Encapsulation into Carbon Nanotubes and Release of Anticancer

Subscriber access provided by George Mason University Libraries & VIVA (Virtual Library of Virginia)

Article

Encapsulation Into Carbon Nanotubes and Release of Anticancer Cisplatin Drug Molecule Alia Mejri, Delphine Vardanega, Bahoueddine Tangour, Tijani Gharbi, and Fabien Picaud J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/jp5102384 • Publication Date (Web): 16 Dec 2014 Downloaded from http://pubs.acs.org on December 20, 2014

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry B is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Encapsulation Into Carbon Nanotubes and Release of Anticancer Cisplatin Drug Molecule Alia Mejri1, Delphine Vardanega2, Bahoueddine Tangour1, Tijani Gharbi2 and Fabien Picaud2,* 1

Unité de Recherche de Modélisation de Sciences Fondamentales et didactiques, Equipe de Chimie Théorique, Université de Tunis El Manar , BP254, El Manar 2, 2096, Tunisia

2

Laboratoire de Nanomédecine, Imagerie et Thérapeutiques, UFR Sciences et Techniques,

Centre Hospitalier Universitaire et Université de Franche Comté, 1- route de Gray, 25030 Besançon * corresponding author: [email protected]

Abstract

Molecular Dynamics simulations have been investigated to study the interactions between single wall carbon nanotubes and an anticancer agent Pt(IV) complex. The optimized diameter of the vector system has been determined to encapsulate in the best conditions the drug molecules. The simulation results show also that several drug molecules can be adsorbed inside the nanotubes that lead to an increased confinement time. Moreover, our simulations show that the release of the drug near a membrane cell model is favored opening the way to natural drug nanocapsule.

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Key-Words: Simulations, Nanoscience, anti-cancer Drug Delivery, Cisplatin Introduction Cisplatin is a drug commonly used to treat different kinds of tumor cells1. While widely studied, the understanding of its action is not yet well achieved. Indeed, Cisplatin can form complex with DNA which blocks the cell transcription mechanism and then leads to cell death2, 3. However, some secondary effects observed in many patients limit its field of action, mainly due to its non selective damage4-6. To increase the therapeutic efficacy, Cisplatin was already transported by several carriers such as liposomes or polymeric micelles nanoparticles7-11 or CNTs. 12, 13 This vectorization enhances the cellular uptake and protects the molecules from degradation during its way to the nuclear region of cancer cell14, 15. Drug molecules can thus be either chemically attached to the nanoparticles or be encapsulated inside the nanoparticles16. Over the past decade, nontoxic gold nanoparticles17, 18 were widely used for imaging and for the delivery of therapeutic drugs19-23. Until now, another good candidate for such vectorization is the carbon nanotubes (CNT). Indeed, while their noncytotoxicity is still a matter of debate, their high degree of functionalization allows them becoming biocompatible when necessary24-26. This cytotoxicity is observed mainly when the CNTs are defected, unpurified and transport the catalytic residues used during their growth. Effects of length and thickness are also described in literature as potential cytotoxic term27-29. However, their huge surface/volume ratio made them an ideal candidate to transport therapeutic molecules. The high hydrophobicity of the carbon cage makes this candidate ideal for their internalization inside the membrane cell and then, the direct release inside the cell of the drugs. The second advantage for CNT, contrarily to gold nanoparticles, is its empty inner volume that can be accessible as far as their ends have been chemical attacked30-32.


Page 2 of 20

Page 3 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


When done, the storage of many drug molecules could be achieved in order to be vectorized until the cancer cell without any interactions during their transportation. The blocking of the drugs inside the CNT to avoid proliferation in unwanted zone and the release of the encapsulated molecules in the close proximity to the cancer cells become thus the key points to achieve to use CNTs as nanocarriers. Some theoretical works were performed on the vectorization of the Cisplatin into CNTs16, 33-39. In particular, in a previous work40, we studied the behavior of the Cisplatin molecule encapsulation inside different CNTs. Preliminary geometry optimizations were carried out thanks to restricted Hartree-Fock method using the aug-cc-pVDZ-PP37 basis sets. In this paper, we report a theoretical study based on molecular dynamics simulations to demonstrate that encapsulation of anticancer Cisplatin molecules is favored in carbon nanotubes. Moreover, the capacity of storage of CNT is quite large and does not need necessarily to close their both ends due to high confinement effects and hydrophobic interactions. We demonstrate also that the release of the drugs can be favored near the membrane cell due to advantageous electrostatic interactions with the hydrophilic part of the cell. The paper is organized as followed. We describe the system and the molecular dynamic package used in these simulations. Then the main results will be presented in pure solvent and near the membrane cell before conclusion. 1. Method a) System The model for the anticancer Cisplatin (CDDP) molecule (structure DB00515) was optimized via ab initio quantum calculations using Gaussian 09 package software41 using the B3lyp approach in the 6-31g(d,p) basis set and the lanl2dz one for Pt atom. Calculations were used to determine the Mulliken partial charges and then extracted the Hessian matrix for the molecular model used in molecular dynamic simulations based on the general procedure described by Norrby and Brandt42.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 20

Before a complete building of the system, CDDP was first equilibrated during 1ns in a water box of 18.5 nm3. Then, equilibrated drug molecule was hydrated in solution containing a (17,0) carbon nanotube (CNT diameter of 0.13nm), water molecules and 0.15 M dissociated NaCl placed randomly in the simulation box. The complete system analyzed hereafter was progressively filled with CDDP until completion. For this, each drug was placed on equivalent position from the nanotube entrance. The carbon nanotube of 2 nm length was modeled according to the Hamada indices equal to 17 and 0 (denoted as (17,0) CNT). The ends of the CNT were not oxidized and dangling C bonds represent the nanotube entrance and exit. We aware of the importance of these unsaturated bonds in experiments since chemical reactions could appear between these dangling bonds and the molecules during the insertion process. Moreover, one may underline that such open ended CNTs show the highest cytotoxicity27-29, which reduces our theoretical approach for potential in vitro (or even in vivo) studies. Functionalized CNTs are essential to limit their cytotoxicity issue. However, it was shown recently that the chemical ends of the BNNTs did not perturb too much the drug energy insertion path43. We could thus hope that chemical modifications of CNT dangling bonds do not change fundamentally the general results demonstrated in this paper. Here, only physical interactions were taken into account, and the carbon nanotube was described as a rigid structure. For carbon nanotube vs. water oxygen (C-O) interactions, we used the Bedrov et al. 44, 45 Lennard-Jones potential parameters (CHARMM27

functional:

σCC=3.895 Å,

εCC=0.066 kcal/mol

and

σCO=3.58 Å,

εCO=0.0936 kcal/mol). The lipid bilayer close in composition of different cell membranes, allows increasing the quality of protein modeling in the membrane environment. Here, the lipids constituting the membrane are composed of POPC (Palmitoyloleoylphosphatidylcholine) molecules. Before


Page 5 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


building the elaborated system, the lipid bilayer was first equilibrated via MD simulations during 15 ns and used further to study the deliverance of drug molecules. All the different molecules are shown on Figure 1.

Figure 1: a) Cisplatin molecule. b) Carbon nanotube. c) POPC membrane. b) Molecular Dynamic simulations All Molecular Dynamics (MD) simulations were carried out in the NPT ensemble using the NAMD_2.7b2 suite of program.46 Langevin dynamics and Langevin piston methods were applied to keep the temperature (300K) and the pressure (1 atm) of the system constant, respectively. Long-range electrostatic forces were taken into account using the particle-mesh Ewald approach,47 and the integration time step was equal to two fs. The water molecules were treated using TIP3P model45 and all-atoms AMBER force field48 (param94) was used for ions and carbon atoms of the rigid nanotube. 2) Results and discussion a) Filling of CNT with CDDP Three different types of CNT have been tested before using the (17,0) one which presented the best conditions to encapsulate the CDDP. First, we studied the insertion of CDDP inside (13,0) CNT whose diameter is equal to 1.02 nm. After 6ns of simulations, CDDP was not



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

entered inside the CNT due to the too small carbon cage. The (17,0) and (19,0) tubes were then used and showed a possible insertion of the therapeutic inside them. This result is compatible with those obtained using HF calculations40. However, the comparison of the interaction energy between the two cages and the CDDP (only composed of van der Waals terms) lead to a favorable energy in case of the (17,0) CNT because of its curvature (19,0±0.9 kcal/mol compared to -13,9±0.6 kcal/mol, respectively). This kind of CNT was thus kept for all the simulations hereafter. To take advantage of the high surface over volume ratio offered by the inner volume of the CNT, we filled progressively the (17,0) CNT by CDDP until completion. This is obtained when the total length of the vector is equal to about the sum of the size of the encapsulated molecules. We can estimate at 0.5nm the diameter of the CDDP and the length of the CNT was about 2nm. We could thus fill the capsule by at least four drug molecules. When the second one was placed behind the entrance of the CNT, it penetrated it rather rapidly (0.085 ns) due to the strong interaction with its neighbor one. The third and fourth ones also inserted and arranged with the others. Note that two other molecules were incorporated inside this small CNT, but were not considered further in this study due to their low residence time (

Encapsulation into Carbon Nanotubes and Release of Anticancer

Recommend Documents