Studies On The Transport Properties Of Carbon Nanotube-A New Drug Delivery System

Carbon nanotubes (CNTs) have been recognized as one of the most fascinating materials because of their unique tubular structural and consequently excellent mechanical, chemical, electronic and optical properties and have already been widely employed in physical, biotechnological, biomedical and biochemical fields. The molecular dynamic simulations (MD) have proved that the carbon nanotubes have emerged as a new alternative and efficient tool for transporting and translocating bioactive molecules (peptides, proteins, nucleic acids and drugs), for CNT can be functionalized with bioactive molecules, and used to deliver their cargos to cells and organs. Because functionalized CNT (f-CNT) display low toxicity and are not immunogenic, such systems hold great potential in the field of nanobiotechnology and nanomedicine. However, the mechanism of transport is far from clearly. Thus, in the present doctoral dissertation, by using density function theory calculations (DFT) and molecular dynamic simulations (MD), we have studied the interaction between single-walled carbon nanotube and two widely used drugs (nifedipine, the calcium channel antagonist and doxorubicin, the anti-cancer drug). As a result, some significant progresses have been made, which can be described as follows.(1) Exploration of the Ca2+-interaction Modes of the Nifedipine Calcium Channel AntagonistTo pave the way for how the calcium cations bind to the proteins in the presence of the drug (nifedipine) that regulate the channels and how they transfer through the channels, we begin with accumulating a quantitative knowledge of how calcium ion interacts with the single drug molecule. Detailed studies of the interaction between them are essential for understanding the role of nifedipine in the biophysical course though the biological processes occur in solution. A good knowledge of geometries and relative energies in the gas phase can be useful for application to condensed-phase by computational techniques. This allows us to perceptively predict and understand the effect of the antagonists on the calcium channels. This work offers a discussion of the chelating structures of Ca2+ with the most important class of the calcium channel antagonists with density functional theory calculations and molecular dynamic simulations. Although the real interaction between the metal ions and nifedipine is much more intricacy because of the complexity of the drug and the surroundings, the performed analyses have also presented a comprehensive understanding about the affinity. There are 25 minima on the PES. The favorable isomer of nifedipine-Ca2+ system without water molecules is a tridentate one in which the Ca2+ interacting with two carboxyl oxygen atoms and one nitryl oxygen atom. The next one is 18.77kcal mol-1 higher than isomer 1 in energy, where Ca2+ cheated with one etheric oxygen atom substituting for the carbonyl oxygen atom. This indicated that the isomer 1 was extremely stable in the gas phase on this theoretical level. Furthermore, the bidentate isomers 5 and 6 are found to be more stable than the tridentate ones 7, implying that the coordination number has no directly connection with the stability of isomers. The chelating structures and energy characters of the first 15 isomers have been investigated from chelating sites, electrostatics and polarizations, steric repulsions, charge distributions and intramolecular H-bond. The bonding ability of the negative atoms is the nitryl O＞the carbonyl O＞the etheric O＞the imine N, and the main binding character is that Ca2+ couples with nifedipine as in the multidentate form as possible. Because of the similarity of the geometric character and relative energy, the interconversions may occur among some structures in gas phase. Furthermore, in vivo, the complexes exist in the bulk solvent. Considering the effect of water, some different phenomena may take place for the nifedipine-Ca2+ complexes. To approach the real biological processes, the hydration effect on the nifedipine-Ca2+ complexes have been investigated systematically. We found that the hexa-coordination is the favorable hydrated geometry no matter how many water molecules are contained at this level of theory, which can be supported by the MD simulations for the nifedipine-Ca2+ system in aqueous solution. Influenced by the ion-ligand electrostatic interaction, charge transfer from ligand to ion, ion-ligand and ligand-ligand repulsions, the increase of the water molecules in the first shell has weakened the interaction between nifedipine and Ca2+, and the hexahydrated complexes are the most stable ones due to the hydration energy. On the other hand, the MD simulations for hexahydrated complexes have also verified that water molecule can transfer from the inner-to the outer-shell because of the formation of H-bond between the two shells ligands. So it can be expected that the "n+m" clusters will play a significant role for nifedipine-Ca2+(H2O) n system (n＞6), when the ligands in the inner shell become too crowed.(2) Interaction Site Preference between Carbon Nanotube and Nifedipine:A Combined Density Functional Theory and Classical Molecular Dynamics StudyUsing a novel DFT, MPWB1K, both internal and external adsorptions of a nifedipine, one of the calcium channel antagonist, on a (10,10) type of single-walled carbon nanotube (SWCNT) were investigated with both C200H40 and C280 cluster models for the SWCNT. The internal adsorption is more stable than the external adsorption in a range of 5.3-7.8 kcal/mol, which indicates that a nifedipine has a preference to internally adsorb on the (10,10) SWCNT. It also proved that the passviated nanotube by hydrogen atoms has no obvious influence for the SWCNT-nifedipine system. Furthermore, molecular dynamics simulations (MD) were then done on the system consisting of nifedipine and the SWCNT (10, 10) in the absence and in the presence of water molecules. The spontaneous encapsulations of nifedipine into the SWCNT channel were observed in both cases; however this process was significantly delayed by including water molecules in the simulation. The nifedipine for both cases also demonstrates an oscillation behavior inside the (10,10) SWCNT, which again occurs later for the system including water than without water. The two competing effects, van der Waals and the hydrophobic forces caused by water molecules, should be responsible for the encapsulation process, yet the van der Waals attraction plays a dominant role on the encapsulation process of nifedipine into the nanotube and the oscillation behavior of nifedipine. In addition, it was found that the water molecules absorbed inside the channel is an irregular monolayer interacting with the nanotube interior surface.(3) Effects of adsorption of Ca2+ on SWCNT-Nifedipine systemThis work offers an exploration of the affection of Ca2+ on the SWCNT-Nifedipine system using density functional theory calculations. First of all, we calculated the interaction between the single-walled carbon nanotube and Ca2+. There are four distinct symmetry sites related to the relative position of Ca2+ with respect to the nanotube carbon rings, which is the center of the carbon rings, the center of the C-C bond along the radical direction of the tube, the center of the C-C bond parallel to the axis of the tube, and the site on the top of a carbon atom. We designed two different situations containing the Ca2+ on the external sidewall of the nanotube and in the internal of the nanotube channel. The most favorable isomer of SWCNT-Ca2+ system is the one that Ca2+ binding to the external sidewall of the nanotueb above the center of the carbon ring, due to the cation-πinteraction between the Ca2+ and the nanotube. The distance of Ca2+ to the surface of the carbon nanotube is 2.3 (?). Then we calculated the effection of nifedipine to the carbon nanotube. We found that the most stable isomer is the one that nifedipine molecule encapsulated into the nanotube channel with the dihydropyridine ring parallel to nanotube surface. Theπ…πstacking interaction between the dihydropyridine ring and the carbon rings and the X-H…π(X=C, N) interaction are overcompensate the steric repulsions caused by the encapsulation of the drug. Finally, four complexes of the SWCNT-N-Ca2+ system are investigated to exploration the affection of Ca2+ to the most stable SWCNT-N complex (complex 1). It is interesting that the Ca2+ is above the center of the carbon rings after optimized in all cases. On the other hand, we discuss the change of the HOMO-LUMO gap and the electron density of states (DOS) of carbon nanotube caused by the adsorption of Ca2+ and nifedipine molecule. It is found that the adsorption of Ca2+ can reduce the HOMO-LUMO gap of the nanotube, and change the DOS around the Fermi level dramatically. Compared with the intrinsic carbon nanotube, the conductivity of the SWCNT-Ca2+ system is improved obviously. However, the adsorption of nifedipine molecule reduced the conductivity of the SWCNT-N system unexpectly. Similar with the SWCNT-Ca2+ system, the reducing HOMO-LUMO gap and the improved conductivity are also found in SWCNT-N-Ca2+ system.(4) Interaction between Single-Walled Carbon Nanotube and Doxorubicin, a very widely used anti-cancer drugTo quantify approximately the thermodynamics of binding, and to obtain putative binding structures, we simulated interaction between the widely used anticancer drug, doxorubicin molecule and the (10,10) armchair carbon nanotube in neutral and in acidic aqueous solutions. The drug could spontaneously encapsulate into the nanotube channel and the process was significantly delayed by the presence of water molecules in neutral solution, The van der Waals attraction plays a dominant role on the encapsulation process. On the other hand, the doxorubicin molecule adsorbed on the external wall of the nanotube in acidic aqueous solution throughπ…πstacking interaction between the aromatic rings and the carbon rings. The present study suggests that the nanotube network could be used as an efficient tool for transporting this kind of anti-cancer drug. Furthermore, the equilibrium distances, adsorption energies, charge transfer, and density of states characteristics are investigated about SWCNT-DOX system in gas phase. The results show that the main contribution comes from theπ…πstacking and X-H…πinteraction (X=O, N, and C) between the doxorubicin and the nanotube. In addition, the presence of the doxorubicin molecule would neither modify the DOS of the SWCNT nor lead to significant changes in the conductivity of the nanotube. The fact that the electronic properties of the SWCNT are preserved upon doxorubicin adsorption is found to be a general feature.