Different mechanisms of DOX and PAX were studied in two physiological (pH=7.4) and cancerous (pH=5.5) conditions to predict cellular penetration, adsorption, and release.
1- Drug adsorption in neutral condition (pH=7.4)
In the fig.1., the interaction of the DOX molecule with the single-walled nanotube is investigated. As shown in the figure at neutral pH, electrostatic energy plays a significant part in the total interaction energy. While in the acidic state, the electrostatic energy is zeroed, and the van der Waals energy has a considerable share of the total interaction energy. This is due to the surface charge of the carboxyl functional groups at the nanotube surface. Because the nanotube is functionalized with carboxyl functional groups. The carboxyl group has a negative charge at neutral pH and no charge at acidic pH.
On the other hand, DOX has a positive charge at both neutral pH and acidic pH. As a result, in the neutral state, drug functional groups and nanotube have anonymous charges, and there are robust electrostatic interactions. The higher the electrostatic energy at neutral pH, the higher the adsorption of the drug onto the nanocarrier surface at this pH. The important thing is that the drug at a neutral pH, which is the pH of the blood, can transfer well to the surface of the nanotube, and the nanotube, having a strong attraction to the DOX drug, is an excellent carrier for this drug.
The following figure(fig.1.) shows the interaction between DOX and chitosan. As it is evident from the picture, the Van der Waals force is close to zero, but there is a considerable negative electrostatic interaction between the drug and the chitosan. This interaction is due to the positive charge of DOX and the negative charge of chitosan at this pH. The negative electrostatic energy indicates a strong attraction between the drug and the chitosan. Chitosan is a critical aid in the adsorption of the drug.
In the following (Fig.2.), the energy interaction of PAX with single-walled nanotubes is investigated. As shown in the figure at neutral pH, van der Waals energy shows a more significant number, and electrostatic energy is close to zero. The nanotubes are functionalized with carboxyl functional groups. The carboxyl group has a negative charge at neutral pH and no charge at acidic pH. On the other hand, PAX has zero charges at neutral pH. As a result, in the neutral state, the electrostatic energy between PAX and the nanotube is close to zero. Van der Waals Energy plays a significant part in the uptake of PAX on carbon nanotubes.
On the other hand, Fig.2. Showed the energy interaction of PAX with chitosan. As shown in the figure at neutral pH, van der Waals energy shows a more significant number, and electrostatic energy is close to zero. PAX has zero charges at neutral pH. As a result, in the neutral state, the electrostatic energy between PAX and chitosan is close to zero. Van der Waals Energy has a significant contribution to the uptake of PAX on chitosan. Hydrogen bonds, which is a significant factor in drug delivery. A comparison between PAX and DOX shows that the DOX-chitosan hydrogen bonds are stronger than the PAX-chitosan hydrogen bonds. Therefore, the addition of chitosan also contributes to better adsorption of DOX because the strength of the hydrogen bonds between DOX and chitosan is relatively high.
Table..1: Number of Averages H bonds-average
|
DOX-CNT
|
DOX-TMC
|
PAX-CNT
|
PAX-TMC
|
pH= 7.4
|
.007
|
2.707
|
0
|
0.342
|
pH=5.5
|
0
|
0.071
|
0.189
|
0.112
|
2- Drug release in acidic condition (pH=5.5)
In the following figure, Fig.3. The interaction of the DOX molecule with single-walled nanotube nanocarriers is investigated. As shown in the picture at acidic pH, the electrostatic energy is shallow
and close to zero. At acidic pH, electrostatic energy is zero, and van der Waals energy has a significant contribution to the total interaction energy. This is due to the surface charge of the carboxyl functional groups on the nanotube surface. The nanotube is functionalized with carboxyl
functional groups. The carboxyl group has a negative charge at neutral pH and no charge at acidic pH.
On the other hand, DOX has a positive charge at neutral pH and acidic pH. As a result, in the neutral state, drug functional groups and nanotube have anonymous and find strong electrostatic interactions. However, at acidic pH, nanotube and carboxyl group charges become zero. Furthermore, the electrostatic interaction energy between the nanotube and DOX is also zero.
The higher energy of the double-walled nanotubes than the single-walled nanoparticles and fullerene indicates that the double-walled nanotubes are a stronger absorbent for DOX at this pH. Furthermore, after that, single-walled nanotubes can absorb DOX molecules better than fullerene.
The following figure (Fig.3.) shows the interactions between DOX and chitosan polymer. The interesting point in the diagram below is that the interaction between the drug and the chitosan in an acidic state has positive electrostatic energy. This means that there is a repulsion between chitosan and the drug, and this is very effective in releasing the drug. Repulsion between chitosan and drug causes the better release of drug from chitosan and nanotube surface. In fact, besides biocompatibility and hydrophilicity, chitosan plays a critical role in the mechanism of drug release in cancer tissue.
The figure (Fig.4.) shows van der Waals and electrostatic interaction between PAX and nanotube. As is clear from the picture, the electrostatic energy is close to zero, and the total energy is approximately equivalent to the van der Waals energy. The loss of electrostatic energy is due to the zero charge of the carboxyl group at acidic pH. Moreover, the surface charge of the PAX is close to zero. Therefore, the electrostatic interaction between PAX and the nanotube is zero, and the van der Waals interaction is fragile. The weak interaction energies lead to a better release of the drug from the nanotubes and are considered a decisive factor for the carrier, which can be very useful in drug release.
Also, The last figure Fig.4. shows the interaction energy between PAX and chitosan in an acidic state. As can be seen from the figure, the electrostatic and van der Waals interaction between the drug and the chitosan is zero, which helps the drug release. The zero electrostatic energy is due to the zero-surface charge of PAX.
Hydrogen bonding between two atoms is defined as a receiver-acceptor pair with an angle between them less than 30 degrees. The graph of changes in the number of hydrogen bonds over time between the polymer-polymer and polymer-drug and CNT-drug for all three simulations are shown in the diagrams below. Hydrogen bonds indicate the amount of hydrophilicity property of carriers. Besides, hydrogen bonding is part of the interatomic forces that can contribute to carrier strength and stability. The following diagrams at Fig.1. And Fig.3. Show that DOX is not bound to CNT but has many hydrogen bonds with TM-chitosan polymer. This chart illustrates the crucial role of chitosan in this drug delivery system. Because chitosan forms carriers more hydrophilic through hydrogen bonding formation. CNTs and DOX, as well as PAX, are hydrophobic compounds, and this is a significant drawback for pharmaceutical carriers. Because hydrophobic compounds aggregate in water and form larger particles that disrupt drug delivery and block the bloodstream. However, Chitosan has solved this problem by hydrophilizing the complex. The graphs in Fig.2. and Fig.4. also show that PAX did not form eligible hydrogen bonds with CNT, while the same drug with chitosan has many.
3- Cell penetration
Gyration radius is a factor that enables the aggregation of molecules such as polymers, resizing of biological macromolecules such as proteins over time. The diagram of the gyration radius is shown below. As shown in the figure below (Fig.5.), the gyration radius indicates the accumulation of polymer molecules in one region. The higher the gyration radius, the greater the dispersion between the molecules. The gyration radius of DOX and PAX is about 3 nm, indicating the complex radius of drug accumulation on the fullerene surface. Due to the fullerenes and box simulations, a useful aggregation of drugs is formed around the SWCNT. This indicates that the polymer molecules are clustered together in this simulation. PAX also has a lower radius than DOX, indicating a better accumulation of PAX than DOX. Complexation due to the accumulation of PAX molecules is more stable and concentrated.
4- radial distribution function
The following diagrams show the radial distribution function of DOX and PAX in the simulation box. For both layouts, there is a steep slope of the graph and peak. Where the peak diagram is seen, and the RDF is high, the accumulation of drug molecules has occurred. This indicates that the drug molecules are aggregated at one point and are concentrated at the same spot and are not distributed in the simulation box. This result corroborates previous results suggesting acceptable drug adsorption on fullerenes and polymers.
5- drug diffusion coefficient
The slope of the mean square displacement curve represents the diffusion coefficient. This chart shows the diffusion coefficient of DOX in the simulation box. The steric hindrance is less an acidic state. Because the adsorption of the drug on the fullerene surface is less, so their accumulation is lower than that of the neutral state, and as a result, the number of collisions and steric hindrance is less.
Eventually, the reduction of the steric hindrance will increase the diffusion coefficient. So, in the acidic state, the drug diffusion rate is higher.