Heat driven release of pyrazinamide

Transcription

1 6 Heat driven release of pyrazinamide molecules encapsulated within singlewall carbon nanotubes In this Chapter, Introduction Computational details Results and discussion Temperature effect in the drug release mechanism, role of fullerene (C 60 fillers) in the elimination of pyrazinamide molecules, diffusion co efficient of PZA molecules as a function of temperature ABSTRACT With an aim at understanding the controlled release of multiple pyrazinamide (PZA) drug molecules encapsulated within single wall carbon nanotubes (SWCNTs) mediated by fullerene (C 60 ) fillers we have performed molecular dynamics (MD) simulations at five different temperatures. Within the nanotube cavity, in absence of any external driving force or agent, the high energy barrier energetically favours the encapsulation of PZA molecules. The simulations of PZA SWCNT in presence of C 60 fillers demonstrate that incorporation of fillers helps in driving the PZA molecules from the nanotube cavity through the mutual displacement process of PZA by C 60, accounted to the comparatively higher π π stacking between C 60 SWCNT compared to PZA SWCNT. The root mean square deviation (RMSD) provides definitive insight into drug release and simultaneous C 60 entrapment within the nanotube. The comparison of the diffusion co efficient, variation of centre of mass (COM) and energetics profile at the studied temperatures suggests enhanced PZA diffusion from the nanotube with increase in temperature.

2 Heat driven release of drug molecules from carbon nanotubes Introduction One dimensional nanomaterials like single wall carbon nanotubes (SWCNTs) formed by the rolling of graphene sheet along its chiral vector draws considerable research interest accounted mainly from its unique structure as well as the electronic properties. Some of the widely explored potential applications of SWCNTs include in biosensors, 1 hydrogen storage devices, 2,3 field effect transistors (FET) devices, 4 gas sensors 5,6 etc. to name a few. Unlike the other class of graphene based nanomaterials, SWCNTs facilitate in the interaction of various molecules both along the sidewall and within the hollow cylindrical cavity (endohedral) leading to the formation of quasi 1D arrays. 7 The noteworthy prospects of using SWCNTs as drug delivery systems for systematic loading and delivery of therapeutic agents at the target site of action can be accounted to its needle like structure which can easily penetrate the cell membrane (nano inject) and transfer the cellular components with reduced side effects The development of new drug delivery systems aim in improving the pharmacological profile of the drug while decreasing the toxicological side effects. SWCNTs with its intrinsic structural properties in addition to its ability to absorb near infrared (NIR) radiation within nm 11 along with Raman and Photoluminescence properties exhibit additional advantages for tracking and real time monitoring of drug trafficking in vivo. 12 The NIR laser irradiation can heat up and destroy malignant tumour cells pre conjugated with SWCNTs as most living organisms are transparent to NIR irradiation. 13 Recent studies have stressed to the fact that SWCNTs because of its needle like structures can easily penetrate the cellular membrane and with proper functionalization high biological accessibility within the body can be achieved. 14,15 The formation of fullerene arrays within the hollow cavity of SWCNT was first observed by Smith et al. in 1998 using high resolution transmission electron microscopy (HRTEM). 16 Buckminster fullerene or buckyballs (C 60 ) was the first studied molecule to be encapsulated within CNTs. Because of the similarity in the structural motif 7 and uniform centre to centre distances the fullerene molecules encapsulated with the nanotubes popularly came to be popularly known as peapods. 17 Governed by the van der Waals (vdw) interactive forces and the highly delocalized π electron network the interior of SWCNTs provide efficient interaction of about 3 ev per C 60 meaning 50 % than the cohesive energy of the fcc fullerene crystal. 18 The encapsulation of fullerene inside CNTs is quite spontaneous

3 182 Chapter 6 and irreversible process basically dependent on nanotube diameter as opposed to the diameter of C 60 and the encapsulation process of C 60 are exothermic for nanotubes of suitable diameters such that the resultant π π interaction stabilizes the host guest structure. 19 Apart from the studies on encapsulation of fullerenes with CNTs a number of organic molecules, 20 organometallic compounds, 21 polymeric chains, 22 DNA oligonucleotides, 23 peptides, 24 proteins, 25,26 and chemotherapeutic molecules 14,27 have been documented which suggest the favourability towards endohedral filling of SWCNTs. Yumura and Yamashita performed density functional studies on interaction of methyl terminated thiophene oligomers inside CNTs. 28 The study highlighted that oligomers prefer to remain localized along the inner wall of the nanotube due to the enhanced π π and CH π interactions coming to interplay. Xue et al. in a recent study investigated the release of encapsulated molecules within CNTs by C 60 fillers through a displacement process which is attributed to the vdw interaction between the nanotube and filler molecules rather than the nanotube and encapsulated molecules. 29 Their study showed that the encapsulation of C 60 within the nanotube is quite spontaneous and driven by the vdw forces, the release of the molecules is also fairly favourable. Similarly, Gao et al. 30 investigated the spontaneous encapsulation of DNA oligonucleotides within SWCNTs and showed that the vdw forces play a major dominant role. Under normal conditions, in absence of any external actuation mechanisms thermal, 31 optical, 32 mechanical, 33 and electric fields, 34 the drug molecules prefer to remain inside the SWCNT due to the high energy barrier thereby preventing from getting expelled from the nanotube. 29 The present study investigates the controlled heat driven release of PZA antitubercular drug molecules encapsulated within SWCNT mediated by fullerene (C 60 ) fillers using a mutual displacement mechanism. To mimic the physiological scenario of heating SWCNT by NIR radiation pre capsulated with multiple PZA molecules we have studied the drug release process as a function of temperature. We analyzed the root mean square deviation (RMSD) for the studied systems at five temperatures to understand the fluctuations induced within the system with rise of temperature. The diffusion coefficient of PZA from SWCNT has been evaluated at the five temperatures to comprehend the temperature effect in release of the chemotherapeutics. Our study thus provides an in hand understanding on the role of C 60 fillers in the expulsion of PZA molecules entrapped within SWCNT and the temperature

4 Heat driven release of drug molecules from carbon nanotubes 183 dependence towards the phenomenon can aid in near future experimental studies pertaining to tuberculosis (TB) chemotherapy. 6.2 Computational details The GROMACS program 35 with OPLSA force field was used to study the MD simulation for the system comprising of SWCNT, PZA and C 60 filler molecules. SWCNT of chirality (10,10) having a diameter of Å and length of Å was chosen for the study. We considered only one model of the nanotube for the simulation due to the computational limitations in modeling large molecular systems. The simulation system consists of (10,10) SWCNT with the encapsulated PZA molecules forming a cluster around the central region of the nanotube depicting a scenario wherein the nanotube loaded drug molecules has been delivered to the target cells but not loaded yet. At the initial configuration, five filler molecules were placed close to the entering cavity along one of the nanotube open axis with the entrapped PZA molecules intact. The MD simulation was performed in an NVT (constant volume and temperature) ensemble using the Berendsen thermostat method to control the system at five temperatures namely 298, 300, 310, 330 and 337 K, respectively. The cut off distance for non bonded interactions i.e. vdw and electrostatic forces were taken as 1.0 nm with a time step of 2 fs for the simulation run. The system was solvated in a periodic box having an inter spacing of 15 Å to neglect any spurious interaction of the system with its replicating images using the TIP3P water model for the solvation. The long range electrostatic interaction was treated with the particle mesh Ewald method 36 and the cutoff for the vdw interaction was set at 15 Å. The system at the five studied temperatures was initially energy minimized for 5 ns followed by production simulation of 1 ns at fixed temperature and constant pressure of 1 bar. Finally the MD simulation for 10 ns was performed at 2 fs time step for each of the SWCNT PZA C 60 system at the five temperatures defined above. In addition we performed test simulation of SWCNT encapsulated with PZA molecules without the fillers in addition to C 60 SWCNT without the PZA molecules at 298 K temperature to contrast the role of fillers in the release of PZA from the nanotube cavity for 5 ns using the NVT ensemble and Berendsen thermostat. The diffusion co efficient of the PZA molecules from (10,10) SWCNT at the five studied temperatures was calculated using the Green Kubo method 37 which determines the

5 184 Chapter 6 exact mathematical expression for transport coefficients in terms of integrals of time correlation functions. 6.3 Results and discussion Simulation of the release of PZA molecules from SWCNT mediated by C 60 The choice for considering C 60 as fillers for replacing PZA drug molecules entrapped within SWCNT is twofold; one due to the small size and confined π electron framework the encapsulation of fullerene is flexible within the nanotube and second C 60 holds biological importance especially in the diagnosis and therapy of diseases, 38 drug delivery, 39 and biosensors. 30,40 Figure 6.1 depicts the stepwise process of the gradual release of PZA molecules for a simulation time of 10 ns at 298 K temperature (25 C). Figure 6.1 Simulation snapshots corresponding to the gradual release of PZA molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 2, (d) 4, (e) 5, (f) 8 and (g) 10 ns at 298 K temperature. In the initial time frame corresponding to 0 ns (Figure 6.1a), C 60 fillers progressively course into the hollow cavity of SWCNT leading to the release of one PZA molecule from the nanotube which continues till the first 1 ns (Figure 6.1b) wherein three of the filler C 60 molecules passage inside the nanotube subsequently pushing the PZA molecules out due to

6 Heat driven release of drug molecules from carbon nanotubes 185 the confinement effect. Within the time frame of 1 to 2 ns, complete encapsulation of all five C 60 fillers is accompanied by release of all the PZA molecules from the nanotube cavity (Figure 6.1c). The diameter of (10,10) SWCNT considered for the study is thus optimum enough to hold the C 60 molecules but space restriction hinders the encapsulation of PZA or water molecules simultaneously along with the C 60. The release of PZA with encapsulation of C 60 is quite spontaneous at 298 K temperature taking place at around 1 2 ns time frame suggesting the favorability towards the encapsulation. Beyond 2 ns till the completion of simulation at 10 ns (Figure 6.1d g) the fillers prefer to remain within the nanotube hollow cavity which can be basically accounted to the strong π π and CH π interactions with the nanotube sidewall. On extending the simulation temperature to 300 K corresponding to 27 C (Figure 6.2), a similar trend is observed as for 298 K, with the gradual filling of C 60 fillers inside the SWCNT cavity. Figure 6.2 Simulation snapshots corresponding to the gradual release of PZA molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 3, (d) 5, (e) 7, (f) 9 and (g) 10 ns corresponding to 300 K temperature.

7 186 Chapter 6 Up to 3 ns simulation time frame (Figure 6.2c), the major changes observed in the snapshots are in the orientation of PZA molecules placed within the nanotube cavity. Between 3 to 5 ns time frames (Figure 6.2d), the filling of all five C 60 fillers and gradual expulsion of all PZA molecules is observed wherein some of the PZA molecules prefer to get stacked onto the nanotube sidewall and the others oriented along the open cap of the SWCNT. Beyond 5 ns following to 10 ns (Figure 6.2e g) the C 60 fillers favor to remain encapsulated within the SWCNT and PZA molecules form a uniform array along the tube sidewall. At 310 K temperature, the pattern remains basically same as observed in 300 K (Figure 6.3), where the complete encapsulation of C 60 molecules takes place between 2 3 ns (Figure 6.3c) and throughout the course of the simulation dynamics, the major changes are basically accounted to the random fluctuations in orientation of PZA molecules with the filler molecules remaining completely entrapped within the nanotube cavity. Figure 6.3 Simulation snapshots corresponding to the gradual release of PZA molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 3, (d) 6, (e) 8, (f) 9 and (g) 10 ns corresponding to 310 K temperature. The simulation at 310 K is taken as the reference as it mimics the body temperature and can provide an in hand information towards the course of drug delivery from SWCNTs upon

8 Heat driven release of drug molecules from carbon nanotubes 187 administration within the body under normal conditions. The vdw interaction which governs the mutual forces between C 60 and SWCNT sidewall attracts the fullerene moieties inside the nanotube and due to interaction amongst the adjoining C 60 molecules; rapid encapsulation follows complete expulsion of PZA and water molecules from within the nanotube. Further increase in simulation temperature to 330 K (57 C), between 0 to 1 ns time frames (Figure 6.4a and b) all the C 60 filler molecules fill the SWCNT cavity leading to complete liberation of PZA molecules. Throughout the course of simulation dynamics till 10 ns, fullerene molecules remain entrapped within the hollow cavity and the major fluctuations in the simulation is contributed to the PZA molecules interacting with the nanotube sidewall. Figure 6.4 Simulation snapshots corresponding to the gradual release of PZA molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 3, (d) 4, (e) 6, (f) 8 and (g) 10 ns corresponding to 330 K temperature. On further elevation of temperature to about 337 K (64 C) corresponding to the case of irradiation (heating) of the nanotube with the encapsulated molecules, at the start of the simulation itself corresponding to 0 ns (Figure 6.5a) complete encapsulation of C 60 filler molecules within SWCNT is observed with the PZA molecules preferring to stay stacked along the nanotube sidewall (Figure 6.5b g). The dynamics snapshots corresponding to 337

9 188 Chapter 6 K show that at comparatively higher temperatures, PZA molecules form a uniform array along the nanotube sidewall, mediated by the strong noncovalent π stacking interaction with less random fluctuations along the simulation box whereas the fullerene molecules undergo spontaneous encapsulation suggesting the temperature effect towards the encapsulation. Figure 6.5 Simulation snapshots corresponding to the gradual release of PZA molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 3, (d) 5, (e) 7, (f) 8, and (g) 10 ns, corresponding to 337 K temperature. The simulations at the five studied temperatures provide a predictive understanding to the temperature dependence on the rate of PZA release from SWCNT, and on the course of C 60 molecules insertion. Increase in temperature which correlates to the heating of SWCNT results in rapid encapsulation of filler arrays and subsequent removal of PZA molecules from SWCNT and the temperature has a direct dependence in the rate of drug release. The diameter of (10,10) SWCNT considered in our study is quite optimum for holding the fullerene fillers within the nanotube cavity. It is interesting to note here that the adequate choice of nanotube diameter is mandatory for fullerene encapsulation although nanotube chirality does not play a dominant role here. Due to our computational limitations we have considered only (10,10) SWCNT of an optimum length to encapsulate the five filler

10 Heat driven release of drug molecules from carbon nanotubes 189 molecules completely within the nanotube and with increase in nanotube diameter multiple stacked arrays of C 60 can be formed within the SWCNT cavity. To get an additional quantitative understanding to the dynamics of PZA release from SWCNT, we compared the root mean square deviation (RMSD) for three set of systems: C 60, PZA drug and SWCNT C 60 PZA combined at the five studied temperatures. The trend in RMSD vs. time scale (ns) illustrates completely different behavior at the five temperatures. At 298 K temperature (Figure 6.6a) between ns, RMSD of the three sets of system gradually increases; the fluctuations in RMSD for PZA molecules is more random compared to the bulky C 60 and SWCNT combined. Figure 6.6 The RMSD of PZA, C 60 fillers and PZA C 60 SWCNT combined at (a) 298 K, (b) 300 K temperatures. The gradual increase in RMSD between ns, is due to the rapid shuffling of PZA within the tube cavity and between 1.5 to 3.1 ns the sudden jump in RMSD (reaching a maximum value of around 3.0 nm) can be accounted to the complete release of the PZA molecules from the nanotube cavity by the C 60 fillers following a displacement mechanism. However, for C 60 and the combined system, beyond 1.3 ns the RMSD remains more or less uniform around 1.15 and 1.35 nm, respectively. The major fluctuations in RMSD are thus contributed from the PZA molecule throughout the course of the simulation time around 1.25 nm, which is in good agreement with the dynamics snapshots of Figure 6.1. The pattern for RMSD at 300 (Figure 6.6b) and 310 K (Figure 6.7a) is somewhat similar in trend to that observed at 298 K temperature. For the C 60, PZA and CNT C 60 PZA combined systems, till 4.5 ns the RMSD gradually increases and then somewhat remains

11 190 Chapter 6 uniform between 0.5 to 0.6 nm, whereas for PZA molecules the RMSD shows a hump reaching a maximum value of 1.75 nm (Figure 6.6b). The RMSD for C 60 fillers remains uniform around 0.50 nm. For PZA molecules the RMSD keeps fluctuating throughout the course of the simulation, somewhat reaching a maximum value of 1.75 nm for the first 4 ns and then increasing further beyond 4.5 ns to a maximum value of 3.15 nm. At 310 K temperature (Figure 6.7a), up to 2 ns time frame, the RMSD for C 60 and combined system remains uniform at an average value of 0.35 and 0.43 nm, respectively whereas for PZA system the RMSD is obtained around 1.0 nm. Beyond 2.25 to 3.0 ns, a sharp increase in RMSD is observed which corresponds to the complete filling of C 60 molecules within SWCNT leading to the removal of all the PZA molecules from the tube cavity as observed in the simulation dynamics in Figure 6.3. Figure 6.7 The RMSD of PZA, C 60 fillers and PZA C 60 SWCNT combined at (a) 310 and (b) 330 K temperatures. Beyond 3 ns till the completion of the simulation, a plateau is reached at around 1.2 nm for C 60 filler molecules and 1.25 nm for the system combined. For PZA molecules, significant fluctuations in RMSD is observed throughout the course of simulation dynamics (average RMSD value of 1.65 nm) which is accounted to the random rattling of PZA molecules along the nanotube sidewall upon complete expulsion from the nanotube cavity. At 300 K temperature although complete filling of C 60 within SWCNT takes place after 4 ns, as opposed to around 2.5 ns in 310 K temperature, the fluctuations in RMSD of PZA is more

12 Heat driven release of drug molecules from carbon nanotubes 191 predominant at 300 K whereas at 310 K, PZA molecule gets more or less stabilized along the vicinity of the tube sidewall. The RMSD corresponding to PZA release from SWCNT by C 60 fillers at 330 K temperature (Figure 6.7b) demonstrates rapid encapsulation of C 60 fillers within the first 0.5 ns, suggesting that as the temperature is elevated the fullerene encapsulation becomes more rapid as opposed to that observed in room temperature (Figure 6.6a) and the biologically viable body temperature (Figure 6.7a). High temperature mimics the scenario of irradiating the nanotubes for active drug release at the target specific site in the body upon administration. The RMSD of the combined system and C 60 fillers increases and then remains uniform at an average value of 1.25 and 1.13 nm, respectively. The RMSD for PZA molecules at the start of the simulation dynamics increases reaching an average value of 1.5 nm till 6.5 ns time and around 7.5 ns, a sudden sharp peak in the RMSD (~ 3.75 nm) is observed which gradually decreases up to the completion of the simulation. The sharp fluctuation is accounted from one of the PZA molecule leaving the nanotube surface and interacting with the simulation box. Overall, it can be said that elevation of temperature results in swift filling of C 60 arrays within the SWCNT and subsequent elimination of entrapped PZA molecules. The RMSD at 337 K temperature (Figure 6.8) illustrate the major fluctuations to be contributed to the PZA molecules throughout the course of the simulation time with the C 60 molecules lying entrapped within the tube cavity. Figure 6.8 The RMSD plot of PZA, C 60 fillers and PZA-C 60 -SWCNT combined at 337 K temperature.

13 192 Chapter 6 The RMSD of C 60 fillers is obtained at a value of 0.30 nm, remaining uniform throughout due to the fillers getting encapsulated at the start of the simulation itself. The RMSD of PZA demonstrates significant fluctuations during the course of simulation, initially increasing from 0 to 1.0 ns and then more or less saturating around 2.35 nm. The RMSD of the combined system follows somewhat similar trend with that of PZA system and lies between the values of PZA molecules and C 60 at an average value of 0.85 nm. Thus, at the five studied temperatures, the major contribution to the fluctuations in RMSD is accounted from the small less bulky PZA molecules rattling randomly along the tube sidewall and simulation box and filler molecules due to the confinement within the SWCNT cavity, it is offered with less degree of freedom towards the free movement. We further computed the disparity in the centre of mass (COM) distances between C 60 SWCNT and PZA SWCNT to comprehend the distance variation during the course of simulation. As observed from Figure 6.9a corresponding to 298 K temperature, during PZA release from SWCNT, the COM distance for the first 0.6 ns remains slightly below 1.25 nm and between ns, the COM distance drops suddenly to 0.18 nm followed by the sharp increase in COM distance to around 1.75 nm beyond 1.35 ns. Figure 6.9 The variation of centre of mass (COM) between PZA (10,10) SWCNT and C 60 SWCNT at (a) 298 K, and (b) 300 K temperatures.

14 Heat driven release of drug molecules from carbon nanotubes 193 From ns, the COM distance reaches a plateau at an average value of 1.75 nm. In case of C 60 SWCNT with progress of the simulation time, C 60 arrays are farthest apart at a distance of ~ 2.15 nm and drops down to 1.5 nm around 0.6 ns and then levels off at ~ 0.2 nm beyond 1.0 ns till the completion of the simulation. During 1.0 ns, the major perturbation in trends of the COM distances for the two systems is observed (Figure 6.9a) which basically corresponds to the complete entrapment of C 60 fillers within the nanotube leading to expulsion of PZA molecules and is in good agreement with the simulation snapshots and RMSD plots. Figure 6.9b provides the variation in COM distance at 300 K temperature corresponding to C 60 SWCNT and PZA SWCNT systems. Although a similar pattern is observed in the variation of COM as observed at 298 K, the basic difference lies in the sudden break in pattern observed around 4.3 ns corresponding to the complete expulsion of all the PZA molecules from the SWCNT cavity by the fillers. At 300 K temperature two plateaus are actually observed for C 60 SWCNT and PZA SWCNT and the nearest interacting distances are calculated as 0.20 and 1.75 nm, respectively. The trend in variation in COM distance at 310 K temperature is almost comparable to that observed at 298 and 300 K as described in Figure 6.10a with the major fluctuation taking place around 2.35 nm corresponding to complete filling of C 60 arrays within the SWCNT. Figure 6.10 The variation of centre of mass (COM) between PZA (10,10) SWCNT and C 60 SWCNT at (a) 310 K, and (b) 330 K temperatures.

15 194 Chapter 6 At 330 (Figure 6.10b) and 337 K temperatures (Fig. 6.11), overall the COM distances do not show any major fluctuations in the values and average COM distance between C 60 SWCNT and PZA SWCNT are observed around 0.23 and 1.75 nm, respectively. At 330 K temperature, the sudden fluctuation in COM distance of C 60 SWCNT and PZA SWCNT is observed below 500 ps beyond which it levels off. The significant differences in trends of COM plots for 330 and 337 K temperatures can be understood from the fact that at the elevated temperatures all the C 60 fillers forming a uniform array, gets stabilized within the nanotube and at the start of the simulation itself complete removal of PZA molecules from the nanotube cavity takes place and thus the major contribution to the fluctuations in distance is less predominant once complete encapsulation occurs. Figure 6.11 The variation of centre of mass (COM) between PZA (10,10) SWCNT and C 60 SWCNT at 337 K temperature. However, it is interesting to note that at the five studied temperatures, the range of variation of the average COM distances are almost similar in values once complete encapsulation of fullerene occurs. The extended delocalized framework of SWCNT holds the fillers as well as the multiple PZA molecules along the nanotube sidewall. As in the simulation medium, except the polar molecules we do not have any receptor group hence the

16 Heat driven release of drug molecules from carbon nanotubes 195 PZA molecules prefer to remain located around the tube sidewall mediated by the weak noncovalent functionalization Simulation of PZA molecules encapsulated within SWCNT To assess the feasibility of self diffusion of PZA molecules from SWCNT, we performed MD simulation of the seven PZA molecules encapsulated within (10,10) SWCNT in absence of C 60 fillers to validate whether drug release is actually feasible in absence of any external driving agent. Figure 6.12a f depicts the simulation snapshots of PZA SWCNT system at 298 K temperature for the duration of 5 ns. Throughout the course of the simulation time PZA molecules prefer to remain within the nanotube cavity rattling in the confined space provided by the hollow region. In absence of any external driving agent, PZA molecules assume a thermodynamically (energetically) favorable situation by preferring to remain stacked onto the tube sidewall mediated by the noncovalent vdw interactions. Figure 6.12 (a) Simulation snapshots of PZA molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 2, (d) 3, (e) 4, and (f) 5 ns, corresponding to 298 K temperature, (b) the variation in RMSD plot of PZA, SWCNT and PZA SWCNT system combined. We further compared the variation in RMSD of PZA and PZA SWCNT system combined at 298 K temperature as depicted in Figure 6.12g. The RMSD of (10,10) SWCNT does not exhibit any perturbation during the course of MD simulation at an average value of 0.05 nm. The RMSD of PZA molecules however, contribute to the major fluctuations;

17 196 Chapter 6 increasing initially for the first 500 ps and then reaching a plateau at an average value of 0.56 nm. The RMSD for PZA/(10,10) SWCNT system combined lies between the RMSD values of PZA and (10,10) SWCNT around 0.2 nm. The RMSD initially increases for the first 500 ps and then levels off at 0.2 nm. The average interacting distance from the COM of PZA molecules and SWCNT inner sidewall is calculated at around 0.52 nm Simulation of the encapsulation of C 60 fillers within SWCNT In addition, MD simulation of C 60 SWCNT system at 298 K temperature for the duration of 5 ns (Figure 6.13a f) demonstrates the instantaneous encapsulation of all C 60 filler molecules within the SWCNT at the start of the simulation itself (Figure 6.13a). The simulation snapshots at different time frames lay stress to the fact that the strong stacking interaction between C 60 molecules and SWCNT leads to rapid trafficking of the fillers and since there is no external hindrance towards the movement of the fillers the encapsulation is quite instantaneous and the fullerene fillers prefer to remain inside the nanotube cavity for the 5 ns simulation dynamics. Figure 6.13 Simulation snapshots of C 60 molecules encapsulated within (10,10) SWCNT at (a) 0, (b) 1, (c) 2, (d) 3, (e) 4, and (f) 5 ns, corresponding to 298 K temperature; (g) variation of COM distance between C 60 SWCNT. The average COM distance of C 60 molecules and SWCNT was calculated to be around 0.32 nm (Figure 6.13g), which is slightly higher than the COM distance calculated in

18 Heat driven release of drug molecules from carbon nanotubes 197 presence of PZA molecules. The probable justifiable reason towards the trend may be that in presence of PZA molecules the interaction is via mutual co-operative (competitive) interaction between SWCNT PZA and SWCNT C 60 molecules due to which the COM distance is somewhat lower. Overall, the individual simulations of PZA SWCNT and C 60 SWCNT systems demonstrate the strong influence of filler molecules in the driving (release) of PZA molecules from the SWCNT cavity and once the C 60 are encapsulated to prefer to remain within the nanotube due to the strong vdw interaction between the aromatic rings Temperature effect on diffusion co efficient of PZA molecules from SWCNT To get a physical essence to the rate of release process of PZA molecules from within the SWCNTs, we compared the diffusion co efficient of PZA molecules as functions of temperature (Figure 6.14). Figure 6.14 The variation in diffusion co efficient of PZA molecules from SWCNT at 298, 300, 310, 330 and 337 K temperatures. With increase in temperature from 298 to 300 K, the diffusion co efficient of PZA molecules initially decreases and then increases beyond 300 K temperature. This sudden deflection in trend can be correlated from RMSD which show that rate of diffusion of PZA at 298 K occurs around 1.1 ns whereas at 300 K it takes place at ~ 4.1 ns suggesting that the complete removal of PZA molecules at 300 K is somewhat lower than 298 K and with

19 198 Chapter 6 further increase in temperature, the diffusion co efficient value steadily increases. Thus, temperatures elevation facilitates the spontaneous release of encapsulated PZA molecules and irradiation of SWCNT assist in better drug discharge. The encapsulation of PZA molecules within SWCNT during drug delivery treatment regime initially prevents the premature degradation within the biological environment and under the conditions that the nanocarrier is delivered within the target site elevation of temperature assists rapid disposition of drug molecules from the encapsulated state helping in active target chemotherapy Energy parameters corresponding to the initial and final structures and the difference for PZA-SWCNT-C 60 combined To investigate the energetics of interaction towards the heat driven release of PZA molecules from SWCNT, we compared the energy parameters like total energy, potential energy, and the non bonded energy terms (vdw) for the studied systems at the five temperatures as summarized in Tables 6.1. In general, the total energy of the system is expressed as a sum of the following terms, 41 E total = E valence + E cross-term +E nonbonded (6.1) where E valence term is further split into: E valence = E bond +E angle +E torsion +E oop +E UB (6.2) E cross term involves the mixing the bond stretch, angle bending and torsional interactions. Although the first four terms are quite clear the Urey Bradlay (UB) term involves interactions between two atoms that is connected by a common atom. The non bonded energy, E nonbonded is defined by: E nonbonded = E vdw + E Coulomb + E H-bond (6.3)

20 Heat driven release of drug molecules from carbon nanotubes 199 Table 6.1 Energy parameters corresponding to the initial and final structures and the difference for PZA SWCNT C 60 system at the five studied temperatures. Temperature (K) Total Energy Difference Potential Energy Difference vdw energy Difference Initial Final Initial Final Initial Final From energetics perspective, the total energy of the system increases with increase in temperature (Table 6.1), and the calculated energy values are quite high due to the large number of atoms in the system (1118 atoms excluding the atoms of water molecules). The non bonded vdw term basically contribute towards the energetics and interaction energy increases with increase in temperature which can be correlated to the temperature effect on rapid encapsulation. The potential energy values initially does not follow a regular trend from the temperature range of 298 to 310 K but with the elevation of temperature from 330 to 337 K, the potential energy value increases which is associated with the increase in contact area between C 60 fillers and SWCNT and suggests that the release of PZA molecules is a process of energy minimization which is in accordance with the lowest energy theory. 29 Overall, the negative energy values highlight the thermodynamic favourability towards the encapsulation and the process of drug release. 6.4 Conclusions Within the dominion of theoretical understanding, we highlight the possibility of using SWCNTs as carrier depots for encapsulating chemotherapeutic agents within the nanotube cavity and the controlled release mechanism of PZA molecules mediated by C 60 filler molecules. The diameter of the SWCNT considered limits the formation of multiple fullerene

21 200 Chapter 6 arrays within the cavity and fillers form a uniform chain like pattern within the nanotube. The strong noncovalent interaction between C 60 and SWCNT favors the rapid encapsulation within the nanotube leading to subsequent removal of PZA molecules. The temperature has a strong dependence on the drug delivery regime, increase in temperature results in rapid drug release from the nanotube and at high temperatures the PZA molecules prefer to form a patterned array along the nanotube sidewall. The RMSD plots at the five studied temperatures help in correlating the simulation dynamics depicting the course of the PZA drugs release from SWCNT cavity by filler molecules. The major contribution to RMSD is from the PZA molecules and fluctuations in C 60 are of less dominance at the five studied temperatures. Likewise, the variation in COM distances provides a definitive understanding to the variation in interacting distance between PZA SWCNT and C 60 SWCNT during the course of the dynamics simulation; distance in COM increases between PZA SWCNT and for C 60 SWCNT, the COM distance decreases as the simulation proceeds. The rate of drug diffusion from SWCNT increases with increase in temperature suggesting that temperature has a strong dependence in the course of PZA drug molecules release from SWCNT. Our study can be quite instrumental in providing a detailed understanding to the temperature effect on the PZA delivery mechanism by SWCNT mediated by C 60 filler molecules and aim at achieving the target specific drug delivery regime within the biological environment of the body. References [1] Veetil, J.V., & Ye, K. Development of immunosensors using carbon nanotubes, Biotechnol. Prog., 23 (3), , [2] Dillon, A.C., et al. Hydrogen storage in carbon single wall nanotubes, Nature 386 (6623), , [3] Park, K.A., et al. Adsorption of atomic hydrogen on single walled carbon nanotubes, J. Phys. Chem. B 109 (18), , [4] Wind, S.J., et al. Vertical scaling of carbon nanotube field-effect transistors using top gate electrodes, Appl. Phys. Lett. 80 (20), , [5] Lucci, M., et al. Role of the Material Electrodes on Resistive Behaviour of Carbon Nanotube-Based Gas Sensors for H 2 S Detection, J. Sensors, , 2012.

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23 202 Chapter 6 [20] Shim, Y., et al. Carbon Nanotubes in Benzene: Internal and External Solvation, Phys. Chem. Chem. Phys. 13 (9), , [21] Li, L.J., et al. Diameter-selective encapsulation of metallocenes in single-walled carbon nanotubes, Nat. Mater. 4, , [22] Kim, G., et al. J. Encapsulation and polymerization of acetylene molecules inside a carbon nanotubes, Chem. Phys. Lett. 415 (4-6), , [23] Gao, H., et al. Spontaneous Insertion of DNA Oligonucleotides into Carbon Nanotubes, Nano Lett. 3 (4), , [24] Liu; Y., & Wang, Q. Dynamic behaviors on zadaxin getting into carbon nanotubes, J. Chem. Phys. 126 (12), , [25] Trzaskowski, B., et al. Molecular dynamics studies of protein-fragment models encapsulated into carbon nanotubes, Chem. Phys. Lett. 430 (1-3), , [26] Chen, Q., et al. Energetics investigation on encapsulation of protein/peptide drugs in carbon nanotubes, J. Chem. Phys. 131, 01510, [27] Liu, J., et al. Affinity of drugs and small biologically active molecules to carbon nanotubes: a pharmacodynamics and nanotoxicity factor? Mol Pharm. 6 (3), , [28] Yamashita, H., & Yumura, T. The Role of Weak Bonding in Determining the Structure of Thiophene Oligomers inside Carbon Nanotubes, J. Phys. Chem. C 116 (17), , [29] Xue, Q., et al. Release of encapsulated molecules from carbon nanotubes using a displacing method: a MD simulation study, RSC Adv. 2, , [30] Gao, H., et al. Spontaneous Insertion of DNA Oligonucleotides into Carbon Nanotubes, Nano Lett. 3 (4), , [31] Longhurst, M.J., & Quirke, N. Temperature-driven pumping of fluid through singlewalled carbon nanotubes, Nano Lett. 7 (11), , [32] Kral, P., & Tomanek, D. Laser-driven atomic pump, Phys. Rev. Lett. 82 (26), , 1999.

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