research article molecular dynamics study of...

Research ArticleMolecular Dynamics Study of Stability and Diffusion ofGraphene-Based Drug Delivery Systems

Xiunan Wang1 Yi Liu12 Jingcheng Xu1 Shengjuan Li1 Fada Zhang1

Qian Ye1 Xiao Zhai1 and Xinluo Zhao2

1School of Materials Science and Engineering University of Shanghai for Science and Technology 516 Jungong RoadShanghai 200093 China2Department of Physics Shanghai University 99 Shangda Road Shanghai 200444 China

Correspondence should be addressed to Yi Liu yiliushueducn

Received 18 December 2014 Accepted 1 March 2015

Academic Editor Shutao Guo

Copyright copy 2015 Xiunan Wang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Graphene a two-dimensional nanomaterial with unique biomedical properties has attracted great attention due to its potentialapplications in graphene-based drug delivery systems (DDS) In this work graphene sheets with various sizes and graphene oxidefunctionalized with polyethylene glycol (GO-PEG) are utilized as nanocarriers to load anticancer drug molecules including CE6DOX MTX and SN38 We carried out molecular dynamics calculations to explore the energetic stabilities and diffusion behaviorsof the complex systems with focuses on the effects of the sizes and functionalization of graphene sheets as well as the numberand types of drug molecules Our study shows that the binding of graphene-drug complex is favorable when the drug moleculesand finite graphene sheets become comparable in sizes The boundaries of finite sized graphene sheets restrict the movementof drug molecules The double-side loading often slows down the diffusion of drug molecules compared with the single-sideloading The drug molecules bind more strongly with GO-PEG than with pristine graphene sheets demonstrating the advantagesof functionalization in improving the stability and biocompatibility of graphene-based DDS

1 Introduction

The clinical use of various potent hydrophobic moleculesmany of which are aromatic is often hampered by theirpoor water solubility and low biocompatibility Althoughwater-soluble prodrugs may circumvent these problemsthe efficacy of the drugs decreases Nanomaterial-baseddrug carriers have become a hot spot of research at theinterface between nanotechnology and biomedicine becausethe nanocarriers allow efficient loading targeted deliveryand controlled release of drugs [1ndash4] Carbon nanotubes(CNTs) have attracted enormous interests in biomedicineas nanocarriers and much effort has been done in in vitroand in vivo biological applications recently [5ndash8] Graphenehas emerged as a two-dimensional (2D) honeycomb latticewith interesting physical properties since it was synthesizedin 2004 [9] The intensive research efforts are ongoing toinvestigate the potential applications of graphene in variousfields including quantum physics transparent conductors

nanoelectronic devices nanocomposite materials catalysisenergy research and biomedicine [10ndash12] Graphene is a 2Dmonolayer nanomaterial composed of carbon atoms form-ing connected six-membered rings Compared with CNTsgraphene sheets possess long edges and large accessible sur-faces with delocalized 120587 electrons [13 14] leading to excellentability to immobilize a large number of substances includingmetals drugs biomolecules and fluorescent molecules [15]Graphene and its derivatives such as graphene oxide (GO)reduced graphene oxide (RGO) and GO-nanocompositeswith every atom and functional group exposed to environ-ments allow ultra-high drug loading efficiency and improvegreatly the water solubility and targeting of drug moleculesThus graphene-based materials may be potentially utilizedin cancer treatments with encouraging therapeutic outcomes[16ndash21]

Tremendous efforts have been made on modification ofgraphene and its derivatives for various biomedical applica-tions Liu and coworkers [22] prepared PEGylated graphene

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2015 Article ID 872079 14 pageshttpdxdoiorg1011552015872079

2 Journal of Nanomaterials

oxide (NGO-PEG) sheets with ultra-small nanosizes (10ndash50 nm) by conjugating the amino groups of PEG with thecarboxyl groups of GO The NGO-PEG sheets exhibit highstability in physiological solutions and can absorb aromaticpolymers such as SN38 via 120587-120587 interactions to improvethe solubility of the carrier-drug systems This researchshowed that the functionalized nanographene sheets arebiocompatible without obvious toxicity and could be usedpotentially for drug delivery Zhang and his coworkers [23]modified graphene oxides by sulfonic acid derivatives Themodified GO were used as nanocarriers to load two typesof anticancer drugs (DOX and SN38) for targeted drugdelivery Other groups have used a series of macromolecularpolymers to modify graphene oxide by covalent chemicalreactions including polyethyleneimine (PEI) chitosan (CS)poval (PVA) poly(N-isopropyl acrylamide) (PNIPAM) andamine-modified dextran (DEX) Another synthesis strategyis noncovalent functionalization via hydrophobic interac-tions 120587-120587 interaction or electrostatic binding [23ndash31] Theseexperimental researches demonstrate that graphene can beused as a nanocarrier to load drug molecules and improvethe solubility of carrier-drug systems effectively when func-tionalized with various hydrophilic molecules or polymersimplying potential applications in clinical treatments Previ-ous theoretical works on similar systems include the studyof the interactions between biomolecules and graphene Qinet al [32] performed density functional theory (DFT) andmolecular dynamics (MD) calculations to explore the inter-action between graphene and L-leucine showing that van derWaals interactions between the L-leucine and graphene playa dominant role in the absorption process

Despite the experimental and theoretical studies men-tioned above the thermodynamics and kinetics of graphene-drug complex remain obscure at a molecular level Fornoncovalent graphene-drug complexes the major practicalconcerns are whether the drug molecules can be loaded ontothe graphene sheets tightly To design stable graphene-baseddrug delivery systems (DDS) therefore it is necessary toinvestigate thermodynamics stability from binding energypoint of view Moreover the diffusion behaviors of drugmolecules on the graphene sheets can be used to measure thekinetic stability of DDS In this work we employedmoleculardynamics method to study the interaction between grapheneand drugmolecules focusing on the various sizes of graphenesheets as well as the types numbers and loading modesof drugs Specifically we studied four types of anticancerdrug molecules (CE6 DOX MTX and SN38 shown inFigure 1) absorbed onto graphene sheets with various sizes(10 A 20 A 30 A 40 A and 50 A finite and periodic graphenesheets) and graphene oxide functionalized with amine-modified polyethylene glycol (GO-PEG) In addition to theabsorption mechanism of drug molecules on graphene wealso investigated the binding strength and diffusion behaviorof various graphene-based drug delivery systems

2 Computation Models and Method

21 Modeling and Geometry Optimizations To study thesize effects of graphene we built graphene sheets with a

variety of sizes a periodic graphene sheet five squaredH-terminated graphene sheets with a side length is 10 A20 A 30 A 40 A and 50 A respectively The periodic GO-PEG complex was constructed for studying the effects ofsurface functionalization We built graphene-drug complexmodels initially by ldquoadsorption locatorrdquomodule implementedin Materials Studio [33] with Dreiding force field [34 35]Dreiding force field is a rule based classical force fieldand has good transferability for organic systems We loadmultiple drug molecules (119873 = even) gradually on eithersingle side or double sides of graphene sheets In total westudied 420 graphene-drug complex models Some examplesof these atomic models are shown in Figure 2 All modelstructures were relaxed by geometry optimization usingDreiding force field QEq charge assignments were adoptedThe convergence criteria 20 times 10minus5 kcalmol of energy and0001 kcalmolA of force were used

22 MD Simulations To investigate the dynamic process ofdrug molecules on the graphene we performed molecu-lar dynamic (MD) simulations to elucidate the absorptionbehavior of drug molecules On the basis of the geometryoptimization we first carried out the simulations at theconstant volume and constant temperature (NVT) ensemble(119879 = 298K) A total computation time of 1 ns and a time stepof 1 fs were used to integrateNewtonrsquos equation ofmotion andthe trajectories of the structures were saved every 01 ps Afterthe dynamics reach equilibrium we used the last 500 ps datafor the following analyses

The binding energy (119864119887

) of drug molecules on grapheneis defined as follows

119864119887

= 119864int (D119899G) + 119864119889 (G) + 119864119889 (D119899) + 119864int (D119899)

= 119864int (D119899G) + 119864119889 (G) + 119864119889119894 (D119899)

=

[119864 (D119899

G) minus 119899119864D minus 119864 (G)]119899

(1)

where 119864(D119899

G) is the average total energy of graphene-drug system 119864D is the average total energy of a singledrug molecule 119864(G) is the average total energy of graphenesheet and 119899 is the number of drug molecules absorbedonto graphene Equation (1) shows that the binding energyof graphene and drug molecules consists of the interactionenergy between graphene and drug molecules 119864int(D119899G)the interaction energy among drug molecules 119864int(D119899) andthe deformation energy of graphene 119864

119889

(G) as well as drugmolecules 119864

119889

(D119899

)Average binding energy is an integrated representation

of binding strength between drug molecules and grapheneIn order to further understand the binding energy wecalculate the instantaneous interaction energy instantaneousdeformation energy and instantaneous binding energy using

Journal of Nanomaterials 3

(a) (CE61

)Gf20

(b) (DOX1

)Gf20

(c) (MTX1

)Gf20

(d) (SN381

)Gf20

Figure 1 Atomic structures of graphene-drug complexD1

Gf20

The radius of gyration119877119892

of the four types of drugmolecules is CE6 (470 A)DOX (479 A) MTX (499 A) and SN38 (431 A) respectively The largest point-to-point distance of these drug molecules is CE6 (1467 A)DOX (1476 A) MTX (1533 A) and SN38 (1397 A) respectively

the last snapshot structures of NVT simulations Theseenergy components are defined as follows

1198641

119887

=

[1198641

(D119899

G) minus 119899119864D minus 119864 (G)]119899

= 1198641

int (D119899G) + 1198641

119889

(G) + 1198641119889

(D119899

) + 1198641

int (D119899)

(2)

1198641

int (D119899G) =[1198641

(D119899

G) minus 1198641 (D119899

) minus 1198641

(G)]119899

(3)

where 1198641int(D119899G) is the instantaneous interaction energybetween graphene and drug molecules 1198641(D

119899

G) is thesingle-point energy of the last snapshot of graphene-drug sys-tem 1198641(D

119899

) is the single-point energy of all drug molecules

as a whole and 1198641(G) is the single-point energy of graphenesheet One has

1198641

119889119894

(D119899

) =

[1198641

(D119899

) minus 119899119864D]

119899

(4)

where 1198641119889119894

(D119899

) is the instantaneous interaction energy anddeformation energy of drug molecules 1198641(D

119899

) is the single-point energy of all drug molecules as a whole and 119864D isthe average energy of a single drug molecule These datawere taken from the last frame structures in the NVT MDsimulations One has

1198641

119889

(G) =[1198641

(G) minus 119864 (G)]119899

1198641

119889

(D119899

) =

sum119899

119873=1

[1198641

(D) minus 119864D]119899

(5)


(a) (CE68

)Gf50

(b) (DOX8

)Gf50

(c) (MTX8

)Gf50

(d) (SN388

)Gf50

Figure 2 Typical atomic structures of graphene-drug complexes (a) CE68

Gf50

(b) DOX8

Gf50

(c) MTX8

Gf50

and (d) SN388

Gf50

Thedashed line in the figure presents the intermolecular or intramolecular hydrogen bonding interaction of drug molecules

40

0

minus40

minus80

minus120

minus160

minus200

minus24010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38CE6DOXMTX

DOX(minus2705)MTX(minus2103)

SN38(minus3075)

CE6(minus6620)

(CE61)(GfL)(DOX1)(GfL)

(MTX1)(GfL)(SN381)(GfL)

(a)

20

0

minus20

minus40

minus60

minus80

minus100

minus120

minus140

minus16010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38

CE6DOX

MTX

CE6(minus1601)

MTX(minus6394)

SN38(minus4755)DOX(minus4571)

(CE61)_(CE61)(GfL)(DOX1)_(DOX1)(GfL)

(MTX1)_(MTX1)(GfL)(SN381)_(SN381)(GfL)

(b)Figure 3 Average binding energies (119864

119887

) of graphene-drug complexes when one drug molecule is loaded onto the graphene sheets with sizesof 10ndash50 A in (a) single-side and (b) double-side modes The dashed lines represent 119864

119887

when one drug molecule is loaded onto the periodicgraphene sheets in (a) single-side and (b) double-side modes


1000

800

600

400

200

0

minus200

minus4000 10 20 30 40 50

E(kcalm

ol)

L (Aring)

E1b(CE61GfL)

E1int(CE61GfL)

E1d(GfL)

E1d(CE61)

E1d(GfL)

E1d(CE61)

E1int

E1b

(a)

E1d(GfL)

E1int

E1b

0 10 20 30 40 50

L (Aring)

E1b(DOX1

E1int(DOX1

E1d(GfL)

E1d(DOX1)

E1d(DOX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(b)

0 10 20 30 40 50

L (Aring)

E1b(MTX1

E1int(MTX1

E1d(GfL)

E1d(MTX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1int

E1d(MTX1)

E1b

E1d(GfL)

GfL)GfL)

(c)

E1d(GfL)

E1b

E1int

E1d(SN381)

0 10 20 30 40 50

L (Aring)

E1b(SN381

E1int(SN381

E1d(GfL)

E1d(SN381)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(d)

Figure 4 Instantaneous binding energies (1198641119887

) interaction energies (1198641int) and deformation energies (1198641119889

) of graphene-drug complexes whenloading one drug molecule namely (a) CE6 (b) DOX (c) MTX and (d) SN38 onto the single side of the graphene sheets with sizes of10ndash50 A

where 1198641119889

(G) is the instantaneous deformation energy ofgraphene 1198641

119889

(D119899

) is the instantaneous deformation energyof drug molecules and 1198641(D) is the single-point energy of asingle drugmolecule from the last snapshot of graphene-drugsystem

After NVT simulations reach equilibrium we used thefinal frame structures of NVT simulations as the initial struc-tures to runNVE (constant volume and constant energy)MDsimulations The total simulation time was 500 ps with a 1 fstime step The MD trajectories were printed out every 100 fsTo study the thermal diffusion behavior of drug moleculeson the surface of graphene we calculated the diffusion

coefficient of drug molecules on the surface of graphene asfollows

119863 = lim119905rarrinfin

1

6119905

⟨1003816100381610038161003816119903119894

(119905) minus 119903119894

(0)1003816100381610038161003816

2

⟩ (6)

where 119903119894

(119905) and 119903119894

(0) stand for the position vector at times 119905and 0 respectively ⟨ ⟩ refers to the fact that data are averagedover the NVE ensemble Moreover we decomposed the totaldiffusion coefficient into its components along the directionof 119909119909 119910119910 and 119911119911 As we mainly concern the diffusionbehavior of drug molecules on the surface of graphene wechose the averaged diffusion coefficients between 119909119909 and 119910119910


CE6(097)

MTX(302)

SN38(777)

DOX(166)

84

80

76

30

25

20

15

10

05

00

minus05

Dxx_y

y(Aring

2s)

10 20 30 40 50

L (Aring)

(CE61)(DOX1)

(MTX1)

(SN381)

DOXCE6

SN38

MTX

GfLGfL

GfLGfL

(a)

40

35

30

25

20

15

08

06

04

02

00

10 20 30 40 50

L (Aring)

(CE61)_(CE61)(DOX1)_(DOX1)

(MTX1)_(MTX1)(SN381)_(SN381)

DOXCE6SN38MTX

DOX(083)

MTX(204)

SN38(330)

CE6(180)

Dxx_y

y(Aring

2s)

GfLGfL GfL

GfL

(b)

Figure 5 Average in-plane diffusion coefficients of one drug molecule loaded on the graphene sheets of 10ndash50 A in (a) single-side and (b)double-side modes The dashed lines represent the average in-plane diffusion coefficients of one drug molecule loaded on periodic graphenein (a) single-side and (b) double-sidemodesThe diffusion coefficients of four types of drugmolecules CE6 DOXMTX and SN38 are shownin the figures respectively

components parallel to the graphene sheet surface denotedas 119909119909 119910119910 as a measure of the diffusion behavior of drugmolecules After the systems reach equilibrium in the NVEsimulations the trajectories in the last 250 ps were used foranalyses

3 Results and Discussion

31 Size Effects of Graphene Sheets on Graphene-Drug BindingTo investigate the influences of sizes of graphene sheetson the binding strength of graphene-drug complexes weload drug molecules on the squared graphene sheets with avariety of finite side lengths for example 10 A 20 A 30 A40 A and 50 A as well as periodic squared sheets with aunit cell 50 times 50 times 20 A modeling infinite large graphenesheets The four types of drug molecules namely CE6 DOXMTX and SN38 are loaded respectively on either oneside (D

119899

Gf119871

) or two sides [(D119899

) (D119899

)Gf119871

] of graphenesheets where D

119899

represent 119899 drug molecules and Gf119871

orGp119871

are finite or periodic graphene sheets with a lengthof 119871 A To focus on the graphene-drug bindings and avoidthe interactions among drug molecules we first load onedrug molecule on one side of graphene sheets denoted assingle-side loadingmode (D

1

Gf119871

) or one drugmolecule oneach side of graphene sheets denoted as double-side loadingmode [(D

1

) (D1

)Gf119871

] To evaluate the binding strength ofgraphene-drug complex we discuss the results of bindingenergies and their components including interaction energiesand deformation energies respectively as follows

311 Average Binding Energy The average binding energy 119864119887

as defined in (1) represents the binding strength of graphene-drug complex with respect to the corresponding isolated

components We calculated the average binding energies 119864119887

as functions of graphene sheet sizes for the four types of drugmolecules (Figure 3) The results show that the average 119864

119887

of graphene-drug complexes vary depending on the sizes ofgraphene sheets Specifically the average 119864

119887

maximizes for20ndash30 A graphene sheets in both single-side and double-sideloading modes When finite graphene sheets are larger orsmaller than 20ndash30 A the average binding energies becomesmaller and comparable to the119864

119887

of periodic graphene sheetsThese results suggest that the appropriate sized graphenesheets or coverage density (20ndash30 A per molecule) helpsstabilize the binding of graphene and drug molecules

Comparisons of 119864119887

between single-side and double-sideloadings show that single-side bindings are stronger thandouble-side bindings for graphene sheets of size 20ndash30 Awhile becoming comparable for graphene sheets of size 40ndash50 A For periodic graphene sheets the double-side bindingis stronger than the single-side binding except for CE6The binding strength between a single drug molecule andperiodic graphene decreases in the order of CE6 gt SN38 gtDOX gt MTX in the single-side loading mode while thebinding strength decreases in the order of MTX gt SN38 gtDOX gt CE6 in the double-side loading mode

312 Instantaneous Binding Energy Interaction Energy andDeformation Energy Instantaneous binding energies (1198641

119887

)calculated based on the last MD snapshots show similartrends as the binding energies (119864

119887

) averaged over the wholeMD trajectories all four types of drug molecules bind moststrongly with the graphene sheets of 20ndash30 A (Figure 4) Tounderstand the origin of such trends we decompose thebinding energy into its components including the interac-tion energy (1198641int) between graphene and drug as well as


DOXCE6

SN38MTX

(CE6n)Gf50(DOXn)Gf50

(MTXn)Gf50(SN38n)Gf50

Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX

(CE6n)_(CE6n)Gf50(DOXn)_(DOXn)Gf50

(MTXn)_(MTXn)Gf50(SN38n)_(SN38n)Gf50

Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX

(CE6n)Gp50(DOXn)Gp50

(MTXn)Gp50(SN38n)Gp50

Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX

(CE6n)_(CE6n)Gp50(DOXn)_(DOXn)Gp50

(MTXn)_(MTXn)Gp50(SN38n)_(SN38n)Gp50

Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)

Figure 6 Average binding energies (119864119887

) of graphene-drug complexes when loading various numbers and types of drug molecules onto((a) and (b)) the finite graphene sheets of 50 A and ((c) and (d)) the periodic graphene sheets in ((a) and (c)) single-side and ((b) and (d))double-side modes

the deformation energies (1198641119889

) of graphene and drug respec-tively (equation (1)) It is clearly seen that the deformationenergies of graphene sheets dominate the binding energiesleading to their very similar trends The graphene sheetsof 20ndash30 A exhibit the smallest deformation energies whenone drug molecule is loaded possibly because the sizes ofgraphene sheets and drug molecules match well at this rangeas shown in Figure 1 On the other hand each drug moleculedeforms similarly from an energy point of view independentof the sizes of graphene sheets Finally the interaction energybetween the graphene and drug barely changes in spite of thevaried sizes and deformation of graphene sheets Combiningall analyses above we conclude that the size match betweenfinite graphene sheets and drug molecules is critical to

determining the deformation of graphene sheets and in turntheir binding strength

313 Size Effects of Graphene Sheets on Diffusion of DrugMolecules on Graphene Sheets The in-plane diffusion coef-ficients 119863

119909119909 119910119910

defined in (6) measure the ease of diffusionbehavior of drug molecules on the surface of graphene sheetsfrom a kinetics point of view We calculated the in-planediffusion coefficients as functions of the sizes of graphenesheets when one drugmolecule is loaded in either single-sideor double-side modes (Figure 5) Our calculations show thatthe diffusion coefficients of the single molecule are negligible(lt02 A2s) when loaded on the graphene sheet of 10ndash20 A


0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894

) of graphene-drug complexeswhen loadingmultiple drugmolecules namely (a) CE6 (b) DOX (c)MTX and (d) SN38 onto the single side of the graphene sheets of 50 A

in both single-side and double-side modes indicating thatthe movement of drug molecule is restricted within thesmall sized graphene sheetsThe diffusion coefficients of drugmolecules increase gradually as the graphene sheets becomelarger and approach towards the corresponding values onthe periodic graphene sheets This trend indicates that largergraphene sheets provide more free spaces for faster diffusion

The diffusion coefficients of drugmolecules loaded on theperiodic graphene sheets in the double-sidemodes are alwayssmaller than those in the single-side modes except for CE6Thismeans that double-side loading often slows down the dif-fusions of drug molecules compared with single-side loadingprobably due to the interactions between the drug moleculesseparated by the graphene sheets The diffusion coefficients

of single molecules loaded on the periodic graphene sheetsincrease in the order of CE6 lt DOX lt MTX lt SN38 in thesingle-side mode while the diffusion coefficient increases inthe order of DOX lt CE6 ltMTX lt SN38 in the double-sidemode

32 Effects of the Number and Types of Drug Molecules onthe Graphene-Drug Binding and Diffusion


defined in (1) for loading multiple drug molecules measuresthe binding strength between multiple drugs and grapheneas well as those among drug molecules normalized by thenumber of drug molecules The diverse configurations of


0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894

) of graphene-drug complexeswhen loading multiple drug molecules namely (a) CE6 (b) DOX (c) MTX and (d) SN38 onto the single side of the periodic graphenesheets

drug molecules and graphene make 119864119887

fluctuate around10ndash50 kcalmol for graphene sheets of 50 A while fluctu-ating around 20ndash70 kcalmol for periodic graphene sheetsindependent of the number and types of drug molecules(Figure 6)

322 Instantaneous Binding Energy Interaction Energy andDeformation Energy of Graphene-Drug Complexes D

119899

Gf50

Instantaneous binding energies (1198641

119887

) as functions of thenumber of drug molecules (119899) were evaluated based on thelast MD snapshots and shown in Figure 7 1198641

119887

of all four typesof drugs decrease monotonically as 119899 increases Specificallythe instantaneous binding energies are relatively small when1 or 2 drug molecules are loaded on the graphene sheets

of 50 A while increasing quickly and approaching towardsconstant values Since these results are obtained based on theindependent systems with a variety of number and types ofdrug molecules the trends of instantaneous binding energiesare statistically meaningful

To understand the trend of the instantaneous bindingenergies we decompose 1198641

119887

further into the interactionenergy (1198641int) between graphene and drugs deformationenergies (1198641

119889

) of graphene and deformation-interaction ener-gies of drugs (1198641

119889119894

) according to (2) It is found that thedeformation energies of graphene exhibit very similar trendsas the instantaneous binding energies while the graphene-drug interaction energies and the deformation-interactionenergies of drugs barely change with the number of drug




CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)

Figure 9 (a) Instantaneous deformation energies and (b) instantaneous interaction energies of different types and numbers of drugmoleculesloaded onto the periodic graphene sheets

moleculesThese results demonstrate that the deformation ofgraphene sheet determines the binding strength of graphene-drug complexwhen drug coverage density is low for example1-2 molecules(50 times 50 A2) The larger drug coverage leadsto almost invariant instantaneous deformation and bindingenergies indicating that the stability of the graphene-drugcomplex is independent of the number of densely loadeddrug molecules The typical atomic structures of graphene-drug complexes exhibit the H-bonding and electrostaticinteractions among drug molecules and vdW interactionsbetween drug molecules and graphene sheets as shown inFigure 2


119899

Gp50

When multiple drug molecules are loaded onto the periodicgraphene sheets neither the instantaneous binding energiesnor their components change significantly with the numberof the drug molecules (Figure 8) These results are differentfrom the case of finite graphene sheets where the deformationenergies of finite graphene sheets vary depending on thenumber of drug molecules Apparently it is hard for theperiodic graphene sheets to deform permanently due tobindingwith drugmolecules besides their thermal vibrations

324 Instantaneous Deformation Energies and InteractionEnergies of Drug Molecules To examine the effects ofdeformation energies and interaction energies of multi-ple drug molecules separately we decompose further thedeformation-interaction energies (1198641

119889119894

) into the deformation(1198641119889

) and interaction (1198641int) energies (Figure 9) The resultsshow that the deformation energies increase slightly exceptfor SN38 while the interaction energies become larger asthe number of drug molecules increases This means that

the drug molecules deform themselves more significantly inorder to interact with each othermore strongly as the numberof drugmolecules increases leading to the total deformation-interaction energies being barely changed

325 Diffusion Coefficients of Multiple Drug Molecules Theaverage diffusion coefficients of multiple drug moleculeson the surface of graphene sheets were calculated as thefunctions of the number of the drug molecules (Figure 10)The results show that with the increase of the number ofdrug molecules the diffusion coefficients of drug moleculeson the surface of graphene fall quickly in both single-side and double-side loading modes When the numberof drug molecules reaches 6ndash8(50 times 50 A2) the diffusioncoefficients become small meaning that the drug moleculesare locked The diffusion coefficients of drug moleculesloaded on the double sides of graphene are lower than thoseloaded on the single side suggesting the dragging effect ofmolecular motion caused by the interactions between thedrug molecules separated by the graphene sheets Moreoverthe drug molecules diffuse more quickly on the surface ofperiodic graphene than on the finite sized graphene sheetsindicating that the limited sizes of graphene sheets slowdown the movement of drug molecules probably due to theboundary effects

4 Loading Drug Molecules onto PEGylatedGraphene Oxide (GO-PEG)

41 Average Binding Energy and Diffusion Coefficient Toinvestigate the effects of surface functionalization we loadeddrug molecules (119899 = 1 4 8) onto the surface of periodicgraphene oxide functionalized by PEG chains (GO-PEG)and calculated their average binding energies and diffusion


CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)

Figure 10 In-plane diffusion coefficients (119863119909119909 119910119910

) of various types and numbers of drugmolecules loaded on ((a) and (b)) the finite graphenesheets of 50 A and ((c) and (d)) the periodic graphene sheets in ((a) and (c)) single-side modes and ((b) and (d)) double-side modes

coefficients (Figure 11) Compared with pristine graphenesheets the absolute values of the binding energies increasesignificantly when loading drugmolecules onto the GO-PEGsheets These mean that the oxidized functional groups andPEG chains on the surface of graphene have strong attractiveinteractions with drug molecules When loading one drugmolecule the binding energies of drug molecule and GO-PEG complexes decrease in the order of DOX gt SN38 gtMTX gt CE6 When the number of drug molecules increasesthe binding energies decrease and the differences of bindingenergies among various types of drug molecules becomesmaller probably because of the fact that multiple drugmolecules distort the flexible PEG chains more significantlycausing energy penalty from the deformation of PEG chains

The typical atomic structures of MD snapshots of D119899

GO-PEG complex are shown in Figure 12 We found that thearrangement of drug molecules is scattered indicating thatthe drug molecules tend to bind with the PEG chains ratherthan aggregate by themselves

The in-plane diffusion coefficients (Figure 11(b)) showthat compared with the drugs loaded on the pristinegraphene sheets the diffusion coefficients of drug moleculesloaded on the GO-PEG sheets decrease significantly(lt01 A2s) and remain unchanged with the increase ofthe number of drug molecules This suggests that the drugmolecules on the GO-PEG sheets are almost immobileConsidering both the large binding energies and smalldiffusion coefficients discussed above the GO-PEG-drug


minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)

(CE6n)(GO-PEG)(DOXn)(GO-PEG)

(MTXn)(GO-PEG)(SN38n)(GO-PEG)

0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)

Figure 11 (a)Average binding energies and (b) diffusion coefficientsof D119899

(GO-PEG) complex with various types and numbers of drugmolecules in single-side loading modes

complexes are obviously more stable than the graphene-drugcomplexes This can be understood by the fact that thereare mainly vdW interactions between drug moleculesand graphene in D

119899

G while additional electrostatic andH-bonding interactions in D

119899

GO-PEG contribute to thestronger bindings

5 Conclusions

In this work molecular dynamic simulations were per-formed to investigate the energetic stabilities and diffusionbehaviors of the graphene-drug complexes We focus onthe influences of the size of graphene sheets the numberand types of drug molecules and the loading modes Our

(a) GO-PEG

(b) (CE68

)(GO-PEG)

Figure 12 (a) Atomic structure of GO-PEG complex The GO-PEG is divided into four parts decorated by four types of functionalgroups (i) hydroxy (ii) carboxide (iii) epoxy group and (iv)carboxyl respectively (b) Typical atomic structures of grapheneoxide-drug complex CE6

8

GO-PEG (top view and side view)

simulations show that the binding strength of graphene-drugcomplex is mainly determined by the deformation of finitegraphene sheets When the areas that drug molecules occupyhave comparable sizes as graphene sheets for example20ndash30 Amolecule the deformation of graphene sheets isminimized and the graphene-drug bindings are the strongestThe average binding strength permolecule fluctuates between10 and 70 kcalmol that is not sensitive to the number andtypes of drug molecule as well as their loading modes Ifthe density of drug coverage is low and graphene sheets arerelatively large the binding strength is mainly determinedby the interaction of graphene-drug The limited sizes ofgraphene sheets restrict the movement of drug moleculesMultiple drug molecules may form clusters that slow down


the diffusion on graphene sheets Diffusion in the double-side loading mode is often slower than that in the single-side loading mode Compared with pristine graphene sheetsgraphene oxide functionalized with PEG chains has strongerbindings with drug molecules so that the drug molecules areessentially immobilized These results give physical insightsinto the stability and dynamics of graphene-drug complexeshelpful for designing novel graphene-based drug deliverysystems

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors are grateful for financial support from ldquoShang-hai Pujiang Talentrdquo program (12PJ1406500) ldquoShanghaiHigh-Tech Area of Innovative Science and Technology(14521100602)rdquo STCSM ldquoKey Program of Innovative Scien-tific Researchrdquo (14ZZ130) and ldquoKey Laboratory of AdvancedMetal-Based Electrical Power Materialsrdquo the EducationCommission of Shanghai Municipality State Key Laboratoryof Heavy Oil Processing China University of Petroleum(SKLOP201402001) Xinluo Zhao thanks National NaturalScience Foundation of China (Grant nos 51202137 61240054and 11274222) Computations were carried out at HujiangHPC facilities at USST Shanghai Supercomputer Center andNational Supercomputing Center in Shenzhen China

References

[1] S K Vashist D Zheng G Pastorin K Al-Rubeaan J H TLuong and F-S Sheu ldquoDelivery of drugs and biomoleculesusing carbon nanotubesrdquoCarbon vol 49 no 13 pp 4077ndash40972011

[2] Z Liu Y Wang and N Zhang ldquoMicelle-like nanoassembliesbased on polymer-drug conjugates as an emerging platform fordrug deliveryrdquo Expert Opinion onDrug Delivery vol 9 no 7 pp805ndash822 2012

[3] P Pahuja S Arora and P Pawar ldquoOcular drug delivery systema reference to natural polymersrdquo Expert Opinion on DrugDelivery vol 9 no 7 pp 837ndash861 2012

[4] A Szuts and P Szabo-Revesz ldquoSucrose esters as natural sur-factants in drug delivery systemsmdashamini-reviewrdquo InternationalJournal of Pharmaceutics vol 433 no 1-2 pp 1ndash9 2012

[5] N W S Kam T C Jessop P A Wender and H DaildquoNanotube molecular transporters internalization of carbonnanotube-protein conjugates into mammalian cellsrdquo Journal ofthe American Chemical Society vol 126 no 22 pp 6850ndash68512004

[6] R P Feazell H Dai N Nakayama-Ratchford and S J LippardldquoSoluble single-walled carbon nanotubes as longboat deliverysystems for platinum (IV) anticancer drug designrdquo Journal ofthe American Chemical Society vol 129 no 27 pp 8438ndash84392007

[7] Z Liu W Cai L He et al ldquoIn vivo biodistribution and highlyefficient tumour targeting of carbon nanotubes in micerdquoNatureNanotechnology vol 2 no 1 pp 47ndash52 2007

[8] S Dhar Z Liu J Thomale H Dai and S J Lippard ldquoTargetedsingle-wall carbon nanotube-mediated Pt(IV) prodrug deliveryusing folate as a homing devicerdquo Journal of the AmericanChemical Society vol 130 no 34 pp 11467ndash11476 2008

[9] K S Novoselov A K Geim S V Morozov et al ldquoElectric fieldin atomically thin carbon filmsrdquo Science vol 306 no 5696 pp666ndash669 2004

[10] S Stankovich D A Dikin G H B Dommett et al ldquoGraphene-based composite materialsrdquo Nature vol 442 no 7100 pp 282ndash286 2006

[11] A K Geim and K S Novoselov ldquoThe rise of graphenerdquo NatureMaterials vol 6 no 3 pp 183ndash191 2007

[12] A K Geim ldquoGraphene status and prospectsrdquo Science vol 324no 5934 pp 1530ndash1534 2009

[13] B Huang Z Li Z R Liu et al ldquoAdsorption of gas moleculeson graphene nanoribbons and its implication for nanoscalemolecule sensorrdquo Journal of Physical Chemistry C vol 112 no35 pp 13442ndash13446 2008

[14] D Li and R B Kaner ldquoMaterials science graphene-basedmaterialsrdquo Science vol 320 no 5880 pp 1170ndash1171 2008

[15] C S Wang J Y Li C Amatore Y Chen H Jiang and X-M Wang ldquoGold nanoclusters and graphene nanocompositesfor drug delivery and imaging of cancer cellsrdquo AngewandteChemiemdashInternational Edition vol 50 no 49 pp 11644ndash116482011

[16] S Zhang B Tian Z Liu K Yang J Wan and Y Zhang ldquoTheinfluence of surface chemistry and size of nanoscale grapheneoxide on photothermal therapy of cancer using ultra-low laserpowerrdquo Biomaterials vol 33 no 7 pp 2206ndash2214 2012

[17] K Yang L Hu X Ma et al ldquoMultimodal imaging guided pho-tothermal therapy using functionalized graphene nanosheetsanchored with magnetic nanoparticlesrdquo Advanced Materialsvol 24 no 14 pp 1868ndash1872 2012

[18] B Tian C Wang S Zhang L Feng and Z Liu ldquoPhotother-mally enhanced photodynamic therapy delivered by nano-graphene oxiderdquo ACS Nano vol 5 no 9 pp 7000ndash7009 2011

[19] S Zhang K Yang L Feng and Z Liu ldquoIn vitro and in vivobehaviors of dextran functionalized graphenerdquo Carbon vol 49no 12 pp 4040ndash4049 2011

[20] K Yang S Zhang G Zhang X Sun S-T Lee and Z LiuldquoGraphene inmice ultrahigh in vivo tumor uptake and efficientphotothermal therapyrdquo Nano Letters vol 10 no 9 pp 3318ndash3323 2010

[21] H Shen L M Zhang M Liu and Z Zhang ldquoBiomedicalapplications of graphenerdquo Theranostics vol 2 no 3 pp 283ndash294 2012

[22] Z Liu J T Robinson X Sun and H Dai ldquoPEGylatednanographene oxide for delivery of water-insoluble cancerdrugsrdquo Journal of the American Chemical Society vol 130 no33 pp 10876ndash10877 2008

[23] L M Zhang J G Xia Q H Zhao L Liu and Z ZhangldquoFunctional graphene oxide as a nanocarrier for controlledloading and targeted delivery ofmixed anticancer drugsrdquo Smallvol 6 no 4 pp 537ndash544 2010

[24] H Q Bao Y Z Pan Y Ping et al ldquoChitosan-functionalizedgraphene oxide as a nanocarrier for drug and gene deliveryrdquoSmall vol 7 no 11 pp 1569ndash1578 2011

[25] X Y Yang X Y Zhang Z F Liu Y Ma Y Huang andY Chen ldquoHigh-efficiency loading and controlled release ofdoxorubicin hydrochloride on graphene oxiderdquo Journal ofPhysical Chemistry C vol 112 no 45 pp 17554ndash17558 2008


[26] V K Rana M-C Choi J-Y Kong et al ldquoSynthesis and drug-delivery behavior of chitosan-functionalized graphene oxidehybrid nanosheetsrdquoMacromolecularMaterials and Engineeringvol 296 no 2 pp 131ndash140 2011

[27] B Chen M Liu L M Zhang J Huang J Yao and ZZhang ldquoPolyethylenimine-functionalized graphene oxide as anefficient gene delivery vectorrdquo Journal of Materials Chemistryvol 21 no 21 pp 7736ndash7741 2011

[28] L M Zhang Z X Lu Q H Zhao J Huang H Shenand Z Zhang ldquoEnhanced chemotherapy efficacy by sequentialdelivery of siRNA and anticancer drugs using PEI-graftedgraphene oxiderdquo Small vol 7 no 4 pp 460ndash464 2011

[29] Y Z Pan H Q Bao N G Sahoo T Wu and L Li ldquoWater-soluble poly(N-isopropylacrylamide)-graphene sheets synthe-sized via click chemistry for drug deliveryrdquoAdvanced FunctionalMaterials vol 21 no 14 pp 2754ndash2763 2011

[30] Y Pan N G Sahoo and L Li ldquoThe application of grapheneoxide in drug deliveryrdquo Expert Opinion on Drug Delivery vol9 no 11 pp 1365ndash1376 2012

[31] Z Liu J T Robinson X M Sun et al ldquoCarbon materials fordrug delivery amp cancer therapyrdquo Nano Letters vol 10 no 7-8pp 3318ndash3329 2010

[32] W Qin X Li W-W Bian X-J Fan and J-Y Qi ldquoDensityfunctional theory calculations andmolecular dynamics simula-tions of the adsorption of biomolecules on graphene surfacesrdquoBiomaterials vol 31 no 5 pp 1007ndash1016 2010

[33] Accelrys Software Inc Materials Studio Release Notes Release70 Accelrys Software Inc San Diego Calif USA 2013

[34] S L Mayo B D Olafson andW A Goddard III ldquoDREIDINGa generic force field for molecular simulationsrdquo The Journal ofPhysical Chemistry vol 94 no 26 pp 8897ndash8909 1990

[35] A K Rappe and W A Goddard III ldquoCharge equilibrationfor molecular dynamics simulationsrdquo The Journal of PhysicalChemistry vol 95 no 8 pp 3358ndash3363 1991

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of



CeramicsJournal of


CompositesJournal of

NanoparticlesJournal of



International Journal of

Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


BioMed Research International

MaterialsJournal of


Nano

materials


Journal ofNanomaterials


oxide (NGO-PEG) sheets with ultra-small nanosizes (10ndash50 nm) by conjugating the amino groups of PEG with thecarboxyl groups of GO The NGO-PEG sheets exhibit highstability in physiological solutions and can absorb aromaticpolymers such as SN38 via 120587-120587 interactions to improvethe solubility of the carrier-drug systems This researchshowed that the functionalized nanographene sheets arebiocompatible without obvious toxicity and could be usedpotentially for drug delivery Zhang and his coworkers [23]modified graphene oxides by sulfonic acid derivatives Themodified GO were used as nanocarriers to load two typesof anticancer drugs (DOX and SN38) for targeted drugdelivery Other groups have used a series of macromolecularpolymers to modify graphene oxide by covalent chemicalreactions including polyethyleneimine (PEI) chitosan (CS)poval (PVA) poly(N-isopropyl acrylamide) (PNIPAM) andamine-modified dextran (DEX) Another synthesis strategyis noncovalent functionalization via hydrophobic interac-tions 120587-120587 interaction or electrostatic binding [23ndash31] Theseexperimental researches demonstrate that graphene can beused as a nanocarrier to load drug molecules and improvethe solubility of carrier-drug systems effectively when func-tionalized with various hydrophilic molecules or polymersimplying potential applications in clinical treatments Previ-ous theoretical works on similar systems include the studyof the interactions between biomolecules and graphene Qinet al [32] performed density functional theory (DFT) andmolecular dynamics (MD) calculations to explore the inter-action between graphene and L-leucine showing that van derWaals interactions between the L-leucine and graphene playa dominant role in the absorption process

Despite the experimental and theoretical studies men-tioned above the thermodynamics and kinetics of graphene-drug complex remain obscure at a molecular level Fornoncovalent graphene-drug complexes the major practicalconcerns are whether the drug molecules can be loaded ontothe graphene sheets tightly To design stable graphene-baseddrug delivery systems (DDS) therefore it is necessary toinvestigate thermodynamics stability from binding energypoint of view Moreover the diffusion behaviors of drugmolecules on the graphene sheets can be used to measure thekinetic stability of DDS In this work we employedmoleculardynamics method to study the interaction between grapheneand drugmolecules focusing on the various sizes of graphenesheets as well as the types numbers and loading modesof drugs Specifically we studied four types of anticancerdrug molecules (CE6 DOX MTX and SN38 shown inFigure 1) absorbed onto graphene sheets with various sizes(10 A 20 A 30 A 40 A and 50 A finite and periodic graphenesheets) and graphene oxide functionalized with amine-modified polyethylene glycol (GO-PEG) In addition to theabsorption mechanism of drug molecules on graphene wealso investigated the binding strength and diffusion behaviorof various graphene-based drug delivery systems

2 Computation Models and Method

21 Modeling and Geometry Optimizations To study thesize effects of graphene we built graphene sheets with a

variety of sizes a periodic graphene sheet five squaredH-terminated graphene sheets with a side length is 10 A20 A 30 A 40 A and 50 A respectively The periodic GO-PEG complex was constructed for studying the effects ofsurface functionalization We built graphene-drug complexmodels initially by ldquoadsorption locatorrdquomodule implementedin Materials Studio [33] with Dreiding force field [34 35]Dreiding force field is a rule based classical force fieldand has good transferability for organic systems We loadmultiple drug molecules (119873 = even) gradually on eithersingle side or double sides of graphene sheets In total westudied 420 graphene-drug complex models Some examplesof these atomic models are shown in Figure 2 All modelstructures were relaxed by geometry optimization usingDreiding force field QEq charge assignments were adoptedThe convergence criteria 20 times 10minus5 kcalmol of energy and0001 kcalmolA of force were used

22 MD Simulations To investigate the dynamic process ofdrug molecules on the graphene we performed molecu-lar dynamic (MD) simulations to elucidate the absorptionbehavior of drug molecules On the basis of the geometryoptimization we first carried out the simulations at theconstant volume and constant temperature (NVT) ensemble(119879 = 298K) A total computation time of 1 ns and a time stepof 1 fs were used to integrateNewtonrsquos equation ofmotion andthe trajectories of the structures were saved every 01 ps Afterthe dynamics reach equilibrium we used the last 500 ps datafor the following analyses

The binding energy (119864119887

) of drug molecules on grapheneis defined as follows

119864119887

= 119864int (D119899G) + 119864119889 (G) + 119864119889 (D119899) + 119864int (D119899)

= 119864int (D119899G) + 119864119889 (G) + 119864119889119894 (D119899)

=

[119864 (D119899

G) minus 119899119864D minus 119864 (G)]119899

(1)

where 119864(D119899

G) is the average total energy of graphene-drug system 119864D is the average total energy of a singledrug molecule 119864(G) is the average total energy of graphenesheet and 119899 is the number of drug molecules absorbedonto graphene Equation (1) shows that the binding energyof graphene and drug molecules consists of the interactionenergy between graphene and drug molecules 119864int(D119899G)the interaction energy among drug molecules 119864int(D119899) andthe deformation energy of graphene 119864

119889

(G) as well as drugmolecules 119864

119889

(D119899

)Average binding energy is an integrated representation

of binding strength between drug molecules and grapheneIn order to further understand the binding energy wecalculate the instantaneous interaction energy instantaneousdeformation energy and instantaneous binding energy using


(a) (CE61

)Gf20

(b) (DOX1

)Gf20

(c) (MTX1

)Gf20

(d) (SN381

)Gf20


Gf20




1198641

119887

=

[1198641

(D119899

G) minus 119899119864D minus 119864 (G)]119899

= 1198641

int (D119899G) + 1198641

119889

(G) + 1198641119889

(D119899

) + 1198641

int (D119899)

(2)

1198641

int (D119899G) =[1198641

(D119899

G) minus 1198641 (D119899

) minus 1198641

(G)]119899

(3)


119899


119899



1198641

119889119894

(D119899

) =

[1198641

(D119899

) minus 119899119864D]

119899

(4)

where 1198641119889119894

(D119899


119899


1198641

119889

(G) =[1198641

(G) minus 119864 (G)]119899

1198641

119889

(D119899

) =

sum119899

119873=1

[1198641

(D) minus 119864D]119899

(5)


(a) (CE68

)Gf50

(b) (DOX8

)Gf50

(c) (MTX8

)Gf50

(d) (SN388

)Gf50


Gf50

(b) DOX8

Gf50

(c) MTX8

Gf50

and (d) SN388

Gf50


40

0

minus40

minus80

minus120

minus160

minus200

minus24010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38CE6DOXMTX


SN38(minus3075)

CE6(minus6620)



(a)

20

0

minus20

minus40

minus60

minus80

minus100

minus120

minus140

minus16010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38

CE6DOX

MTX

CE6(minus1601)

MTX(minus6394)





119887


119887



1000

800

600

400

200

0

minus200

minus4000 10 20 30 40 50

E(kcalm

ol)

L (Aring)

E1b(CE61GfL)

E1int(CE61GfL)

E1d(GfL)

E1d(CE61)

E1d(GfL)

E1d(CE61)

E1int

E1b

(a)

E1d(GfL)

E1int

E1b

0 10 20 30 40 50

L (Aring)

E1b(DOX1

E1int(DOX1

E1d(GfL)

E1d(DOX1)

E1d(DOX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(b)

0 10 20 30 40 50

L (Aring)

E1b(MTX1

E1int(MTX1

E1d(GfL)

E1d(MTX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1int

E1d(MTX1)

E1b

E1d(GfL)

GfL)GfL)

(c)

E1d(GfL)

E1b

E1int

E1d(SN381)

0 10 20 30 40 50

L (Aring)

E1b(SN381

E1int(SN381

E1d(GfL)

E1d(SN381)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(d)




where 1198641119889


119889

(D119899





1

6119905

⟨1003816100381610038161003816119903119894

(119905) minus 119903119894

(0)1003816100381610038161003816

2

⟩ (6)

where 119903119894

(119905) and 119903119894



CE6(097)

MTX(302)

SN38(777)

DOX(166)

84

80

76

30

25

20

15

10

05

00

minus05

Dxx_y

y(Aring

2s)

10 20 30 40 50

L (Aring)

(CE61)(DOX1)

(MTX1)

(SN381)

DOXCE6

SN38

MTX

GfLGfL

GfLGfL

(a)

40

35

30

25

20

15

08

06

04

02

00

10 20 30 40 50

L (Aring)

(CE61)_(CE61)(DOX1)_(DOX1)

(MTX1)_(MTX1)(SN381)_(SN381)

DOXCE6SN38MTX

DOX(083)

MTX(204)

SN38(330)

CE6(180)

Dxx_y

y(Aring

2s)

GfLGfL GfL

GfL

(b)





119899

Gf119871


) (D119899

)Gf119871


119899


orGp119871


1

Gf119871


1

) (D1

)Gf119871






119887


119887


119887





119887


119887



DOXCE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)







119909119909 119910119910



0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




(a) (CE61

)Gf20

(b) (DOX1

)Gf20

(c) (MTX1

)Gf20

(d) (SN381

)Gf20


Gf20




1198641

119887

=

[1198641

(D119899

G) minus 119899119864D minus 119864 (G)]119899

= 1198641

int (D119899G) + 1198641

119889

(G) + 1198641119889

(D119899

) + 1198641

int (D119899)

(2)

1198641

int (D119899G) =[1198641

(D119899

G) minus 1198641 (D119899

) minus 1198641

(G)]119899

(3)


119899


119899



1198641

119889119894

(D119899

) =

[1198641

(D119899

) minus 119899119864D]

119899

(4)

where 1198641119889119894

(D119899


119899


1198641

119889

(G) =[1198641

(G) minus 119864 (G)]119899

1198641

119889

(D119899

) =

sum119899

119873=1

[1198641

(D) minus 119864D]119899

(5)


(a) (CE68

)Gf50

(b) (DOX8

)Gf50

(c) (MTX8

)Gf50

(d) (SN388

)Gf50


Gf50

(b) DOX8

Gf50

(c) MTX8

Gf50

and (d) SN388

Gf50


40

0

minus40

minus80

minus120

minus160

minus200

minus24010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38CE6DOXMTX


SN38(minus3075)

CE6(minus6620)



(a)

20

0

minus20

minus40

minus60

minus80

minus100

minus120

minus140

minus16010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38

CE6DOX

MTX

CE6(minus1601)

MTX(minus6394)





119887


119887



1000

800

600

400

200

0

minus200

minus4000 10 20 30 40 50

E(kcalm

ol)

L (Aring)

E1b(CE61GfL)

E1int(CE61GfL)

E1d(GfL)

E1d(CE61)

E1d(GfL)

E1d(CE61)

E1int

E1b

(a)

E1d(GfL)

E1int

E1b

0 10 20 30 40 50

L (Aring)

E1b(DOX1

E1int(DOX1

E1d(GfL)

E1d(DOX1)

E1d(DOX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(b)

0 10 20 30 40 50

L (Aring)

E1b(MTX1

E1int(MTX1

E1d(GfL)

E1d(MTX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1int

E1d(MTX1)

E1b

E1d(GfL)

GfL)GfL)

(c)

E1d(GfL)

E1b

E1int

E1d(SN381)

0 10 20 30 40 50

L (Aring)

E1b(SN381

E1int(SN381

E1d(GfL)

E1d(SN381)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(d)




where 1198641119889


119889

(D119899





1

6119905

⟨1003816100381610038161003816119903119894

(119905) minus 119903119894

(0)1003816100381610038161003816

2

⟩ (6)

where 119903119894

(119905) and 119903119894



CE6(097)

MTX(302)

SN38(777)

DOX(166)

84

80

76

30

25

20

15

10

05

00

minus05

Dxx_y

y(Aring

2s)

10 20 30 40 50

L (Aring)

(CE61)(DOX1)

(MTX1)

(SN381)

DOXCE6

SN38

MTX

GfLGfL

GfLGfL

(a)

40

35

30

25

20

15

08

06

04

02

00

10 20 30 40 50

L (Aring)

(CE61)_(CE61)(DOX1)_(DOX1)

(MTX1)_(MTX1)(SN381)_(SN381)

DOXCE6SN38MTX

DOX(083)

MTX(204)

SN38(330)

CE6(180)

Dxx_y

y(Aring

2s)

GfLGfL GfL

GfL

(b)





119899

Gf119871


) (D119899

)Gf119871


119899


orGp119871


1

Gf119871


1

) (D1

)Gf119871






119887


119887


119887





119887


119887



DOXCE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)







119909119909 119910119910



0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




(a) (CE68

)Gf50

(b) (DOX8

)Gf50

(c) (MTX8

)Gf50

(d) (SN388

)Gf50


Gf50

(b) DOX8

Gf50

(c) MTX8

Gf50

and (d) SN388

Gf50


40

0

minus40

minus80

minus120

minus160

minus200

minus24010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38CE6DOXMTX


SN38(minus3075)

CE6(minus6620)



(a)

20

0

minus20

minus40

minus60

minus80

minus100

minus120

minus140

minus16010 20 30 40 50

Eb(kcalm

ol)

L (Aring)

SN38

CE6DOX

MTX

CE6(minus1601)

MTX(minus6394)





119887


119887



1000

800

600

400

200

0

minus200

minus4000 10 20 30 40 50

E(kcalm

ol)

L (Aring)

E1b(CE61GfL)

E1int(CE61GfL)

E1d(GfL)

E1d(CE61)

E1d(GfL)

E1d(CE61)

E1int

E1b

(a)

E1d(GfL)

E1int

E1b

0 10 20 30 40 50

L (Aring)

E1b(DOX1

E1int(DOX1

E1d(GfL)

E1d(DOX1)

E1d(DOX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(b)

0 10 20 30 40 50

L (Aring)

E1b(MTX1

E1int(MTX1

E1d(GfL)

E1d(MTX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1int

E1d(MTX1)

E1b

E1d(GfL)

GfL)GfL)

(c)

E1d(GfL)

E1b

E1int

E1d(SN381)

0 10 20 30 40 50

L (Aring)

E1b(SN381

E1int(SN381

E1d(GfL)

E1d(SN381)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(d)




where 1198641119889


119889

(D119899





1

6119905

⟨1003816100381610038161003816119903119894

(119905) minus 119903119894

(0)1003816100381610038161003816

2

⟩ (6)

where 119903119894

(119905) and 119903119894



CE6(097)

MTX(302)

SN38(777)

DOX(166)

84

80

76

30

25

20

15

10

05

00

minus05

Dxx_y

y(Aring

2s)

10 20 30 40 50

L (Aring)

(CE61)(DOX1)

(MTX1)

(SN381)

DOXCE6

SN38

MTX

GfLGfL

GfLGfL

(a)

40

35

30

25

20

15

08

06

04

02

00

10 20 30 40 50

L (Aring)

(CE61)_(CE61)(DOX1)_(DOX1)

(MTX1)_(MTX1)(SN381)_(SN381)

DOXCE6SN38MTX

DOX(083)

MTX(204)

SN38(330)

CE6(180)

Dxx_y

y(Aring

2s)

GfLGfL GfL

GfL

(b)





119899

Gf119871


) (D119899

)Gf119871


119899


orGp119871


1

Gf119871


1

) (D1

)Gf119871






119887


119887


119887





119887


119887



DOXCE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)







119909119909 119910119910



0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




1000

800

600

400

200

0

minus200

minus4000 10 20 30 40 50

E(kcalm

ol)

L (Aring)

E1b(CE61GfL)

E1int(CE61GfL)

E1d(GfL)

E1d(CE61)

E1d(GfL)

E1d(CE61)

E1int

E1b

(a)

E1d(GfL)

E1int

E1b

0 10 20 30 40 50

L (Aring)

E1b(DOX1

E1int(DOX1

E1d(GfL)

E1d(DOX1)

E1d(DOX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(b)

0 10 20 30 40 50

L (Aring)

E1b(MTX1

E1int(MTX1

E1d(GfL)

E1d(MTX1)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1int

E1d(MTX1)

E1b

E1d(GfL)

GfL)GfL)

(c)

E1d(GfL)

E1b

E1int

E1d(SN381)

0 10 20 30 40 50

L (Aring)

E1b(SN381

E1int(SN381

E1d(GfL)

E1d(SN381)

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

GfL)GfL)

(d)




where 1198641119889


119889

(D119899





1

6119905

⟨1003816100381610038161003816119903119894

(119905) minus 119903119894

(0)1003816100381610038161003816

2

⟩ (6)

where 119903119894

(119905) and 119903119894



CE6(097)

MTX(302)

SN38(777)

DOX(166)

84

80

76

30

25

20

15

10

05

00

minus05

Dxx_y

y(Aring

2s)

10 20 30 40 50

L (Aring)

(CE61)(DOX1)

(MTX1)

(SN381)

DOXCE6

SN38

MTX

GfLGfL

GfLGfL

(a)

40

35

30

25

20

15

08

06

04

02

00

10 20 30 40 50

L (Aring)

(CE61)_(CE61)(DOX1)_(DOX1)

(MTX1)_(MTX1)(SN381)_(SN381)

DOXCE6SN38MTX

DOX(083)

MTX(204)

SN38(330)

CE6(180)

Dxx_y

y(Aring

2s)

GfLGfL GfL

GfL

(b)





119899

Gf119871


) (D119899

)Gf119871


119899


orGp119871


1

Gf119871


1

) (D1

)Gf119871






119887


119887


119887





119887


119887



DOXCE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)







119909119909 119910119910



0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




CE6(097)

MTX(302)

SN38(777)

DOX(166)

84

80

76

30

25

20

15

10

05

00

minus05

Dxx_y

y(Aring

2s)

10 20 30 40 50

L (Aring)

(CE61)(DOX1)

(MTX1)

(SN381)

DOXCE6

SN38

MTX

GfLGfL

GfLGfL

(a)

40

35

30

25

20

15

08

06

04

02

00

10 20 30 40 50

L (Aring)

(CE61)_(CE61)(DOX1)_(DOX1)

(MTX1)_(MTX1)(SN381)_(SN381)

DOXCE6SN38MTX

DOX(083)

MTX(204)

SN38(330)

CE6(180)

Dxx_y

y(Aring

2s)

GfLGfL GfL

GfL

(b)





119899

Gf119871


) (D119899

)Gf119871


119899


orGp119871


1

Gf119871


1

) (D1

)Gf119871






119887


119887


119887





119887


119887



DOXCE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)







119909119909 119910119910



0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




DOXCE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16

n

(a)

DOX

CE6

SN38MTX



Eb(kcalm

ol)

40

20

0

minus20

minus40

minus60

minus800 2 4 6 8 10 12 14 16 18

n

(b)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus20

minus40

minus60

minus80

minus100

0 2 4 6 8 10 12 14 16 18

n

(c)

DOX

CE6

SN38

MTX



Eb(kcalm

ol)

0

minus10

minus20

minus30

minus40

minus50

minus60

minus70

minus800 2 4 6 8 10 12 14 16 18

n

(d)







119909119909 119910119910



0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

E1b(CE6nGf50)

E1int(CE6nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(CE6n)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGf50)

E1int(DOXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(DOXn)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 12 14 16

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(b)

E1b(MTXnGf50)

E1int(MTXnGf50)

E1d(Gf50)

E1d(Gf50)

E1di(MTXn)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(c)

E1b(SN38nGf50)

E1int(SN38nGf50)

E1d(Gf50)

E1d(Gf50)

E1di(SN38n)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 12 14 16 18

n

1000

800

600

400

200

0

minus200

minus400

E(kcalm

ol)

(d)



or 1198641119889119894









0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




0 2 4 6 8 10 12 14

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1b(CE6nGp50)

E1int(CE6nGp50)

E1d(Gp50)

E1di(CE6n)

E1d(Gp50)

E1di(CE6n)

E1b

E1int

(a)

E1b(DOXnGp50)

E1int(DOXnGp50)

E1d(Gp50)

E1di(DOXn)

E1d(Gp50)

E1di(DOXn)

E1b

E1int

0 2 4 6 8 10 1412 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(b)

E1b(MTXnGp50)

E1int(MTXnGp50)

E1d(Gp50)

E1di(MTXn)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

E1d(Gp50)

E1di(MTXn)

(c)

E1b(SN38nGp50)

E1int(SN38nGp50)

E1d(Gp50)

E1di(SN38n)

E1d(Gp50)

E1di(SN38n)

E1b

E1int

0 2 4 6 8 10 14 1812 16

n

200

160

120

80

40

0

minus40

minus80

minus120

E(kcalm

ol)

(d)



or 1198641119889119894





119899

Gf50


119887


119887




119887


119889


119889119894





CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials






CE6DOX

MTX

SN38

E1 d(D

n)(kcalm

ol)

60

40

20

0

minus20

minus40

minus60

0 2 4 6 8 10 12

n

(a)

CE6

DOX

MTX

SN38

E1 int(D

n)(kcalm

ol)

4

2

0

minus2

minus4

minus6

minus8

minus100 2 4 6 8 10 12

n



(b)




119899

Gp50



119889119894








CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




CE6

DOXMTX

SN38

0 2 4 6 8 10 12 14 16 18

n

20

16

12

08

04

00



Dxx_y

y(Aring

2s)

(a)

CE6

DOX

MTXSN38

0 2 4 6 8 10 12 14 16 18

n

10

08

06

04

02

00

Dxx_y

y(Aring

2s)



(b)

CE6DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

9

8

7

6

5

4

3

2

1

0

(c)

CE6

DOX

MTX

SN38



0 2 4 6 8 10 12 14 16 18

n

Dxx_y

y(Aring

2s)

40

35

30

25

20

15

10

05

00

(d)








minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




minus40

minus60

minus80

minus100

minus120

minus140

minus160

minus180

Eb(kcalm

ol)



0 2 4 6 8

n

CE6

DOX

MTX

SN38

(a)

012

010

008

006

004

002

000



0 2 4 6 8

n

CE6

DOX

MTX

SN38

Dxx_y

y(Aring

2s)

(b)




119899


119899


5 Conclusions


(a) GO-PEG

(b) (CE68

)(GO-PEG)


8







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials







Acknowledgments


References












































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



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