Nashrieh Shimi va Mohandesi Shimi Iran

Nashrieh Shimi va Mohandesi Shimi Iran

Graphene Oxide Nanosheets as Bortezomib Drug Carriers in a Targeted Drug Delivery System: A Novel Approach for Cancer Therapy

Document Type : Research Article

Authors
Hooriye Yahyaei
Amir Reza Saeni
Department of Chemistry, Zanjan Branch, Islamic Azad University, Zanjan, I.R. IRAN
Abstract
This study, for the first time, investigates the interaction between the anticancer drug bortezomib and graphene oxide nanoparticles using quantum mechanical calculations employing density functional theory and NBO calculations at the B3LYP/6-311+G* level of theory, as well as molecular mechanics simulations using the Monte Carlo method with AMBER, OPLS, CHARMM (Bio), and MM+ force fields over a range of temperatures (298-316 K) in water solvent. Calculations have shown that hydroxyl and epoxy groups in graphene oxide form hydrogen bonds with the N-H group of the bortezomib molecule, while the carboxyl group at the edges of the graphene oxide sheet creates a negative surface charge. Therefore, graphene oxide is well dispersed in water and other polar solvents, and this amphiphilic structure, when faced with the bortezomib drug, introduces it as a suitable carrier. This is also observed in molecular docking simulations and molecular dynamics simulations through the establishment of precise hydrogen bonds and hydrophobic π bonds in this drug system; which, due to intramolecular hydrogen bonds of bortezomib with graphene oxide and hydrophobic bonds, provides intermolecular stabilization and stability of this drug system with the surrounding environment. According to NBO results, which are based on π-π interactions of graphene oxide and bortezomib, van der Waals, ionic, and hydrogen bonding interactions occur due to the presence of a large number of oxygen-containing groups, which has a significant impact on the stabilization of the anticancer drug bortezomib. Also, evaluations of the molecular electrostatic potential and molecular charges by examining the electrostatic interactions of this drug system in terms of electronegativity, desirability, and BTZ-GO stability have shown results consistent with NBO results. Monte Carlo calculations also show that the results extracted from the Amber force field are consistent with the results of quantum mechanics.
Keywords
Bortezomib
Nano graphene oxide
Natural bond orbitals (NBO)
Molecular electrostatic potential(MEP)
Mulliken atomic charges
Molecular docking(MDs)
Subjects
[1] Gazzaroli G., Angeli A., Giacomini A., Ronca R., Proteasome Inhibitors as Anticancer Agents. Expert opinion on therapeutic patents, 1–22. Advance online publication (2023).
[2] Gavriatopoulou M., Malandrakis P., Ntanasis-Stathopoulos I., Dimopoulos M.A., Nonselective Proteasome Inhibitors in Multiple Myeloma and Future Perspectives. Expert opinion on pharmacotherapy, 23(3): 335–347 (2022).
[3] Hu Y., He L., Ma W., Chen L., Reduced Graphene Oxide‐Based Bortezomib Delivery System for Photothermal Chemotherapy with Enhanced Therapeutic Efficacy. Polymer International, 67(12): 1648-1654 (2018).
[4] Chen X., Dou Q.P., Liu J., Tang D., Targeting Ubiquitin-Proteasome System With Copper Complexes for Cancer Therapy. Frontiers in molecular biosciences, 8: 649151 (2021).
[5] Moriya S., Kazama H., Hino H., Takano N., Hiramoto M., Aizawa S., Miyazawa K., Clarithromycin Overcomes Stromal Cell-Mediated Drug Resistance Against Proteasome Inhibitors in Myeloma Cells Via Autophagy Flux Blockage Leading to High NOXA Expression. PloS one, 18(12): e0295273 (2023).
[6] Fricker L.D., Proteasome Inhibitor Drugs. Annual review of pharmacology and toxicology, 60: 457–476  (2020).
[7] Robak P., Robak T., Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later. Drugs in R&D, 19(2): 73–92 (2019).  .
[8] Offidani M., Corvatta L., Morè S., Nappi D., Martinelli G., Olivieri A., Cerchione C., Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments. Frontiers in oncology, 10: 624661  (2021).  
[9] Sharp P.S., Stylianou M., Arellano L.M., Neves J.C., Gravagnuolo A.M., Dodd A., ... Kostarelos K., Graphene Oxide Nanoscale Platform Enhances the Anti‐Cancer Properties of Bortezomib in Glioblastoma Models. Advanced Healthcare Materials, 12(3): 2201968  (2023).
[10] Zeng S., Ji Y., Shen Y., Zhu R., Wang X., Chen L., Chen J., Molecular Dynamics Simulations of Loading and Unloading of Drug Molecule Bortezomib on Graphene Nanosheets. RSC advances, 10(15): 8744-8750 (2020). 
[11] Korani M., Korani S., Zendehdel E., Nikpoor A.R., Jaafari M.R., Orafai H.M., Johnston T.P., Sahebkar A., Enhancing the Therapeutic Efficacy of Bortezomib in Cancer Therapy Using Polymeric Nanostructures. Current pharmaceutical design, 25(46): 4883–4892  (2019).
[12] Sharp P.S., Stylianou M., Arellano L.M., Neves J.C., Gravagnuolo A.M., Dodd A., Barr K., Lozano N., Kisby T., Kostarelos K., Graphene Oxide Nanoscale Platform Enhances the Anti-Cancer Properties of Bortezomib in Glioblastoma Models. Advanced healthcare materials, 12(3): e2201968 (2023).
 [13] Kaur H., Garg R., Singh S., Jana A., Bathula C., Kim H.S., Kumbar S.G., Mittal M., Progress and Challenges of Graphene and Its Congeners for Biomedical Applications. Journal of molecular liquids, 368(A): 120703 (2022).
[14] Barati F., Avatefi M., Moghadam N.B., Asghari S., Ekrami E., Mahmoudifard M., A Review of Graphene Quantum Dots and Their Potential Biomedical Applications. Journal of biomaterials applications, 37(7): 1137–1158 (2023).
[15] Mousavi S.M., Hashemi S.A., Kalashgrani M.Y., Omidifar N., Bahrani S., Vijayakameswara Rao N., Babapoor A., Gholami A., Chiang W.H., Bioactive Graphene Quantum Dots Based Polymer Composite for Biomedical Applications. Polymers, 14(3): 617 (2022). 
[16] Banerjee A.N., Graphene and Its Derivatives as Biomedical Materials: Future Prospects and Challenges. Interface focus, 8(3): 20170056 (2018).
[17] Chen S.H., Bell D.R., Luan B., Understanding Interactions Between Biomolecules and Two-Dimensional Nanomaterials Using in Silico Microscopes. Advanced drug delivery reviews, 186: 114336 (2022).
[18] Han Y., Zhao J., Guo X., Jiao T., Enhanced Methane Storage in Graphene Oxide Induced by an External Electric Field: A Study by MD Simulations and DFT Calculation. Langmuir : the ACS journal of surfaces and colloids, 39(22): 7648–7659 (2023).
[19] Palma A.S., Casadei B.R., Lotierzo M.C., de Castro R.D., Barbosa L.R.S., A Short Review on the Applicability and Use of Cubosomes as Nanocarriers. Biophysical reviews, 15(4): 553–567 (2023). 
[20] Matiyani M., Rana A., Pal M., Dokwal S., Sahoo N.G., Polyamidoamine Dendrimer Decorated Graphene Oxide as a pH-Sensitive Nanocarrier for the Delivery of Hydrophobic Anticancer Drug Quercetin: A Remedy for Breast Cancer. The Journal of pharmacy and pharmacology, 75(6): 859–872 (2023). 
[21] Kim Y., Patel R., Kulkarni C.V., Patel M., Graphene-Based Aerogels for Biomedical Application. Gels (Basel, Switzerland), 9(12): 967 (2023).
[22] Li R., Wang Y., Du J., Wang X., Duan A., Gao R., Liu J., Li B., Graphene Oxide Loaded with Tumor-Targeted Peptide and Anti-Cancer Drugs for Cancer Target Therapy. Scientific reports, 11(1): 1725 (2021).
[23] Matiyani M., Rana A., Pal M., Rana S., Melkani A.B., Sahoo N.G., Polymer Grafted Magnetic Graphene Oxide as a Potential Nanocarrier for pH-Responsive Delivery of Sparingly Soluble Quercetin Against Breast Cancer Cells. RSC advances, 12(5): 2574–2588 (2022).
[24] Zeng S., Ji Y., Shen Y., Zhu R., Wang X., Chen L., Chen J., Molecular Dynamics Simulations of Loading and Unloading of Drug Molecule Bortezomib on Graphene Nanosheets. RSC advances, 10(15): 8744–8750 (2020).
[25] Lado-Touriño I., Páez-Pavón A., Interaction Between Graphene-Based Materials and Small Ag, Cu, and CuO Clusters: A Molecular Dynamics Study. Nanomaterials (Basel, Switzerland), 11(6): 1378 (2021).
[26] Mahdavi M., Fattahi A., Nouranian, S., Doxorubicin Stability and Retention on PEGylated Graphene Oxide Nanocarriers Adjacent to Human Serum Albumin. ACS applied bio materials, 3(11): 7646–7653 (2020).
[27] Kulkarni P.U., Shah H., Vyas V.K., Hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) Simulation: A Tool for Structure-Based Drug Design and Discovery. Mini reviews in medicinal chemistry, 22(8): 1096–1107 (2022).
[28] Spivak M., Stone J.E., Ribeiro J., Saam J., Freddolino P.L., Bernardi R.C., Tajkhorshid E., VMD as a Platform for Interactive Small Molecule Preparation and Visualization in Quantum and Classical Simulations. Journal of chemical information and modeling, 63(15): 4664–4678 (2023).
[29]  Vidal-Limon A., Aguilar-Toalá J.E., Liceaga A.M., Integration of Molecular Docking Analysis and Molecular Dynamics Simulations for Studying Food Proteins and Bioactive Peptides. Journal of agricultural and food chemistry, 70(4): 934–943 (2022).
[30] Shuli Z., Linlin L., Li G., Yinghu Z., Nan S., Haibin W., Hongyu X., Bioinformatics and Computer Simulation Approaches to the Discovery and Analysis of Bioactive Peptides. Current pharmaceutical biotechnology, 23(13): 1541–1555 (2022).
[31] Santos L.H.S., Ferreira R.S., Caffarena E.R., Integrating Molecular Docking and Molecular Dynamics Simulations. Methods in molecular biology (Clifton, N.J.), 2053: 13–34 (2019).
[32] Kordylewski S.K., Bugno R., Bojarski A.J., Podlewska S., Uncovering the Unique Characteristics of Different Groups of 5-HT5AR Ligands with Reference to Their Interaction with the Target Protein. Pharmacological reports : PR, 76(5): 1130–1146. (2024).
[33] Karunarathna B., Wanniarachchi J.D., Prashantha M.A.B., Govender K.K., Enhancing Styrene Monomer Recovery from Polystyrene Pyrolysis: Insights from Density Functional Theory. Journal of molecular modeling, 29(8): 255 (2023).
[34] Cárdenas G., Lucia-Tamudo J., Mateo-delaFuente H., Palmisano V.F., Anguita-Ortiz N., Ruano L., Pérez-Barcia Á., Díaz-Tendero S., Mandado M., Nogueira J.J., MoBioTools: A Toolkit to Setup Quantum Mechanics/Molecular Mechanics Calculations. Journal of computational chemistry, 44(4): 516–533 (2023).
[35] Morad R., Akbari M., Maaza M., Theoretical Study of Chemical Reactivity Descriptors of Some Repurposed Drugs for COVID-19. MRS advances, 1–5. Advance online publication (2023).
[36] S C.J., A M.F.B., K K., Vibrational, Spectroscopic, Chemical Reactivity, Molecular Docking and in Vitro Anticancer Activity Studies Against A549 Lung Cancer Cell Lines of 5-Bromo-Indole-3-Carboxaldehyde. Journal of molecular recognition : JMR, 34(3): e2873 (2021).
[37] Jiao Y., Weinhold F., NBO/NRT Two-State Theory of Bond-Shift Spectral Excitation. Molecules (Basel, Switzerland), 25(18), 4052 (2020).
[38] Wu T., Fang Z., Wang Z., Liu L., Song J., Song J., Stability, Electronic and Catalytic Properties of ConMoP(n = 1 ~ 5) Clusters: A DFT Study. Journal of molecular modeling, 29(8): 269 (2023).
[39] Nandi A., Conte R., Qu C., Houston P.L., Yu Q., Bowman J.M., Quantum Calculations on a New CCSD(T) Machine-Learned Potential Energy Surface Reveal the Leaky Nature of Gas-Phase Trans and Gauche Ethanol Conformers. Journal of chemical theory and computation, 18(9): 5527–5538 (2022).
[40] Edet H.O., Louis H., Gber T.E., Idante P.S., Egemonye T.C., Ashishie P.B., Oyo-Ita E.E., Benjamin I., Adeyinka A.S., Heteroatoms (B, N, S) Doped Quantum Dots as Potential Drug Delivery System for Isoniazid: Insight from DFT, NCI, and QTAIM. Heliyon, 9(1): e12599  (2022).
[41] Chutia T., Kalita D.J., Theoretical Investigation of Fused N-Methyl-Dithieno-Pyrrole Derivatives in the Context of Acceptor-Donor-Acceptor Approach. RSC advances, 12(23): 14422–14434 (2022). 
[42] Jiang Z., Yu Q., Zhao Z., Song X., Zhang Y., Reason for the Increased Electroactivity of Extracellular Polymeric Substances with Electrical Stimulation: Structural Change of α-Helix Peptide of Protein. Water research,   238: 119995 (2023).
[43] Ejuh G.W., Ndjaka J.M.B., Tchangnwa Nya F., Ndukum P.L., Fonkem C., Tadjouteu Assatse Y., Yossa Kamsi R.A., Determination of the Structural, Electronic, Optoelectronic and Thermodynamic Properties of the Methylxanthine Molecules Theophylline and Theobromine. Optical and quantum electronics, 52(11): 498 (2020).
[44] جعفری ف.، شهسواری ش.، سیف کردی ع.ا.، آذرخشی ف.، انکپسوله کردن ویتامین ب6 توسط نانولوله بور نیترید با استفاده از محاسبات .DFT نشریه شیمی و مهندسی شیمی ایران، 42(3): 151-167 (1402).