Journal of Molecular Graphics and Modelling 29 (2011) 591–596 Contents lists available at ScienceDirect Journal of Molecular Graphics and Modelling journal homepage: www.elsevier.com/locate/JMGM How do carbon nanotubes serve as carriers for gemcitabine transport in a drug delivery system? Uthumporn Arsawang a , Oraphan Saengsawang b,c , Thanyada Rungrotmongkol b,c , Purinchaya Sornmee a , Kitiyaporn Wittayanarakul b,c,e , Tawun Remsungnen d , Supot Hannongbua b,c,∗ a Department of Mathematics, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand b Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand c Center of Innovative Nanotechnology, Chulalongkorn University, Bangkok 10330, Thailand d Department of Mathematics, Faculty of Science, Khon Kaen University, Khonkaen 40002, Thailand e Program of Natural Resource and Environmental Management, School of Science and Technology, Khon Kaen University, Nongkhai Campus, Nongkhai 43000, Thailand article info Article history: Received 24 June 2010 Received in revised form 1 November 2010 Accepted 1 November 2010 Available online 11 November 2010 Keywords: Carbon nanotube Gemcitabine Drug delivery Molecular dynamics simulations Steered molecular dynamics simulations abstract Aiming at understanding the molecular properties of the encapsulation of the anticancer drug gem- citabine in the single-walled carbon nanotube (SWCNT), molecular dynamics (MD) simulations were applied to the two scenarios; that of gemcitabine filling inside the SWCNT, and that of the drug in the free state. Inside the SWCNT, the cytosine ring of gemcitabine was found to form a – stacking confor- mation with the SWCNT surface, and this movement is not along the centerline of the tube from one end to the other of the tube where the distance from the center of gravity of the molecule to the surface is 4.7 ˚ A. A tilted angle of 19 ◦ was detected between the cytosine ring of gemcitabine and the inner surface of SWCNT. In comparison to its conformation in the free form, no significant difference was observed on the torsion angle between the five- (ribose) and the six- (cytosine) membered rings. However, gemcitabine inside the SWCNT was found to have a lower number of solvating water molecules but with a stronger net solvation than the drug in the free state. This is due to the collaborative interactions between gem- citabine and the surface of the SWCNT. In addition, the steered molecular dynamics simulation (SMD) approach was employed to investigate the binding free energy for gemcitabine moving from one end to another end throughout the SWCNT. In excellent agreement with that yielded from the classical MD, the SMD energy profile confirms that the drug molecule prefers to locate inside the SWCNT. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Since the discovery of carbon nanotubes (CNTs) in 1991 [1], they have been considered as the ideal material for a variety of applica- tions owing to their unique properties. These properties include their potential biocompatibility in pharmaceutical drug delivery systems [2–4] and their excellent role as drug carriers with a highly site-selective delivery and sensitivity [5–10]. To accelerate the opti- mal development of CNT as a new effective drug transporter, it is required to better understand the structural properties of the drug–CNT complex. As reported by the Centers for Disease Control and Preven- tion (CDC), cancer is the second leading cause in the number of deaths worldwide [11], and ovarian cancer, found in the female ∗ Corresponding author at: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand. Tel.: +66 22 187602; fax: +66 22 187603. E-mail address: supot.h@chula.ac.th (S. Hannongbua). reproductive malignant cells [12], is the fifth most common can- cer. Gemcitabine, in combination with carboplatin, is the main anticancer drug used to treat ovarian cancer [13]. Gemcitabine is a pro-drug, and as the active di- and tri-phosphate nucleosides, exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the G1/S-phase boundary. The cytotoxic effects of gemcitabine are exerted through incorporation of gemcitabine triphosphate (dFdCTP) into DNA, resulting in the inhibition of DNA synthesis and induction of apoptosis. However, this is not cancer cell specific and so the main problem, common to most cancer treat- ments and therapy, is the serious side effects to normal cells. Bone marrow toxicity is one such effect in patients who show adverse reactions to gemcitabine. To avoid such effects, the development of a drug delivery system to transport the drug molecules efficiently and specifically to the targeted tumor cells, without harming the surrounding tissue is one promising approach. This can lead to a more sustained and localized delivery of the drug, reducing the systemic loads and side effects to non-target cells. To this end CNTs have been found to show good carrier properties by serving as a 1093-3263/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2010.11.002