Computational Modeling of Drug Delivery System Based on MOF-5 Metal- Organic Framework /Graphene Oxide Nanohybrid

Computational Modeling of Drug Delivery System Based on MOF-5 Metal- Organic Framework /Graphene Oxide Nanohybrid | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Computational Modeling of Drug Delivery System Based on MOF-5 Metal- Organic Framework /Graphene Oxide Nanohybrid Marzieh Eskandarzadeh, Saeed Pourmand, Sara Zareei, Hamid Erfan-Niya, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6396496/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In the present work, the designed MOF-5 metal-organic framework/graphene oxide (MOF-5/GO) nanocomposite is evaluated as a novel platform for efficient delivery of 5Fluorouracil (5FU) and Doxorubicin (DOX) anti-cancer drugs by molecular dynamics (MD) simulations. The details of the adsorption mechanism for 5FU and DOX drug molecules on MOF-5/GO are examined based on the total intermolecular interaction energy (Einter), the number of hydrogen bonds (HBs), the number of atomic contacts and radial distribution functions (RDF) analyses. Depending on their structure and size, different affinity of drugs to MOF-5/GO nanocomposite is found during time of simulation. The van der Waals interaction energy has been identified as the main responsible for drug loading on the nanocomposite. The geometric considerations reveal that the π-π interaction between aromatic rings of graphene oxide and benzene ring of drug molecules along HBs facilitate loading of the anti-cancer drugs on MOF-5/GO nanocomposite. Since the association of nanomaterials with natural polymers influences efficiency of drug delivery systems, the adsorption mechanism of DOX drug on the chitosan polymer-coated MOF-5/GO is also studied. Our simulation results highlight the application of MOF-5/GO nanocomposite as a promising candidate for efficient loading of drug molecules. Biological sciences/Computational biology and bioinformatics Health sciences/Molecular medicine Physical sciences/Chemistry Doxorubicin 5Fluorouracil MOF-5/GO nanocomposite Drug delivery system Coating process Molecular dynamics simulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Recently, development of the design and fabrication of new efficient drug delivery carriers with the control drug release ability has great attention in the field of the modern medicine. Smart drug delivery systems (DDS) enhance the quality and effectiveness of poorly water-soluble medications and prevent their deactivation until reaching target locations 1 . Beside to the improvement of therapeutic efficiency, target delivery of anti-cancer drugs can decrease side effects and prevent drug accumulation 2 – 4 . Up to date, various nanostructures such as graphene-based materials 5 – 9 and metal-organic frameworks (MOFs) 10 – 13 with low toxicity, high adjustability, and facile synthesis have investigated in the field of biomedicine. In recent years, graphene oxide (GO) has attracted great attention in the field of drug delivery and targeting owing its remarkable physiochemical characteristics and distinct planar structure 14 – 17 . In addition to π-π stacking, the existence of different oxygen-containing functional groups on GO provides an exceptional adsorption capacity for numerous therapeutic molecules through electrostatic interactions and hydrogen bonding 14 , 15 . In spite of high specific surface area and free π electron availability in the structures of GO, its aggregation in physiological solutions is a major drawback in the biomedical applications 18 . Nowadays, zinc-based metal-organic frameworks are found to be attractive porous materials for controlled drug delivery 19 – 21 owing to large specific surface area, low toxicity and tunable pore morphology and good biodegradability 22 – 25 . However, the low water stability of MOFs limits their efficiency in drug delivery system 26 . It is well known that the composing MOFs to other materials results in a new class of porous structures with altered construction and improved physiochemical properties 27 – 29 . Recently, some research reported the application of GO, MOFs and GO composites with various MOFs in the field of drug delivery systems 27 – 32 . It is known that the combination of MOF and GO may overcome the drawbacks of these materials. The combination of GO with MOFs shows increased porosity and dispersion force as well as improved material stability and adsorption performance 26 – 29 . Compared to other drug delivery systems, GO/MO nanohybrid have exceptional biocompatibility, high drug loading, increased stability and low cytotoxicity 32 . As proven by many experimental and theoretical researches, GO, MOFs and MOF-based nanocomposites have been widely investigated in the delivery of various biomolecules. The high loading capacity of GO for DOX drug under neutral conditions was attributed to hydrogen bond interactions as the principal driving force for drug loading onto GO nanocarriers 33 , 34 . The atom-scale loading of Paclitaxel and Curcumin drugs onto MXenes-Cu-BTC nanocomposites demonstrated that the formation of hydrogen bonds between Curcumin drug and oxygen termination of MXenes’s surface results in the improvement of the adsorption capacity of the nanocomposite 35 . The significant payload of up to 35.7% for DOX drug on the inorganic MXene/MOF-5 nanostructure was achieved, which would be because of the interactions between the nanocarrier and DOX 36 . Correspondingly, a co-drug delivery system based on aluminum-succinic acid MOF and GO was developed to enhance biodegradability, augmented biocompatibility, and facilitated release of 5FU and DOX drugs under cancerous extracellular conditions due to the integration of chitosan (CS) within the nanocomposite 37 . DOX release from carboxymethylcellulose (CMC) coated-MOF-5/GO bio-nanocomposite was observed under the tumor cell microenvironment condition 38 . In addition, loading and release of Tetracycline on the designed CMC/MOF-5/GO material was investigated 32 . The 5FU loaded on the CS/Zn-MOF@GO microspheres could effectively treat tumor cells 39 . The synthesized sericin/chitosan/Ag@MOF-GO nanocomposite showed hemostatic and antibacterial activity, water-solubility and biocompatibility 40 . However, the research of MOF-based nanocomposite carriers is still in its early stages, the underlying adsorption characteristic and mechanism of loading and delivery of drug molecules have been rarely studied. With the help of computational tools such as molecular dynamics (MD) simulation, qualitatively and quantitatively of the physio-chemical mechanism and interactions in DDSs can be revealed. MD simulation provides a quick screening of a large number of drug candidates as well as the ability to study phenomena that are difficult to observe experimentally. In the present work, inspired by these concepts, we have explored the possibility of MOF-5/GO nanocomposite as 5FU and DOX anti-cancer drug delivery systems with atomic details using MD simulations. Additionally, the assessment of delivery performance of coated MOF-5/GO composite by chitosan chain polymer has acceptable novelty on more efficiency of the designed nanocomposite for loading 5FU/DOX as the current drugs in cancer therapy. It is high expected that the designed MOF-5/GO nanocomposite and, specifically, chitosan polymer-coated nanocomposite (CS@MOF-5/GO), could serve as the ideal candidates to explore the underlying mechanism of MOF-based nanocomposite carriers for efficient delivery of 5FU/DOX. MD simulation procedure The MD simulation is applied to explore the capability of MOF-5/GO nanocomposite for loading of 5FU and DOX anti-cancer drug molecules in physiological media. For those, two systems are constructed; each simulation system containing of eight molecules of each anti-cancer drug and MOF-5/GO nanocomposite (i.e., 5FU@MOF-5/GO and DOX@MOF-5/GO). Since the association of nanomaterials with natural polymers influences efficiency of drug delivery systems, the adsorption mechanism of DOX drug on CS@MOF-5/GO is also studied. The simulation system is comprised of CS@MOF-5/GO nanohybrid and eight DOX drug molecules (DOX@CS@MOF-5/GO). It is noted that the coating process of MOF-5/GO nanocomposite by CS has already been simulated for 60 ns using GROMACS software 41 , that the simulated system includes MOF-5/GO nanocomposite and eight chains of CS with three monomer units per chain. The structures of DOX, 5FU, chitosan monomer, the designed nanohybrid and its components are presented in Figs. 1 and 2 . The MOF-5 framework which is extracted from the ChemTube 3D 42 , 43 is used. MOF-5 consists of Zn 4 O as the metal oxide cluster and 1,4-benzenedicarboxylate (BDC) as organic linker. The framework structure of MOF-5 is constructed with eight metal clusters and twelve organic linkers as shown in Fig. 2 . The GO components are also established based on the Lerf-Klinowski method 44 based on a graphene with dimensions of 2.7 nm× 2.6 nm. The simulation boxes with dimensions of 9 nm×9 nm×11 nm are hydrated with 28327, 28203 and 28022 water molecules, respectively, using the TIP3P model 45 . All atoms of MOF-5 and GO components of the designed nanocomposite are proposed as charged Lenard-Jones (LJ) particles. For GO components, all sp 2 carbon atoms are treated as uncharged and the partial charges of the oxygen-containing functional groups are taken from work of Schneible et al. 46 . Force field parameters for GO are extracted from the general CHARMM36 force field (CGenFF) 47 . The Lenard-Jones parameters and the partial atomic charges of MOF-5 atom species are obtained from the works of Greathouse et al. 48 and Manz et al 49 , respectively. The same parameters have been used by other researchers for similar works 50 , 51 . The topology and parameter files for DOX, 5FU and CS are also determined based on the CGenFF in CHARMM-GUI webserver 52 . Overall, the solvated systems contain negatively charged nanocomposite and neutral drug molecules. Then, adding the appropriate number of sodium (Na + ) and chloride (Cl − ) to preserve neutrality and a physiological concentration (0.15 M) 53 neutralized the charges in the simulation systems. The LJ interactions are subjected to a cutoff radius of 12 Å and the particle mesh Ewald (PME) method is applied to treat the long-range electrostatic interactions 54 . All bond length involving hydrogen atoms are constrained with LINCS algorithm 55 . The energy minimization of the initial conformation for each simulated system is conducted using steepest descent method for 50000 steps. Next, NVT simulations are performed to relax the systems for 1000 ps, followed by NPT simulations for 1000 ps. The temperature and pressure are controlled using Nose-Hoover thermostat 56 and Parrinello–Rahman barostat 57 . The equations of motion are integrated using the leapfrog algorithm. The production runs are conducted under periodic boundary conditions in three directions for a 90 ns and within the isothermal–isobaric (NPT) simulation at 310 K and 1 bar. The classical MD simulations are conducted in GROMACS 41 software with a time step of 1.5 fs. The Visual molecular dynamics (VMD) software is applied to preparing the molecular graphic images 58 . Results and Discussion At the first stage, the equilibrium state for the designed systems is evaluated by quantities such as density and pressure curves against simulation time, as illustrated in Supplementary Figure S1. The constant density seen throughout simulation time serves as evidence that the systems have achieved proper equilibrium. The time dependence of pressure has also confirmed the equilibrium state of systems (Figure S1). In order to quantitatively analyze how 5FU/DOX approaches MOF-5@GO adsorbent, a series of descriptors, including the minimum distance, contact number, hydrogen bonds (HBs), radial distribution functions (RDF) and the intermolecular interaction energy are calculated throughout the simulation trajectory. Drug adsorption mechanism onto MOF-5/GO Analysis of the distances is performed based on the geometry center of the drug and the MOF-5/GO nanocomposite to ascertain drug adsorption behavior from water bulk region toward the drug delivery system. The observed minimal fluctuations of Figure 3 indicate the stable configuration of drug molecules on the nanohybrid. It is observed that the distances between DOX and the components of the designed nanocomposite rapidly decrease during first 10 ns of the simulation. In the case of 5FU, the adsorption capacity of GO components reach equilibrium in approximate 5 ns. At about 7 ns, the distance between 5FU and MOF-5 minimize by movement of one 5FU molecule in the interfacial region of MOF-5 and GO. Then, drug desorption occurs as a result of weakly interaction of this molecule with MOF. The shifting distance shows the insertion of 5FU molecule within the interfacial region between MOF and GO. As observed from Figure 3, the distance between each drug and GO remains stable in shorter range compared to that of MOF. The trajectory snapshots of 5FU and DOX delivery by MOF-5/GO nanocomposite are shown in Figure 4 and 5, respectively. As a result of fast movement of 5FU toward the nanohybrid, one 5FU molecule adsorbs on the graphene oxide surface (Figure 4). Within the simulation, some drug molecules penetrate into the interfacial region of MOF-5 and GO components and drug molecules interact efficiently with oxygen-containing functional groups of GO. After that, 5FU drugs fluctuate over the nanocomposite surface to obtain proper position on GO and MOF surface. Over time of simulation, loading of 5FU on the surface of GO as well as the interfacial region of GO and MOF-5 is observed (Figure 4). Monitoring the simulation trajectory of DOX@MOF-5/GO system reveals that DOX drugs diffuses rapidly to the nanocomposite at the initial time of simulation (Figure 5). DOX drug molecules adsorb on the surface of MOF-5 metal-organic framework and graphene oxide nanosheets (Figure 5, t ~5 ns). The self-aggregation of two DOX molecules in the vicinity of MOF-5 surface is found at about t ~ 8 ns. Within the simulation, this structure moves to the interfacial region of MOF-5/GO. Over time of simulation, DOX molecules show affinity for the adsorption on GO nanosheets (Figure 5). In the DOX@MOF-5/GO system, drug molecules adsorb on both GO components with maximum distribution on GO compared to MOF-5. In the case of 5FU@MOF-5/GO system, a large number of 5FU drugs can be found on GO. Intensity of Interactions The total interaction energy (Einter) which includes the van der Waals (EvdW) and electrostatic (Eelec) attractions between drug@MOF-5 and drug@GO, is tabulated in Table 1 . Inspection of this table indicates that the vdW contribution is dominated in the total intermolecular interaction energy. Table 1 . The calculated values of the van der Waals (EvdW) and electrostatic (Eelec) energy as well as the total intermolecular interaction energy (Einter) between the considered fragments at the simulation systems. Component EvdW (kJ/mol) Eelec (kJ/mol) Einter (kJ/mol) 5FU@MOF-5 -9.628 -1.310 -10.920 5FU@GO (down) -190.004 -60.710 -250.713 5FU@GO (up) -100.967 -43.967 -144.934 5FU@MOF-5/GO -300.599 -105.986 -406.567 DOX@MOF-5 -74.961 -15.829 -90.790 DOX@GO (down) -412.460 -144.869 -557.328 DOX@GO (up) -281.914 -92.058 -373.971 DOX@MOF-5/GO -769.334 -252.755 -1022.089 The average total intermolecular interaction energy values for 5FU@MOF-5 and 5FU@GOs at 5FU@MOF-5/GO system are -10.920 kJ/mol and -395.647 kJ/mol, respectively. The average vdW and electrostatic interactions between 5FU@GOs are -290.971 kJ/mol and -104.677 kJ/mol, respectively. Also, 5FU drugs interact with MOF-5 with the average vdW and electrostatic energy values of -9.628 kJ/mol and -1.310 kJ/mol, respectively. Thus, the trapped 5FU molecules in the interfacial region have effective interactions with GO components with respect to MOF-5 as indicating with the intermolecular energies (Table 1). It can be clearly seen from Table 1, the average total intermolecular interaction energy between DOX and GO is higher than that with MOF-5. The vdW and electrostatic interaction energies of DOX with GOs is found to be about of -694.374 kJ/mol and -236.927 kJ/mol, respectively. There is a strong intermolecular interaction between DOX molecule and GO component with a much-pronounced vdW interaction energy. This fact can be explained by the structure of DOX molecule having a great number of atoms. Generally, these results can be attributed to the presence of a large number of DOX molecules on GO as well as in the interfacial region of MOF-5/GO and further the intermolecular interactions between DOX@GOs (Figure 5). As observed, a correlation between uptake number of drug molecules and the intermolecular interaction energy is found. Evolution of the Intermolecular HBs and Number of Contacts The number of HBs formed between different fragments of the simulation systems are analyzed as shown in Figure 6. The HBs are considered based on the maximum distance of 0.35 nm between donor and acceptor atoms and the HB donor-H-acceptor angle of < 30° 14 . The average number of HBs between 5FU and GO (5FU@GOs) and between 5FU and MOF-5 (5FU@MOF-5) are 6.654 and 0.016, respectively. In the case of DOX drug delivery system, analysis of the average number of HBs along the simulation trajectory indicates that up to 15.294 and 0.515 HBs can be formed between DOX and GO (DOX@GOs) as well as DOX and MOF-5 (DOX@MOF-5), respectively. The obtained results are in accordance with the difference of the number of contacts in the simulation systems, as presented in Figure 6. The contact number between the considered fragments are calculated using “gmx mindist” module. As observed, the number of contacts of DOX-GOs is significantly increases from 0 to 5000 after free of diffusion of drug molecules in bulk water to interaction with GO surface. This result confirms the effective loading of DOX on the oxygen-containing groups of the basal plane of GO component. The average contact number of DOX with MOF-5 is nine-fold lower than that with GO component. As a result, the reduction of the number of atomic contacts has negative impact on the average HBs number between the considered fragments (Figure 6). Close inspection of Figure 6 reveals that the number of atomic contacts of 5FU with GO is also significantly greater than that of with MOF-5. As expected, the number of hydrogen bonds between 5FU@MOF-5 is lower. A significant increase in the number of atomic contacts demonstrates that 5FU molecules can be strongly adsorbed on GO surface. As observed, the uptake number of drug molecules can affect the number of atomic contacts and further the HBs number with the nanocomposite components. Radial distribution function analysis The probability of finding drug molecules relative to the center of the mass of the components of the designed nanocomposite is investigated by radial distribution function (RDF) analysis and the results are presented in Supplementary Figure S2. A great accumulation of 5FU around GO compared to MOF-5 is highlighted by higher RDF strength. The intensity of RDF pattern of 5FU drug with GO surfaces exhibits maximum peak at a distance of 0.43 nm in 5FU@MOF-5/GO system. As can be clearly observed from Figure S2, the distance for the maximum distribution of 5FU molecule around GO of the nanocomposite is similar. 5FU molecules are distributed farther away from the MOF-5 at a distance of 1.65 nm in 5FU@MOF-5/GO system. RDF patterns of drug molecules with components of the studied nanocomposite in DOX@MOF-5/GO system are also shown in Figure S2. In the case of DOX@MOF-5/GO system, RDF of DOX@MOF-5 has been maximized in a large separation distance in comparison with DOX@GOs. As observed in Figure S2, a greater number of DOX molecules are adsorbed on GO components and further, the probability distribution of DOX around GO is higher than that of it’s on MOF-5. The observed peaks at distances between 0.5 nm and 1 nm are related to π-π stacking interaction between aromatic rings of the drug molecules and π-conjugated structure of GO 59 . Mobility of Drug Molecules The movement of drug molecules toward the drug delivery system can be quantified through the calculation of mean square displacement (MSD). The ability of 5FU/DOX molecule to move around in the environment is quantified using MSD calculation as following equation: Where r(t) is the atomic position of the drug molecule at time t , r(0) is the reference position of the drug molecule and the brackets denote the averaged ion position parameters in the simulated system 60 . The self-diffusion coefficient (D) can be used to reflect the intensity of drug molecule's mobility and can be expressed according to the Einstein equation as follow: According to eq (2), the slope the MSD can be used to calculation of the self-diffusion coefficient. The migration rate of drug into the designed nanocomposite in the simulation system is calculated through linear regression only between 35-70 ns of the production run where there is linear correlation between the MSD and time (Supplementary Figure S3). The self-diffusion coefficient of 5FU and DOX molecules within the 5FU@MOF-5/GO and DOX@MOF-5/GO systems is determined to be 0.378×10 −5 cm² s −1 and 0.057×10 −5 cm² s −1 , respectively. The low diffusion coefficient of DOX along its high strong interaction with MOF-5/GO reduce the movement of DOX molecules onto the designed nanocomposite. Whereas, there is a vise-versa situation for 5FU drug at 5FU@MOF-5/GO system. In summary, MD simulations demonstrate the adsorption capacity of the designed MOF-5/GO nanocomposite for loading 5FU and DOX drug molecules. The loading mechanism of 5FU/DOX on the designed nanohybrid is governed through the π-π stacking, the vdW and electrostatic interactions and HBs network. DOX Drug Delivery via Chitosan Polymer-Coated MOF-5/GO Nanocomposite Since MOF-5/GO nanocomposite showed better drug delivery performance for DOX drug, the effect of covering the surface of nanocomposite by CS polymers on DOX drug adsorption mechanism is also investigated. The final snapshot of chitosan polymer-coated MOF-5/GO nanocomposite is shown in Figure 7. As clearly observed from this figure, a great number of CS polymers interact with functional groups of GO component and some adsorb on the surface of MOF-5. This observation is proved by decreasing the total intermolecular interaction energy of CS@GO and CS@MOF-5 as shown in Supplementary Figure S4. The coating process of MOF-5/GO nanocomposite by CS polymers is also characterized by calculation of the atomic number of contacts between CS and components of the designed nanocomposite. The obtained results are presented in Figure S4. The effective coating CS on the surface of nanocomposite is manifested by the results of the number of atomic contacts. Figure 7 shows final MD configurations of DOX molecules at CS@MOF-5/GO nanocomposite. From Figure 7, it is found that the adsorption behavior of DOX on CS@MOF-5/GO nanocomposite is different to that of DOX on MOF-5/GO. At CS@MOF-5/GO, self-aggregation of five DOX molecules in the vicinity of MOF-5 surface is obvious. As seen, DOX molecule tends to adsorb on top of the chitosan coated the surface of GO component. In addition, distribution of drug molecules on basal plane of GO and the interfacial region of MOF-5/GO is found. The calculated intermolecular interaction energy values, the number of atomic contacts, HBs number and RDF patterns of the simulation system is presented in Figure 8. As observed from Figure 7, the presence of CS molecules on the nanocomposite blocks the active sites of the nanocomposite surface. Thus, the average total intermolecular interaction energy between DOX and MOF-5/GO in CS@MOF-5/GO system is significantly lower than that with MOF-5/GO without CS (Figure 8). However, the same number of DOX molecules are located in the considered systems. As clearly observed, the interaction between DOX and GO is significantly weak at CS@MOF-5/GO system in comparison with MOF-5/GO simulation system. Compared to DOX@MOF-5/GO system, the interaction strength of DOX with GO at polymer-coated nanocomposite is significantly diminished (EvdW= -264.537 kJ/mol and Eelec= -81.009 kJ/mol). Close inspection of Figure 8 and Table 1 reveals that there is no significant change of the interaction energy of DOX with MOF-5 at CS@MOF-5/GO system in comparison to MOF-5/GO system. It is observed that π-π stacking interaction peak of DOX with GO in the presence of CS polymers has lower intensity due to the weakening the intermolecular interaction of DOX@GO (Figure 8). The results are agreed well with the results of the average intermolecular interaction energy. As can be observed in Figure 8, the peak position of DOX with GO (down) is shifted to a larger distance (r max = 1.00 nm) in comparison with DOX@GO (up) (r max = 0.64 nm). This result may be attributed to this observation that one DOX molecule is adsorbed on chitosan polymers covering GO surface (down). It is found that there are the intermolecular interactions between DOX@CS (Figure 7). The calculated vdW and electrostatic interaction energy values of DOX@CS are -87.521 kJ/mol and -32.202 kJ/mol, respectively. Analysis of RDF profile of DOX around CS@MOF-5/GO nanocomposite reveals that the maximum distribution of DOX drug is located 1.85 nm away from MOF-5 metal-organic framework. The coated surface of nanocomposite with chitosan polymers has a significant effect on the diffusion behavior of DOX drug in such a way the self-diffusion coefficient of drug molecule is increased to 0.818× 10 −5 cm 2 s −1 (Supplementary Figure S5). In other word, the weak intermolecular interaction of DOX in CS@MOF-5/GO enhances the molecular motion of drug molecules in the studied simulation system. Inspection the obtained results shows that the average contact number for DOX and CS is about two-fold greater than that with GO (down). In accordance with the number of atomic contacts, the average HBs formed between DOX@CS is higher than DOX@GO (down). The more intermolecular atomic contacts of DOX with GO (up) are accomplished more DOX loading on the surface and further more HBs numbers (Figures 7 and 8). Conclusions In summary, the adsorption capacity of the designed MOF-5/GO nanocomposite toward loading of 5FU and DOX drugs is investigated by MD simulation. Different affinity of drugs to MOF-5/GO nanocomposite is found based on their structures. The stability of the simulation systems can be attributed to the predominant vdW interaction. The drug molecules spontaneously adsorb on the MOF-5/GO nanocomposite by π-π stacking between aromatic rings of drugs and components of the drug delivery carrier. It has been observed that the coating of the nanocomposite surface by CS has a significant effect on the absorption behavior of DOX drugs as well as the strength of its intermolecular interaction with the drug delivery system. This study provides new insight on the application of the designed MOF-5/GO nanocomposite drug delivery system at atomic level. Declarations Author Contribution Marzieh Eskandarzadeh conceived and designed the analysisSaeed Pourmand designed and performed the analysisSara Zareei Collected the data and Wrote the paperHamid Erfan-Niya corresponding authorSima Majidi designed the analysis Data Availability The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request. References Lázaro, I. A., Lázaro, S. A. & Forgan, R. S. 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Mesoporous metal organic framework–boehmite and silica composites. Chemical Communications 46 , 6798-6800 (2010). O'Neill, L. D., Zhang, H. & Bradshaw, D. Macro-/microporous MOF composite beads. Journal of materials Chemistry 20 , 5720-5726 (2010). Petit, C. & Bandosz, T. J. Synthesis, characterization, and ammonia adsorption properties of mesoporous metal–organic framework (MIL (Fe))–graphite oxide composites: exploring the limits of materials fabrication. Advanced Functional Materials 21 , 2108-2117 (2011). Xiang, Z. et al. Metal–organic frameworks with incorporated carbon nanotubes: improving carbon dioxide and methane storage capacities by lithium doping. Angewandte Chemie International Edition 50 , 491-494 (2011). Alnaqbi, M. A. et al. Chemistry and applications of s-block metal–organic frameworks. Journal of Materials Chemistry A 9 , 3828-3854 (2021). Lázaro, I. A. & Forgan, R. S. Application of zirconium MOFs in drug delivery and biomedicine. Coordination chemistry reviews 380 , 230-259 (2019). Karimzadeh, Z., Javanbakht, S. & Namazi, H. Carboxymethylcellulose/MOF-5/Graphene oxide bio-nanocomposite as antibacterial drug nanocarrier agent. BioImpacts: BI 9 , 5 (2018). Wang, C. et al. Design and evaluation of galactosylated chitosan/graphene oxide nanoparticles as a drug delivery system. Journal of colloid and interface science 516 , 332-341 (2018). Yang, X. et al. High-efficiency loading and controlled release of doxorubicin hydrochloride on graphene oxide. The Journal of Physical Chemistry C 112 , 17554-17558 (2008). Taherpoor, P., Farzad, F. & Zaboli, A. Engineering of surface-modified CuBTC-MXene nanocarrier for adsorption and co-loading of curcumin/paclitaxel from aqueous solutions for synergistic multi-therapy of cancer. Journal of Biomolecular Structure and Dynamics 42 , 1145-1156 (2024). Rabiee, N. et al. Natural polymers decorated MOF-MXene nanocarriers for co-delivery of doxorubicin/pCRISPR. ACS applied bio materials 4 , 5106-5121 (2021). Asl, E. A., Pooresmaeil, M. & Namazi, H. Chitosan coated MOF/GO nanohybrid as a co-anticancer drug delivery vehicle: synthesis, characterization, and drug delivery application. Materials Chemistry and Physics 293 , 126933 (2023). Javanbakht, S., Pooresmaeil, M. & Namazi, H. Green one-pot synthesis of carboxymethylcellulose/Zn-based metal-organic framework/graphene oxide bio-nanocomposite as a nanocarrier for drug delivery system. Carbohydrate polymers 208 , 294-301 (2019). Pooresmaeil, M., Asl, E. A. & Namazi, H. A new pH-sensitive CS/Zn-MOF@ GO ternary hybrid compound as a biofriendly and implantable platform for prolonged 5-Fluorouracil delivery to human breast cancer cells. Journal of Alloys and Compounds 885 , 160992 (2021). Zhang, M. et al. Bioinspired design of sericin/chitosan/Ag@ MOF/GO hydrogels for efficiently combating resistant bacteria, rapid hemostasis, and wound healing. Polymers 13 , 2812 (2021). Lindahl, E., Hess, B. & Van Der Spoel, D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. Molecular modeling annual 7 , 306-317 (2001). Tranchemontagne, D. J., Hunt, J. R. & Yaghi, O. M. Room temperature synthesis of metal-organic frameworks: MOF-5, MOF-74, MOF-177, MOF-199, and IRMOF-0. Tetrahedron 64 , 8553-8557 (2008). Ferrareze, J. V., Hassunuma, R. M., Garcia, P. C. & Messias, S. H. N. CHEMTUBE3D: UM RECURSO DIDÁTICO PARA O ENSINO DE BIOQUÍMICA ESTRUTURAL POR MEIO DE ANIMAÇÕES. Revista Multidisciplinar de Educação e Meio Ambiente 5 , 78-94 (2024). Lerf, A., He, H., Forster, M. & Klinowski, J. Structure of graphite oxide revisited. The Journal of Physical Chemistry B 102 , 4477-4482 (1998). Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. The Journal of chemical physics 79 , 926-935 (1983). Schneible, J. D. et al. Modified gaphene oxide (GO) particles in peptide hydrogels: a hybrid system enabling scheduled delivery of synergistic combinations of chemotherapeutics. Journal of Materials Chemistry B 8 , 3852-3868 (2020). Vanommeslaeghe, K. et al. CHARMM general force field: A force field for drug‐like molecules compatible with the CHARMM all‐atom additive biological force fields. Journal of computational chemistry 31 , 671-690 (2010). Greathouse, J. A. & Allendorf, M. D. The interaction of water with MOF-5 simulated by molecular dynamics. Journal of the American Chemical Society 128 , 10678-10679 (2006). Manz, T. A. & Sholl, D. S. Chemically meaningful atomic charges that reproduce the electrostatic potential in periodic and nonperiodic materials. Journal of Chemical Theory and Computation 6 , 2455-2468 (2010). Hong, T. Z. X. et al. 2D CuBDC and IRMOF-1 as reverse osmosis membranes for seawater desalination: A molecular dynamics study. Applied Surface Science 601 , 154088 (2022). Mahdavi, M., Fattahi, A., Tajkhorshid, E. & Nouranian, S. Molecular insights into the loading and dynamics of doxorubicin on PEGylated graphene oxide nanocarriers. ACS applied bio materials 3 , 1354-1363 (2020). Kim, S. et al. (Wiley Online Library, 2017). Shenol, A. et al. Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91. Molecular Cell 84 , 955-966. e954 (2024). York, D. M., Darden, T. A. & Pedersen, L. G. The effect of long‐range electrostatic interactions in simulations of macromolecular crystals: A comparison of the Ewald and truncated list methods. The Journal of chemical physics 99 , 8345-8348 (1993). Hess, B., Bekker, H., Berendsen, H. J. & Fraaije, J. G. LINCS: A linear constraint solver for molecular simulations. Journal of computational chemistry 18 , 1463-1472 (1997). Evans, D. J. & Holian, B. L. The nose-hoover thermostat. Journal of Chemical Physics 83 , 4069-4074 (1985). Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. Journal of Applied physics 52 , 7182-7190 (1981). Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. Journal of molecular graphics 14 , 33-38 (1996). Shahabi, M. & Raissi, H. A new insight into the transfer and delivery of anti-SARS-CoV-2 drug Carmofur with the assistance of graphene oxide quantum dot as a highly efficient nanovector toward COVID-19 by molecular dynamics simulation. RSC advances 12 , 14167-14174 (2022). Wang, J. & Hou, T. Application of molecular dynamics simulations in molecular property prediction II: diffusion coefficient. Journal of computational chemistry 32 , 3505-3519 (2011). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6396496","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":449077048,"identity":"c41b5db3-bf56-4882-985a-ef81d9ed99ee","order_by":0,"name":"Marzieh Eskandarzadeh","email":"","orcid":"","institution":"Lorestan University of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Marzieh","middleName":"","lastName":"Eskandarzadeh","suffix":""},{"id":449077049,"identity":"e1ff22c0-c21e-46cd-9b68-8efb13663971","order_by":1,"name":"Saeed Pourmand","email":"","orcid":"","institution":"University of Tabriz","correspondingAuthor":false,"prefix":"","firstName":"Saeed","middleName":"","lastName":"Pourmand","suffix":""},{"id":449077050,"identity":"7f5f9628-2989-41b7-ae7e-bccaea415091","order_by":2,"name":"Sara Zareei","email":"","orcid":"","institution":"Kharazmi University","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Zareei","suffix":""},{"id":449077051,"identity":"d2949c8c-6b1f-4163-8935-85a77ae729f4","order_by":3,"name":"Hamid Erfan-Niya","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIie3RPQrCQBCG4W8IaCVp10K9QlKJ4M9ZRMgRLCUhMDYG24CX0M5yg2Aa0TYQQUWwE7TTQvCvE0lMZ7EvTLPwwAwLqFR/mPGYE1AHBCDfb2SnEfIBS2Qmsxf5rWre29nX6aqnj7xdcGVUdFvjUxKpDULT8RaxEOvQkEWG6Uty/cTFIiu/LXAsEFmQJoPGIDf5ls2BnBsvReVJ2oxWOoly5BZYCuNJAkY7nSwsckvcKU7WcwT2UnT8WRoJ5+QcuamXY9bOl269Mez394nks8fvaJmASqVSqb51B+OaSwytPBqXAAAAAElFTkSuQmCC","orcid":"","institution":"University of Tabriz","correspondingAuthor":true,"prefix":"","firstName":"Hamid","middleName":"","lastName":"Erfan-Niya","suffix":""},{"id":449077052,"identity":"56973f0f-1a9a-4056-bbdd-42c08fc9e85d","order_by":4,"name":"Sima Majidi","email":"","orcid":"","institution":"University of Tabriz","correspondingAuthor":false,"prefix":"","firstName":"Sima","middleName":"","lastName":"Majidi","suffix":""}],"badges":[],"createdAt":"2025-04-07 17:23:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6396496/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6396496/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81952346,"identity":"19f211db-f929-4852-a8c3-8c082b46d5c3","added_by":"auto","created_at":"2025-05-05 09:23:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47455,"visible":true,"origin":"","legend":"\u003cp\u003e2D chemical structures of (I) chitosan monomer (II) 5Fluorouracil and (III) Doxorubicin.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/ae0b62f6e9a23173ce776711.jpg"},{"id":81952374,"identity":"4a4773f5-8bae-4c7d-88af-91fd160ab4eb","added_by":"auto","created_at":"2025-05-05 09:23:54","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":139151,"visible":true,"origin":"","legend":"\u003cp\u003eThe chemical structures of (I) Graphene oxide, (II) MOF-5 and (III) MOF-5/GO nanocomposite.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/e2b61e9c0d9bc3401a9b84f9.jpg"},{"id":81952348,"identity":"e733f6ae-8b71-4516-a0a5-262e25088937","added_by":"auto","created_at":"2025-05-05 09:23:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":79532,"visible":true,"origin":"","legend":"\u003cp\u003eThe distances of DOX (I) and 5FU (II) drugs with components of MOF-5/GO nanocomposite.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/f93cb547e83e03afd00538b0.jpg"},{"id":81952340,"identity":"17bde11e-e930-4f67-bf50-d3bfe00697b0","added_by":"auto","created_at":"2025-05-05 09:23:51","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":94002,"visible":true,"origin":"","legend":"\u003cp\u003eTrajectory snapshots of 5FU drug delivery by MOF-5/GO nanocomposite during time of simulation (color codes: graphene oxide: cyan; MOF-5: purple; 5FU: yellow).\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/a15857aaf620519ba4cee892.jpg"},{"id":81952378,"identity":"bcbdeb88-f6c6-4ad7-a8cb-9be7f887bda8","added_by":"auto","created_at":"2025-05-05 09:23:55","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":121097,"visible":true,"origin":"","legend":"\u003cp\u003eTrajectory snapshots of DOX drug delivery by MOF-5/GO nanocomposite during time of simulation (DOX: green color; Water and ions molecules are not shown for clarity).\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/38e1128710e3c899517ec3f9.jpg"},{"id":81952393,"identity":"e32d7536-f037-4af5-b592-7b91c0181aaa","added_by":"auto","created_at":"2025-05-05 09:23:55","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":157256,"visible":true,"origin":"","legend":"\u003cp\u003eThe number of hydrogen bonds and the number of atomic contacts between DOX (I , II) and 5FU (III, IV) with the components of the designed MOF-5/GO nanocomposite.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/ce37cc1a94d43257a21b1fd2.jpg"},{"id":81953642,"identity":"48b188fe-49df-4ff2-8693-052b7072414e","added_by":"auto","created_at":"2025-05-05 09:39:51","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":118250,"visible":true,"origin":"","legend":"\u003cp\u003eThe final snapshots for chitosan polymer-coated MOF-5/GO nanocomposite (I) and configuration of DOX molecules in CS@MOF-5/GO system (II) (color codes: chitosan: red and Doxorubicin: green).\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/27bd764c61f55d1b81ccaa09.jpg"},{"id":81952775,"identity":"c0ad0dcf-5fb5-41a4-9270-98820325142c","added_by":"auto","created_at":"2025-05-05 09:31:55","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":99051,"visible":true,"origin":"","legend":"\u003cp\u003e(I) The average values of the van der Waals (EvdW) and electrostatic (Eelec) energy as well as the total intermolecular interaction energy (Einter); (II) the number of hydrogen bonds; (III) the number of atomic contacts and (IV) comparison of the RDF function for the interaction of DOX with the considered fragments at DOX@CS@MOF-5/GO system.\u003c/p\u003e","description":"","filename":"Figure8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/3bb6774ae6aefbb14eca890d.jpg"},{"id":83763965,"identity":"e24443e5-d22d-4bd4-9813-8a95da8a1c74","added_by":"auto","created_at":"2025-06-02 10:23:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1551809,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/a1c7ba89-743d-4429-8bba-da9544cf5e8b.pdf"},{"id":81952342,"identity":"6e0e3584-7adf-424c-8765-b058eaba0552","added_by":"auto","created_at":"2025-05-05 09:23:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1820107,"visible":true,"origin":"","legend":"","description":"","filename":"RevisedSupplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-6396496/v1/fd012bc65db555682162051d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Computational Modeling of Drug Delivery System Based on MOF-5 Metal- Organic Framework /Graphene Oxide Nanohybrid","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRecently, development of the design and fabrication of new efficient drug delivery carriers with the control drug release ability has great attention in the field of the modern medicine. Smart drug delivery systems (DDS) enhance the quality and effectiveness of poorly water-soluble medications and prevent their deactivation until reaching target locations\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Beside to the improvement of therapeutic efficiency, target delivery of anti-cancer drugs can decrease side effects and prevent drug accumulation \u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Up to date, various nanostructures such as graphene-based materials \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and metal-organic frameworks (MOFs) \u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e with low toxicity, high adjustability, and facile synthesis have investigated in the field of biomedicine.\u003c/p\u003e \u003cp\u003eIn recent years, graphene oxide (GO) has attracted great attention in the field of drug delivery and targeting owing its remarkable physiochemical characteristics and distinct planar structure \u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In addition to π-π stacking, the existence of different oxygen-containing functional groups on GO provides an exceptional adsorption capacity for numerous therapeutic molecules through electrostatic interactions and hydrogen bonding \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. In spite of high specific surface area and free π electron availability in the structures of GO, its aggregation in physiological solutions is a major drawback in the biomedical applications\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Nowadays, zinc-based metal-organic frameworks are found to be attractive porous materials for controlled drug delivery \u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e owing to large specific surface area, low toxicity and tunable pore morphology and good biodegradability \u003csup\u003e\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, the low water stability of MOFs limits their efficiency in drug delivery system\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. It is well known that the composing MOFs to other materials results in a new class of porous structures with altered construction and improved physiochemical properties \u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Recently, some research reported the application of GO, MOFs and GO composites with various MOFs in the field of drug delivery systems \u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29 CR30 CR31\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. It is known that the combination of MOF and GO may overcome the drawbacks of these materials. The combination of GO with MOFs shows increased porosity and dispersion force as well as improved material stability and adsorption performance \u003csup\u003e\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Compared to other drug delivery systems, GO/MO nanohybrid have exceptional biocompatibility, high drug loading, increased stability and low cytotoxicity \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs proven by many experimental and theoretical researches, GO, MOFs and MOF-based nanocomposites have been widely investigated in the delivery of various biomolecules. The high loading capacity of GO for DOX drug under neutral conditions was attributed to hydrogen bond interactions as the principal driving force for drug loading onto GO nanocarriers \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. The atom-scale loading of Paclitaxel and Curcumin drugs onto MXenes-Cu-BTC nanocomposites demonstrated that the formation of hydrogen bonds between Curcumin drug and oxygen termination of MXenes\u0026rsquo;s surface results in the improvement of the adsorption capacity of the nanocomposite \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. The significant payload of up to 35.7% for DOX drug on the inorganic MXene/MOF-5 nanostructure was achieved, which would be because of the interactions between the nanocarrier and DOX \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Correspondingly, a co-drug delivery system based on aluminum-succinic acid MOF and GO was developed to enhance biodegradability, augmented biocompatibility, and facilitated release of 5FU and DOX drugs under cancerous extracellular conditions due to the integration of chitosan (CS) within the nanocomposite \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. DOX release from carboxymethylcellulose (CMC) coated-MOF-5/GO bio-nanocomposite was observed under the tumor cell microenvironment condition \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. In addition, loading and release of Tetracycline on the designed CMC/MOF-5/GO material was investigated \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The 5FU loaded on the CS/Zn-MOF@GO microspheres could effectively treat tumor cells \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. The synthesized sericin/chitosan/Ag@MOF-GO nanocomposite showed hemostatic and antibacterial activity, water-solubility and biocompatibility \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, the research of MOF-based nanocomposite carriers is still in its early stages, the underlying adsorption characteristic and mechanism of loading and delivery of drug molecules have been rarely studied. With the help of computational tools such as molecular dynamics (MD) simulation, qualitatively and quantitatively of the physio-chemical mechanism and interactions in DDSs can be revealed. MD simulation provides a quick screening of a large number of drug candidates as well as the ability to study phenomena that are difficult to observe experimentally. In the present work, inspired by these concepts, we have explored the possibility of MOF-5/GO nanocomposite as 5FU and DOX anti-cancer drug delivery systems with atomic details using MD simulations. Additionally, the assessment of delivery performance of coated MOF-5/GO composite by chitosan chain polymer has acceptable novelty on more efficiency of the designed nanocomposite for loading 5FU/DOX as the current drugs in cancer therapy. It is high expected that the designed MOF-5/GO nanocomposite and, specifically, chitosan polymer-coated nanocomposite (CS@MOF-5/GO), could serve as the ideal candidates to explore the underlying mechanism of MOF-based nanocomposite carriers for efficient delivery of 5FU/DOX.\u003c/p\u003e"},{"header":"MD simulation procedure","content":"\u003cp\u003eThe MD simulation is applied to explore the capability of MOF-5/GO nanocomposite for loading of 5FU and DOX anti-cancer drug molecules in physiological media. For those, two systems are constructed; each simulation system containing of eight molecules of each anti-cancer drug and MOF-5/GO nanocomposite (i.e., 5FU@MOF-5/GO and DOX@MOF-5/GO).\u003c/p\u003e \u003cp\u003eSince the association of nanomaterials with natural polymers influences efficiency of drug delivery systems, the adsorption mechanism of DOX drug on CS@MOF-5/GO is also studied. The simulation system is comprised of CS@MOF-5/GO nanohybrid and eight DOX drug molecules (DOX@CS@MOF-5/GO). It is noted that the coating process of MOF-5/GO nanocomposite by CS has already been simulated for 60 ns using GROMACS software \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, that the simulated system includes MOF-5/GO nanocomposite and eight chains of CS with three monomer units per chain.\u003c/p\u003e \u003cp\u003eThe structures of DOX, 5FU, chitosan monomer, the designed nanohybrid and its components are presented in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The MOF-5 framework which is extracted from the ChemTube 3D \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e is used. MOF-5 consists of Zn\u003csub\u003e4\u003c/sub\u003eO as the metal oxide cluster and 1,4-benzenedicarboxylate (BDC) as organic linker. The framework structure of MOF-5 is constructed with eight metal clusters and twelve organic linkers as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The GO components are also established based on the Lerf-Klinowski method \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e based on a graphene with dimensions of 2.7 nm\u0026times; 2.6 nm. The simulation boxes with dimensions of 9 nm\u0026times;9 nm\u0026times;11 nm are hydrated with 28327, 28203 and 28022 water molecules, respectively, using the TIP3P model \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAll atoms of MOF-5 and GO components of the designed nanocomposite are proposed as charged Lenard-Jones (LJ) particles. For GO components, all sp\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e carbon atoms are treated as uncharged and the partial charges of the oxygen-containing functional groups are taken from work of Schneible et al. \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Force field parameters for GO are extracted from the general CHARMM36 force field (CGenFF) \u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. The Lenard-Jones parameters and the partial atomic charges of MOF-5 atom species are obtained from the works of Greathouse et al. \u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e and Manz et al \u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, respectively. The same parameters have been used by other researchers for similar works \u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. The topology and parameter files for DOX, 5FU and CS are also determined based on the CGenFF in CHARMM-GUI webserver \u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. Overall, the solvated systems contain negatively charged nanocomposite and neutral drug molecules. Then, adding the appropriate number of sodium (Na\u003csup\u003e+\u003c/sup\u003e) and chloride (Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e) to preserve neutrality and a physiological concentration (0.15 M) \u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e neutralized the charges in the simulation systems. The LJ interactions are subjected to a cutoff radius of 12 \u0026Aring; and the particle mesh Ewald (PME) method is applied to treat the long-range electrostatic interactions \u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. All bond length involving hydrogen atoms are constrained with LINCS algorithm \u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe energy minimization of the initial conformation for each simulated system is conducted using steepest descent method for 50000 steps. Next, NVT simulations are performed to relax the systems for 1000 ps, followed by NPT simulations for 1000 ps. The temperature and pressure are controlled using Nose-Hoover thermostat \u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e and Parrinello\u0026ndash;Rahman barostat \u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. The equations of motion are integrated using the leapfrog algorithm. The production runs are conducted under periodic boundary conditions in three directions for a 90 ns and within the isothermal\u0026ndash;isobaric (NPT) simulation at 310 K and 1 bar. The classical MD simulations are conducted in GROMACS \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e software with a time step of 1.5 fs. The Visual molecular dynamics (VMD) software is applied to preparing the molecular graphic images \u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eAt the first stage, the equilibrium state for the designed systems is evaluated by quantities such as density and pressure curves against simulation time, as illustrated in Supplementary Figure S1. The constant density seen throughout simulation time serves as evidence that the systems have achieved proper equilibrium. The time dependence of pressure has also confirmed the equilibrium state of systems (Figure S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn order to quantitatively analyze how 5FU/DOX approaches MOF-5@GO adsorbent, a series of descriptors, including the minimum distance, contact number, hydrogen bonds (HBs), radial distribution functions (RDF) and the intermolecular interaction energy are calculated throughout the simulation trajectory. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDrug adsorption mechanism onto MOF-5/GO\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis of the distances is performed based on the geometry center of the drug and the MOF-5/GO nanocomposite to ascertain drug adsorption behavior from water bulk region toward the drug delivery system. The observed minimal fluctuations of Figure 3 indicate the stable configuration of drug molecules on the nanohybrid. It is observed that the distances between DOX and the components of the designed nanocomposite rapidly decrease during first 10 ns of the simulation. In the case of 5FU, the adsorption capacity of GO components reach equilibrium in approximate 5 ns. At about 7 ns, the distance between 5FU and MOF-5 minimize by movement of one 5FU molecule in the interfacial region of MOF-5 and GO. Then, drug desorption occurs as a result of weakly interaction of this molecule with MOF. The shifting distance shows the insertion of 5FU molecule within the interfacial region between MOF and GO. As observed from Figure 3, the distance between each drug and GO remains stable in shorter range compared to that of MOF.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trajectory snapshots of 5FU and DOX delivery by MOF-5/GO nanocomposite are shown in Figure 4 and 5, respectively. As a result of fast movement of 5FU toward the nanohybrid, one 5FU molecule adsorbs on the graphene oxide surface (Figure 4). Within the simulation, some drug molecules penetrate into the interfacial region of MOF-5 and GO components and drug molecules interact efficiently with oxygen-containing functional groups of GO. After that, 5FU drugs fluctuate over the nanocomposite surface to obtain proper position on GO and MOF surface. Over time of simulation, loading of 5FU on the surface of GO as well as the interfacial region of GO and MOF-5 is observed (Figure 4).\u003c/p\u003e\n\u003cp\u003eMonitoring the simulation trajectory of DOX@MOF-5/GO system reveals that DOX drugs diffuses rapidly to the nanocomposite at the initial time of simulation (Figure 5). DOX drug molecules adsorb on the surface of MOF-5 metal-organic framework and graphene oxide nanosheets (Figure 5, t ~5 ns). The self-aggregation of two DOX molecules in the vicinity of MOF-5 surface is found at about t ~ 8 ns. Within the simulation, this structure moves to the interfacial region of MOF-5/GO. Over time of simulation, DOX molecules show affinity for the adsorption on GO nanosheets (Figure 5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the DOX@MOF-5/GO system, drug molecules adsorb on both GO components with maximum distribution on GO compared to MOF-5. In the case of 5FU@MOF-5/GO system, a large number of 5FU drugs can be found on GO.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntensity of Interactions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe total interaction energy (Einter) which includes the van der Waals (EvdW) and electrostatic (Eelec) attractions between drug@MOF-5 and drug@GO, is tabulated in Table 1\u003cstrong\u003e.\u003c/strong\u003e Inspection of this table indicates that the vdW contribution is dominated in the total intermolecular interaction energy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e. The calculated values of the van der Waals (EvdW) and electrostatic (Eelec) energy as well as the total intermolecular interaction energy (Einter) between the considered fragments at the simulation systems.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"402\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;Component\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eEvdW (kJ/mol)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eEelec\u003c/p\u003e\n \u003cp\u003e(kJ/mol)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eEinter\u003c/p\u003e\n \u003cp\u003e(kJ/mol)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e5FU@MOF-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-9.628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-1.310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-10.920\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e5FU@GO (down)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-190.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-60.710\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-250.713\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e5FU@GO (up)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-100.967\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-43.967\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-144.934\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e5FU@MOF-5/GO\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-300.599\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-105.986\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-406.567\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003eDOX@MOF-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-74.961\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-15.829\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-90.790\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003eDOX@GO (down)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-412.460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-144.869\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-557.328\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003eDOX@GO (up)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-281.914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-92.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-373.971\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003eDOX@MOF-5/GO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e-769.334\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e-252.755\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-1022.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe average total intermolecular interaction energy values for 5FU@MOF-5 and 5FU@GOs at 5FU@MOF-5/GO system are -10.920 kJ/mol and -395.647 kJ/mol, respectively. The average vdW and electrostatic interactions between 5FU@GOs are -290.971 kJ/mol and -104.677 kJ/mol, respectively. Also, 5FU drugs interact with MOF-5 with the average vdW and electrostatic energy values of -9.628 kJ/mol and -1.310 kJ/mol, respectively. Thus, the trapped 5FU molecules in the interfacial region have effective interactions with GO components with respect to MOF-5 as indicating with the intermolecular energies (Table 1). It can be clearly seen from Table 1, the average total intermolecular interaction energy between DOX and GO is higher than that with MOF-5. The vdW and electrostatic interaction energies of DOX with GOs is found to be about of -694.374 kJ/mol and -236.927 kJ/mol, respectively. There is a strong intermolecular interaction between DOX molecule and GO component with a much-pronounced vdW interaction energy. This fact can be explained by the structure of DOX molecule having a great number of atoms. Generally, these results can be attributed to the presence of a large number of DOX molecules on GO\u0026nbsp;as well as in the interfacial region of MOF-5/GO and further the intermolecular interactions between DOX@GOs (Figure 5). As observed, a correlation between uptake number of drug molecules and the intermolecular interaction energy is found.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvolution of the Intermolecular HBs and Number of Contacts\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe number of HBs formed between different fragments of the simulation systems are analyzed as shown in Figure 6. The HBs are considered based on the maximum distance of 0.35 nm between donor and acceptor atoms and the HB donor-H-acceptor angle of \u0026lt; 30\u0026deg; \u003csup\u003e14\u003c/sup\u003e. The average number of HBs between 5FU and GO (5FU@GOs) and between 5FU and MOF-5 (5FU@MOF-5) are 6.654 and 0.016, respectively. In the case of DOX drug delivery system, analysis of the average number of HBs along the simulation trajectory indicates that up to 15.294 and 0.515 HBs can be formed between DOX and GO (DOX@GOs) as well as DOX and MOF-5 (DOX@MOF-5), respectively. The obtained results are in accordance with the difference of the number of contacts in the simulation systems, as presented in Figure 6.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe contact number between the considered fragments are calculated using \u0026ldquo;gmx mindist\u0026rdquo; module. As observed, the number of contacts of DOX-GOs is significantly increases from 0 to 5000 after free of diffusion of drug molecules in bulk water to interaction with GO surface. This result confirms the effective loading of DOX on the oxygen-containing groups of the basal plane of GO component. The average contact number of DOX with MOF-5 is nine-fold lower than that with GO component. As a result, the reduction of the number of atomic contacts has negative impact on the average HBs number between the considered fragments (Figure 6). Close inspection of Figure 6 reveals that the number of atomic contacts of 5FU with GO is also significantly greater than that of with MOF-5. As expected, the number of hydrogen bonds between 5FU@MOF-5 is lower. \u0026nbsp;A significant increase in the number of atomic contacts demonstrates that 5FU molecules can be strongly adsorbed on GO surface. As observed, the uptake number of drug molecules can affect the number of atomic contacts and further the HBs number with the nanocomposite components.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadial distribution function analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe probability of finding drug molecules relative to the center of the mass of the components of the designed nanocomposite is investigated by radial distribution function (RDF) analysis and the results are presented in Supplementary Figure S2. A great accumulation of 5FU around GO compared to MOF-5 is highlighted by higher RDF strength. The intensity of RDF pattern of 5FU drug with GO surfaces exhibits maximum peak at a distance of 0.43 nm in 5FU@MOF-5/GO system. As can be clearly observed from Figure S2, the distance for the maximum distribution of 5FU molecule around GO of the nanocomposite is similar. 5FU molecules are distributed farther away from the MOF-5 at a distance of 1.65 nm in 5FU@MOF-5/GO system. RDF patterns of drug molecules with components of the studied nanocomposite in DOX@MOF-5/GO system are also shown in Figure S2. In the case of DOX@MOF-5/GO system, RDF of DOX@MOF-5 has been maximized in a large separation distance in comparison with DOX@GOs. As observed in Figure S2, a greater number of DOX molecules are adsorbed on GO components and further, the probability distribution of DOX around GO is higher than that of it\u0026rsquo;s on MOF-5. The observed peaks at distances between 0.5 nm and 1 nm are related to \u0026pi;-\u0026pi; stacking interaction between aromatic rings of the drug molecules and \u0026pi;-conjugated structure of GO \u003csup\u003e59\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMobility of Drug Molecules\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe movement of drug molecules toward the drug delivery system can be quantified through the calculation of mean square displacement (MSD). The ability of 5FU/DOX molecule to move around in the environment is quantified using MSD calculation as following equation:\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"746\" height=\"66\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eWhere \u003cem\u003er(t)\u003c/em\u003e is the atomic position of the drug molecule at time \u003cem\u003et\u003c/em\u003e, \u003cem\u003er(0)\u003c/em\u003e is the reference position of the drug molecule and the brackets denote the averaged ion position parameters in the simulated system \u003csup\u003e60\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe self-diffusion coefficient (D) can be used to reflect the intensity of drug molecule\u0026apos;s mobility and can be expressed according to the Einstein equation as follow:\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" height=\"66\" width=\"746\"\u003e\u003c/p\u003e\n\u003cp\u003eAccording to eq (2), the slope the MSD can be used to calculation of the self-diffusion coefficient.\u003c/p\u003e\n\u003cp\u003eThe migration rate of drug into the designed nanocomposite in the simulation system is calculated through linear regression only between 35-70 ns of the production run where there is linear correlation between the MSD and time (Supplementary Figure S3). The self-diffusion coefficient of 5FU and DOX molecules within the 5FU@MOF-5/GO and DOX@MOF-5/GO systems is determined to be 0.378\u0026times;10\u003csup\u003e\u0026minus;5\u003c/sup\u003e cm\u0026sup2; s\u003csup\u003e\u0026minus;1\u003c/sup\u003e and 0.057\u0026times;10\u003csup\u003e\u0026minus;5\u003c/sup\u003e cm\u0026sup2; s\u003csup\u003e\u0026minus;1\u003c/sup\u003e, respectively. The low diffusion coefficient of DOX along its high strong interaction with MOF-5/GO reduce the movement of DOX molecules onto the designed nanocomposite. Whereas, there is a vise-versa situation for 5FU drug at 5FU@MOF-5/GO system.\u003c/p\u003e\n\u003cp\u003eIn summary, MD simulations demonstrate the adsorption capacity of the designed MOF-5/GO nanocomposite for loading 5FU and DOX drug molecules. The loading mechanism of 5FU/DOX on the designed nanohybrid is governed through the \u0026pi;-\u0026pi; stacking, the vdW and electrostatic interactions and HBs network.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOX Drug Delivery via Chitosan Polymer-Coated MOF-5/GO Nanocomposite\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince MOF-5/GO nanocomposite showed better drug delivery performance for DOX drug, the effect of covering the surface of nanocomposite by CS polymers on DOX drug adsorption mechanism is also investigated. The final snapshot of chitosan polymer-coated MOF-5/GO nanocomposite is shown in Figure 7. As clearly observed from this figure, a great number of CS polymers interact with functional groups of GO component and some adsorb on the surface of MOF-5. This observation is proved by decreasing the total intermolecular interaction energy of CS@GO and CS@MOF-5 as shown in Supplementary Figure S4. The coating process of MOF-5/GO nanocomposite by CS polymers is also characterized by calculation of the atomic number of contacts between CS and components of the designed nanocomposite. The obtained results are presented in Figure S4.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe effective coating CS on the surface of nanocomposite is manifested by the results of the number of atomic contacts.\u003c/p\u003e\n\u003cp\u003eFigure 7 shows final MD configurations of DOX molecules at CS@MOF-5/GO nanocomposite. From Figure 7, it is found that the adsorption behavior of DOX on CS@MOF-5/GO nanocomposite is different to that of DOX on MOF-5/GO. At CS@MOF-5/GO, self-aggregation of five DOX molecules in the vicinity of MOF-5 surface is obvious. As seen, DOX molecule tends to adsorb on top of the chitosan coated the surface of GO component. In addition, distribution of drug molecules on basal plane of GO and the interfacial region of MOF-5/GO is found. The calculated intermolecular interaction energy values, the number of atomic contacts, HBs number and RDF patterns of the simulation system is presented in Figure 8.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs observed from Figure 7, the presence of CS molecules on the nanocomposite blocks the active sites of the nanocomposite surface. Thus, the average total intermolecular interaction energy between DOX and MOF-5/GO in CS@MOF-5/GO system is significantly lower than that with MOF-5/GO without CS (Figure 8). However, the same number of DOX molecules are located in the considered systems.\u003c/p\u003e\n\u003cp\u003eAs clearly observed, the interaction between DOX and GO is significantly weak at CS@MOF-5/GO system in comparison with MOF-5/GO simulation system. Compared to DOX@MOF-5/GO system, the interaction strength of DOX with GO at polymer-coated nanocomposite is significantly diminished (EvdW= -264.537 kJ/mol and Eelec= -81.009 kJ/mol). Close inspection of Figure 8 and Table 1 reveals that there is no significant change of the interaction energy of DOX with MOF-5 at CS@MOF-5/GO system in comparison to MOF-5/GO system. It is observed that \u0026pi;-\u0026pi; stacking interaction peak of DOX with GO in the presence of CS polymers has lower intensity due to the weakening the intermolecular interaction of DOX@GO (Figure 8). The results are agreed well with the results of the average intermolecular interaction energy. As can be observed in Figure 8, the peak position of DOX with GO (down) is shifted to a larger distance (r\u003csub\u003emax\u003c/sub\u003e= 1.00 nm) in comparison with DOX@GO (up) (r\u003csub\u003emax\u003c/sub\u003e= 0.64 nm). This result may be attributed to this observation that one DOX molecule is adsorbed on chitosan polymers covering GO surface (down).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIt is found that there are the intermolecular interactions between DOX@CS (Figure 7). The calculated vdW and electrostatic interaction energy values of DOX@CS are -87.521 kJ/mol and -32.202 kJ/mol, respectively. Analysis of RDF profile of DOX around CS@MOF-5/GO nanocomposite reveals that the maximum distribution of DOX drug is located 1.85 nm away from MOF-5 metal-organic framework. The coated surface of nanocomposite with chitosan polymers has a significant effect on the diffusion behavior of DOX drug in such a way the self-diffusion coefficient of drug molecule is increased to 0.818\u0026times; 10\u003csup\u003e\u0026minus;5\u003c/sup\u003e cm\u003csup\u003e2\u003c/sup\u003e s\u003csup\u003e\u0026minus;1\u0026nbsp;\u003c/sup\u003e(Supplementary Figure S5). In other word, the weak intermolecular interaction of DOX in CS@MOF-5/GO enhances the molecular motion of drug molecules in the studied simulation system. Inspection the obtained results shows that the average contact number for DOX and CS is about two-fold greater than that with GO (down). In accordance with the number of atomic contacts, the average HBs formed between DOX@CS is higher than DOX@GO (down). The more intermolecular atomic contacts of DOX with GO (up) are accomplished more DOX loading on the surface and further more HBs numbers (Figures 7 and 8).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, the adsorption capacity of the designed MOF-5/GO nanocomposite toward loading of 5FU and DOX drugs is investigated by MD simulation. Different affinity of drugs to MOF-5/GO nanocomposite is found based on their structures. The stability of the simulation systems can be attributed to the predominant vdW interaction. The drug molecules spontaneously adsorb on the MOF-5/GO nanocomposite by π-π stacking between aromatic rings of drugs and components of the drug delivery carrier. It has been observed that the coating of the nanocomposite surface by CS has a significant effect on the absorption behavior of DOX drugs as well as the strength of its intermolecular interaction with the drug delivery system. This study provides new insight on the application of the designed MOF-5/GO nanocomposite drug delivery system at atomic level.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMarzieh Eskandarzadeh conceived and designed the analysisSaeed Pourmand designed and performed the analysisSara Zareei Collected the data and Wrote the paperHamid Erfan-Niya corresponding authorSima Majidi designed the analysis\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. 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Application of molecular dynamics simulations in molecular property prediction II: diffusion coefficient. \u003cem\u003eJournal of computational chemistry\u003c/em\u003e \u003cstrong\u003e32\u003c/strong\u003e, 3505-3519 (2011).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Doxorubicin, 5Fluorouracil, MOF-5/GO nanocomposite, Drug delivery system, Coating process, Molecular dynamics simulation","lastPublishedDoi":"10.21203/rs.3.rs-6396496/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6396496/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn the present work, the designed MOF-5 metal-organic framework/graphene oxide (MOF-5/GO) nanocomposite is evaluated as a novel platform for efficient delivery of 5Fluorouracil (5FU) and Doxorubicin (DOX) anti-cancer drugs by molecular dynamics (MD) simulations. The details of the adsorption mechanism for 5FU and DOX drug molecules on MOF-5/GO are examined based on the total intermolecular interaction energy (Einter), the number of hydrogen bonds (HBs), the number of atomic contacts and radial distribution functions (RDF) analyses. Depending on their structure and size, different affinity of drugs to MOF-5/GO nanocomposite is found during time of simulation. The van der Waals interaction energy has been identified as the main responsible for drug loading on the nanocomposite. The geometric considerations reveal that the π-π interaction between aromatic rings of graphene oxide and benzene ring of drug molecules along HBs facilitate loading of the anti-cancer drugs on MOF-5/GO nanocomposite. Since the association of nanomaterials with natural polymers influences efficiency of drug delivery systems, the adsorption mechanism of DOX drug on the chitosan polymer-coated MOF-5/GO is also studied. Our simulation results highlight the application of MOF-5/GO nanocomposite as a promising candidate for efficient loading of drug molecules.\u003c/p\u003e","manuscriptTitle":"Computational Modeling of Drug Delivery System Based on MOF-5 Metal- Organic Framework /Graphene Oxide Nanohybrid","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-05 09:23:40","doi":"10.21203/rs.3.rs-6396496/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e5fcdab7-7df8-4158-9e7f-5e997b8654fb","owner":[],"postedDate":"May 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47786439,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":47786440,"name":"Health sciences/Molecular medicine"},{"id":47786441,"name":"Physical sciences/Chemistry"}],"tags":[],"updatedAt":"2025-06-02T10:23:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-05 09:23:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6396496","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6396496","identity":"rs-6396496","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}