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Journal of Biomolecular Structure & Dynamics
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Graphene as a drug carrier for gemcitabine anti-cancer drug

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in aqueous solvent: An applied DFT analysis
Journal: Journal of Biomolecular Structure & Dynamics

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Manuscript ID Draft
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Manuscript Type: Research Article
Date Submitted by the

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Author:
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Complete List of Authors: Zaidi, Syed; University of the Punjab

Raza, Muhammad; University of the Punjab
Harito, Christian; Bina Nusantara University, Industrial Engineering
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Department
Yuliarto, Brian; Bandung Institute of Technology
Ponce de León, Carlos; University of Southampton
Walsh, Frank; University of Southampton
Keywords: cancer, drug delivery, DFT, graphene, gemcitabine

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URL: http://mc.manuscriptcentral.com/jbsd Email: TBSD-peerreview@journals.tandf.com

Page 1 of 15 Journal of Biomolecular Structure & Dynamics
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Graphical Abstract
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Journal of Biomolecular Structure & Dynamics Page 2 of 15
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4 Graphene as a drug carrier for gemcitabine anti-
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cancer drug in aqueous solvent: An applied DFT
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analysis
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14 S. Z. J. Zaidi1,*, M. Raza1, C. Harito2,*, B. Yuliarto3,4, S. Hassan5, C. Ponce de León6, F. C.
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16 Walsh6
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19 1. Institute of Chemical Engineering and Technology, University of the Punjab, Lahore,
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20 Pakistan.
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22 2. Industrial Engineering Department, Faculty of Engineering, Bina Nusantara University,
23 11480 Jakarta, Indonesia.
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25 3. Advanced Functional Materials (AFM) Laboratory, Engineering Physics, Institut
26 Teknologi Bandung, 40132, Bandung, Indonesia
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28 4. Research Center for Nanosciences and Nanotechnology (RCNN), Institut Teknologi
29 Bandung, 40132, Bandung, Indonesia
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31 5. Mechanical Engineering, Faculty of Engineering and Physical Sciences, University of
32 Southampton, U.K.
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34 6. Electrochemical Engineering Laboratory, Energy Technologies University of
35 Southampton, U.K.
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Corresponding authors: zohaib.icet@pu.edu.pk; christian.harito@binus.ac.id
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4 Graphene as a drug carrier for gemcitabine anti-
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cancer drug in aqueous solvent: An applied DFT
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analysis
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14 Abstract (≈2700 words without references)
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16 Cancer is one of the most common causes for worldwide illness-related deaths. Graphene has
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been studied as a drug carrier for various cancer-related drugs. In the present work, we apply
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19 hybrid theoretical models to study the electrons interactions, thermodynamic properties, and
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20 solvent interaction of the drug-carrier configuration. The density functional theory (DFT) was
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used to study the electronic and thermodynamic of the graphene-gemcitabine configuration in
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23 water as a solvent to simulate the biological environment of the human body. The stability of
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24 graphene means that it can be a nanocarrier in the biological system. The simulation result shows
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that graphene provides a stable base, where gemcitabine is highly dissolvable, as it is a
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27 hydrophile and a highly reactive drug and it helps the anticancer drug reach the targeted area.
28 The adsorption of gemcitabine on the graphene was physical. The drug carrier configuration
29 formed a highly impactful drug-carrier design. The thermal energy of the graphene-gemcitabine
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31 configuration is higher than either graphene or gemcitabine, while the enthalpy and Gibbs energy
32 of the configuration is lower than that of graphene or gemcitabine. The configuration showed the
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33 reversibility of the concentration of electron from gemcitabine to graphene in the configured

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35 drug delivery design.
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39 Keywords: aqueous solvent, cancer, computational study, drug delivery, DFT, gemcitabine,
40 graphene, thermodynamic
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Abbreviations
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47 EHOMO = Energy of the highest occupied molecular orbital
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49 ELUMO = Energy of the lowest unoccupied molecular orbital
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51 Ead = Adsorption Energy
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53 G = Gibbs Free energy
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55 H = Enthalpy
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3 E = Thermal Energy
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6 Introduction
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8 Cancer is a group of diseases that involve abnormal cell growth in the body with the potential to
9 invade or spread to other organs [1, 2]. Cancer is the cause of a massive number of deaths
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11 annually all over the world. Recently, advances have been made in using graphene and graphene-
12 based compounds for cancer detection and treatment, e.g., with chemotherapy drug delivery
13 systems [3-7]. In various medical applications, from regenerative medicine to therapeutical
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15 medicine, graphene has been studied widely due to its unique properties like excellent
16 physicochemical, electrical, large surface area, and biocompatibility [8-10]. Gemcitabine, an
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17 anti-cancer drug, has been widely used in chemotherapy for various cancers such as breast
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19 cancer, pancreatic bladder, tumour, and lung cancer [11].
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In principle, gemcitabine works by incorporating itself in the DNA of the cancer cell and
22 inhibiting the growth of the cancer cell. When DNA is rewritten, gemcitabine is incorporated
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into the DNA of the structure instead of the cytosine nucleoside as it does not mate with other
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nucleosides [12-14]. The use of a prodrug strategy improves selectivity while also improving
26 bioavailability for the intended target, and in chemotherapy, and this strategy may also decrease
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27 cytotoxicity [15-16]. Gemcitabine is a hydrophilic drug, which means that it dissolves easily in
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water; this leads towards a high degree of dissolvability and disassociation in the biological
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30 setting of the human body [17-18].

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32 As gemcitabine is highly hydrophilic and reactive, it means that for the drug to have a high
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33 impact on the targeted area, it needs a stable delivery system that will protect the drug from
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degradation before it reaches its target region. For the drug delivery system, graphene has been
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36 widely reported to be used as a safe and stable method, as it is biocompatible which means that it
37 has insigificant effect on the biological features of the human body [19-23].
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39 The density functional theory (DFT) is a quantum mechanical computing method that is mainly
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used to study electronic structures in the fields of chemistry, physics, and material sciences [23-
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25]. The DFT has also been used to study various cancer-related drugs, including their treatment
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43 effects, delivery systems, and hence increase efficiency [26, 27]. The computational studies also
44 include graphene [28-30], graphene oxide [31], and carbon nanotubes [32] and their interacions
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46 with specific to cancer drugs. The encapsulation of gemcitabine between two sheets of graphene
47 has been modelled with generalized gradient approximation (GGA) DFT [33]. However, the
48 interaction of graphene and gemcitabine in a solvent has not been studied.
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50 In the present study, the hybrid functional DFT computational method of B3LYP/6-31 g(d) was
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52 used with water as the solvent to evaluate the performance of graphene as a drug delivery
53 method for gemcitabine anti-cancer. The simulation was carried out using Gaussian 09 software,
54 with 6-31g(d) B3LYP was used as basis sets for the electronic evaluation and AM1 semi-
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56 empirical basis sets for the thermodynamic evaluation of the configured graphene-gemcitabine
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3 structure. The stability and biocompatibility of graphene protect gemcitabine, which is
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5 hydrophilic, from dissolving in the water solvent to deliver the anti-cancer drug at the targeted
6 area.
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11 Computational Details
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13 The computational details are given below:
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16 Simulation design
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18 Multiple simulations were run to study graphene as a carrier for gemcitabine. First, the structures
19 of graphene and gemcitabine understudy, as shown in Figure 1(a) and 1(b), were geometrically
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21 optimized to a minimum. The basis set model of 6-31g(d) with B3LYP was used. The non-polar
22 basis was selected for the optimization of graphene. Vibrational Frequencies were calculated at
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the same level that the optimized geometries were at true local minima.
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25 The Hartree-Fock theory was used to evaluate the optimization of both graphene and
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gemcitabine. The functionals normally used in DFT are integrals of some function of the density
28 and possibly the density gradient [34-35]:
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30 EX[P] = ∫f(ρα(r),ρβ(r),∇ρα(r),∇ρβ(r))dr
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32 where the methods differ in which function f is used for EX and which (if any) f is used for E.C.
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33 This model with the specific basis set shows the most accurate result.
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35 Then, the graphene-gemcitabine, as shown in figure 1(c),was optimized using the same model
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and basis set. Water was introduced in the model as a solvent to simulate real-life biological
conditions of the human body. This model also helps in evaluating the structural density of
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39 electron in the whole molecule.
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Different values calculations
46 The Ehomo-lumo gap is calculated by subtracting Ehomo and Elumo. The adsorption energy Ead is calculated as:
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48 Ead = Enanostructure - Enanostructure complex
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50 Where Enanostructure is the energy of the studied nanostructure and Enanostructure complex is the energy of the
51 studied complexes.
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53 Furthermore, different thermodynamic values given in Table 2 were evaluated by using the Semi-
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Empirical model with AM 1 as a basis set. Moreover, the Frequency with the same model and basis set
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56 was used to get multiple thermodynamic values.
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Results and Discussions
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9 The DFT calculations were performed in order to evaluate the extremely relevant potential of
10 graphene as an efficient carrier for targeted drug delivery, including gemcitabine anti-cancer
11 drug. Figure 1 shows graphene and gemcitabine's initial and optimized structures. There were a
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13 total of 9 intermediate geometries observed for graphene and a total of 34 intermediate
14 geometries observed for gemcitabine. The final optimized structures were used to study the
15 effectiveness of graphene as a delivery method for gemcitabine.
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38 Fig.1|Initial structures and final optimized geometriesa,Gemcitabineinitial Geometry b, Graphene Initial Geometry c, Optimized structures of
39 graphene and gemcitabine forming the delivery system d, Optimized geomertry of gemcitabine e, Optimized geometry of graphene f, Optimized
40 structure of drug delivery system with graphene as a delivery base.
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44 Study of the initial geometries
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46 The initial structures and final optimized structures of all the studied complexes are shown in
47 Figure 1. It can be seen from Figure 1b and 1e that graphene during its optimization remains
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fairly stable throughout the whole simulation. This stability retained throughout the whole
50 process means that graphene is non-volatile, which makes it extremely useful as a delivery base.
51 It means that it will not interact with the cells in the human body or change their chemistry or
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have any negative effect. It will also protect gemcitabine from degradation before it reaches its
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54 destination. The graphene and gemcitabine form a bond through the attraction of highly negative
55 oxygen atom with a carbon of graphene.
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3 When gemcitabine is optimized, it shows significant changes with some bond changes, as can be
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5 seen in Figure 1a and 1c. This shows the volatile nature of the compound. From Figure 1c and
6 1f, it can be seen that the designed delivery system goes through some very significant changes
7 in the form of bonds breakage and also bond length changes. The complex shown in Figure 1c
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9 was optimized in the presence of water as a solvent. The graphene remains stable as a drug
10 carrier, but the volatility of gemcitabine means it is highly soluble in water. It also tells us about
11 gemcitabine’s reactivity. The simulated results show that in the presence of water as a solvent,
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13 the reactivity of gemcitabine increases, where graphene provides a stable delivery method while
14 reducing its degradation during the delivery. Gemcitabine in a biological setting in the presence
15 of water increases its reactivity which is also noted in Table 1. Table 1 shows first the adsorption
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17 energy of gemcitabine when it does not have a delivery method, and then it shows adsorption
18 energy when water is used as a solvent and graphene is used as a drug delivery method. The
19 whole process provides an excellent working condition for gemcitabine to show its full potential
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as a cancer drug.
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Table 1. Energy table
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24 Name Ehomo Elumo Ehomo-lumo Ead

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26 Unit hartree hartree Hartree kJ/mol
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27 graphene -0.14742 -0.04713 0.10029 -47.657

28 gemcitabine -0.20742 -0.03524 0.17218 -41.262
29 Graphene- -0.14453 -0.04090 0.10363 -145.48
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gemcitabine
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34 Graphene and gemcitabine electronic and orbitals evaluation
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Figure 2 shows various electronic properties of graphene and gemcitabine from HOMO and
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LUMO orbitals to charge distribution.
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Fig. 2 | Evaluated electronic properties of graphene and gemcitabine a, Charge distribution on gemcitabine b, HOMO of gemcitabine c, LUMO
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orbital of gemcitabine d, Laplacian occupied orbital of gemcitabine e,Charge distribution on graphene f, HOMO of graphene g, Laplacian
30 occupied orbital of graphene h, LUMO of graphene.
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32 These various properties showed in Figure 2 will help us evaluate the configuration of our
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graphene-gemcitabine. The charge distribution and charge on each atom of graphene and
35 gemcitabine are shown in Figure 2a and 2e. Gemcitabine has highly negative oxygen, whereas
36 the charge distribution of graphene is relatively evenly distributed. Highly negative from the
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inside and highly positive as we move away from the centre. This means a reasonably stable
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39 configuration will be the introduction of gemcitabine on graphene from its highly negatively
40 charged oxygen. Even though gemcitabine overall shows almost no polarity, but we can use the
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highly negative oxygen to configure our design.
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The HOMO of gemcitabine is shown in Figure 2b, and the electron distribution is high on the
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45 lower side of the molecule; the red area shows where electrons concentration is very high and
46 green which represents extremely low electronic concentration. From Figure 2f, we see again a
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highly stable distribution of electrons; this means that graphene will be a highly excellent base
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49 for highly reactive gemcitabine.
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51 Figure 2d and 2g show us the laplacian occupied orbitals for gemcitabine, respectively. The
52 laplacian contour for the occupied orbitals was carried out for both. The laplacian contour here
53 tells us the divergence of gradient on Euclidean space. It means that it will tell us where the
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55 electrons will be during the whole process. Here, graphene shows perfect symmetry which
56 further supports our conclusion that graphene is highly stable, whereas gemcitabine shows a
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3 highly divergent result, which shows the volatility and reactivity of graphene. It also shows that
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5 the stability of graphene combined with gemcitabine has the potential to be a highly effective
6 drug delivery system for various treatments.
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Graphene-gemcitabine configuration electronic and orbitals
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25 Fig. 3 |Graphene-gemcitabine configuration charges and orbitals a, Charge distribution on the graphene-gemcitabine b, HOMO of the
configuration c, LUMO laplace contour of the configuration.
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29 The various properties related to electronic interactions are shown in Figure 3, and the bond
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30 length of optimized gemcitabine is shown in Figure 4. The charge distribution changes when
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32 graphene and gemcitabine configure is optimized with water as the solvent. This change in the
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33 overall charge distribution may be due to graphene stabilizing gemcitabine in a water

34 environment. As we have noted before, in the presence of water, the dissolvability, and reactivity
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36 of gemcitabine increases. This charge distribution shows that the whole configuration is trying to
37 stabilize itself. The same can be seen in Figure 3b wherein HOMO the electron density is highly
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38 configured towards graphene in the whole configuration. Figure 3c shows the Laplacian contour
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of LUMO of the configuration. The configuration is not static, but very mobile. Figure 4 shows
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Fig 4: Atomic bond lengths in the configuration.
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Energy, forces and displacements
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35 Figure 5 shows the total energy, various forces, and displacement at each intermediate geometry
36 or optimization step of graphene, gemcitabine, and graphene-gemcitabine configuration all
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plotted together. One thing that can be noted is graphene has way less intermediate geometries as
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39 compared to gemcitabine and graphene-gemcitabine configuration design that both have 34 and
40 31 intermediate geometries, respectively. The less intermediate geometries that are seen in
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graphene-gemcitabine configurations are due to the introduction of graphene that provides a
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43 stable base to gemcitabine in the configured design of our delivery method which results in
44 increased stability of the whole configuration.The total energy for all three is on a decreasing
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trend as shown in Figure 5a.
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39 Fig. 5| a, Total energy graph at each optimization step for graphene, gemcitabine, and graphene-gemcitabine configuration b, Max internal force
40 of all three c, Max internal displacement d, RMS gradient e, RMS internal displacement f, RMS internal force.
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42 All figures show a stable and decreasing trend except for Figure 5c and 5e, where gemcitabine
43 and graphene-gemcitabine show a volatile trend, an up and downtrend, whereas graphene is still
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45 on a steady decreasing trend with each optimization step. This further enforces our conclusion
46 that graphene is a point of stability for the whole configuration. The max and R.M.s internal
47 displacement shown in Figure 5 c and e respectively show how many electrons change their
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positions relative to the centre of atom or molecule. This means that graphene-gemcitabine
50 configured structure is highly volatile and has high reactivity in a water environment, while all
51 the other figures show a stable decreasing trend, the drug delivery system lower total energy at
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each step, while a volatile internal displacement means that it can be reasonably concluded that it
54 will deliver a stable highly effective dose at the targeted area. The various thermodynamics
55 properties are noted in Table 2.
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5 Table 2 Theoratical thermodynamics properties at standard temperature and pressure.
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7 Here G is Gibbs free energy, H is Enthalpy and E is the thermal energy all expressed in kcal/mol.
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Compound Properties Value in kcal/mol
9 graphene G -2.09
10 H -2.64
11 E 2.63
12 gemcitabine G -1.938
13 H -2.466
14 E 2.4566
15 graphene-gemcitabine G -4.256
H -5.026
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Conclusion
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22 In this paper, graphene was studied as a potential drug delivery method for the gemcitabine drug,
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24 where graphene becomes a base for the drug. The Gibbs free energy and Enthalpy are both
25 decreasing from their stand-alone compound in the graphene-gemcitabine configuration, as
26 shown in Table 2. This means that the process is reversible, which can lead to the conclusion that
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when gemcitabine reaches the targeted area, the configuration splits up and gemcitabine is
29 delivered. The graphene here has a dual usage. It not only protects gemcitabine from degradation
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but also reduces gemcitabine's reactivity before it reaches the target area. While graphene’s
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33 highly stable structure has also been evaluated in the paper, this stability means that graphene
34 does not interact with the cells in our body or disturbs the biological function in any way. In our
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current studied configuration, graphene acts as a carrier for our drug delivery system, without
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37 disturbing or affecting any of the surroundings. Thus, it can be reasonably concluded that the
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great potential.
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In this paper, the theoretical models are used to design a drug delivery design system with
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43 graphene, but it is based on theoretical assumption, therefore experimental studies should be
44 done to evaluate the performance of graphene-gemcitabine configuration under various real-life
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physiological conditions.
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50 Disclosure statement
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52 The authors state that there is no conflict of interest
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Journal of Biomolecular Structure & Dynamics

Graphene as a drug carrier for gemcitabine anti-cancer drug

Journal: Journal of Biomolecular Structure & Dynamics

Manuscript Type: Research Article

Date Submitted by the

Complete List of Authors: Zaidi, Syed; University of the Punjab

Keywords: cancer, drug delivery, DFT, graphene, gemcitabine

URL: http://mc.manuscriptcentral.com/jbsd Email: TBSD-peerreview@journals.tandf.com

33 92x71mm (144 x 144 DPI)

33 reversibility of the concentration of electron from gemcitabine to graphene in the configured

30 setting of the human body [17-18].

24 Name Ehomo Elumo Ehomo-lumo Ead

27 graphene -0.14742 -0.04713 0.10029 -47.657

33 overall charge distribution may be due to graphene stabilizing gemcitabine in a water

38 oxide-based scaffolds in regenerative medicine, International Journal of Pharmaceutics, 580, 11926.

42 Molecules, 22, 1322.

24 correction, The Journal of Chemical Physics, 96, 2155.

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