
50000
Fig. 8. Hydrogen bonds between the SWNT and DOX in neutral pH (adsorption)
7 Hydrogen bonds
Number of Hbonds
6 5 4 3 2 1 0 0
10000
20000
30000
Time (ps)
37
40000
50000
Fig. 9. Total interaction energy (Total), Van der Waals (VDW) and electrostatic energy (Elec) between DOX and SWNT in acidic pH (release)
0 VDW Elec Total
Energy (KJ/mol)
-100 -200 -300 -400 -500 -600 -700 -800 0
10000
20000
30000
Time (ps)
38
40000
50000
Fig. 10. Number of hydrogen bonds between SWNT and DOX in acidic pH (release)
4
Number of Hbonds
3
2
1
0 0
10000
20000
30000
Time (ps)
39
40000
50000
Fig. 11. The DOX loading and release based on MWNT
Uptake
Release
40
Fig. 12.a. Total interaction energy (Total), van der Waals (VDW) and electrostatic energy (Elec) between DOX and SWNT in acidic pH(release) and neutral pH (uptake)
0
Uptake
-1000
VDW Elec Total
Energy (KJ/mol)
-2000 -3000 -4000 -5000 -6000 -7000 -8000 0
10000
20000
30000
Time (ps)
41
40000
50000
Fig. 12.b. Total interaction energy (Total), van der Waals (VDW) and electrostatic energy (Elec) between DOX and SWNT in acidic pH(release) and neutral pH (uptake)
0
Energy (KJ/mol)
-100
VDW Elec Total
-200 -300 -400 -500 -600 -700 -800 0
10000
20000
30000
Time (ps)
42
40000
50000
Fig. 13.a. The hydrogen bonds between the MWNT and neutral pH (uptake)
8
Uptake
7
Number of Hbonds
6 5 4 3 2 1 0 0
10000
20000
30000
Time (ps)
43
40000
50000
Fig. 13.b. The hydrogen bonds between the MWNT and DOX in acidic pH (release(
6
Release
Number of Hbonds
5
4
3
2
1
0 0
10000
20000
30000
Time (ps)
44
40000
50000
Fig. 14.a. MSD of DOX in neutral pH (loading)
2
MSD (nm2)
Uptake
1
0 0
10000
20000
Time (ps)
45
30000
40000
Fig. 14.b. MSD of DOX in acidic pH (release)
15 14 13
Release
12
MSD (nm2)
11 10 9 8 7 6 5 4 3 2 1 0 0
10000
20000
Time (ps)
46
30000
40000
Fig. 15. The root-mean-squared deviation (RMSD) of the system as a function of time
16 14
RMSD(0A)
12 SWNT-Neutral pH SWNT-Acidic pH MWNT-Neutral pH MWNT-Acidic pH
10 8 6 4 2 0
10000
20000
30000
Time (ps)
47
40000
50000
60000
Table 1: number of hydrogen bonds between DOX-Nanocarrier, DOX-Water and Water-Nanocarrier Average Number of H-bond System DOXWaterDOX-Water Nanocarrier Nanocarrier SWNT 0.5 19 93 Acidic pH SWNT 2.4 18 224 Neutral pH MWNT 1.46 18 160 Acidic pH MWNT 2.24 18 372 Neutral pH
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Table 2: diffusion coefficient of SWNT and MWNT in acidic pH and neutral pH D (105 System Average Adsorption Time (ps) cm2/s) SWNT 1.7 2100 Acidic pH SWNT 0.7 4200 Neutral pH MWNT 1.13 1600 Acidic pH MWNT 0.87 18000 Neutral pH
49