Simulation of the molecular dynamics of the passage of liposome with cinnarizine through the blood-brain barrier

Keywords: Molecular dynamics, Liposomes, Cinnarizine, Blood-brain barrier

Abstract

     Liposomal preparations have a number of advantages: they protect the cells of the body from the toxic effects of drugs; prolong the action of the drug introduced into the body; protect medicinal substances from degradation; promote the manifestation of targeted specificity due to selective penetration from blood into tissues; change the pharmacokinetics of drugs, increasing their pharmacological effectiveness; make it possible to create a water-soluble form of a number of medicinal substances, thereby increasing their bioavailability. In this work, studies were carried out for the development of the method for determining the degree of inclusion of cinnarizine used as a corrector of cerebrovascular accidents into liposomes from soy lecithin. The aim of this study was to determine the distance between the membranes of endotheliocytes,
which is critical for the passage of a liposome through the blood-brain barrier.
       A simulation of changes in the structure of a liposome with cinnarizine located between two cell membranes was carried out using the molecular dynamics method at various distances between the membranes. A square planar fragment of a bilayer phospholipid membrane was assembled using the Internet service Charmm-GUI->Input Generator->Martini Maker‑>BilayerBuilder (http://www.charmm-gui.org/?doc=input/mbilayer). Geometry optimization and molecular dynamics simulation were performed in Gromacs 2019 using Martini 2.2 force field. According to the results of the simulation of coarse-grained molecular dynamics, a liposome from purified soy lecithin with cinnarizine adsorbed on its inner and outer
surface is able to maintain integrity, being between the membranes of endotheliocytes at a distance between membranes of more than 8 nm. When the distance between the membranes of endothelial cells is less than 8 nm, the liposome with cinnarizine located between the endotheliocytes can lose its structural integrity due to fusion with the endothelial cell membrane.
    As a result of the studies, the distance between the membranes of endotheliocytes was established, at which point the liposome with cinnarizine, located between endotheliocytes, can lose its structural integrity due to fusion with the endothelial cell membrane.

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Author Biography

Yulia A. Polkovnikova, Voronezh State University, 1 Universitetskaya pl., Voronezh 394018, Russian Federation

Cand Sci. (Pharmacy),
Associate Professor at the Department of
Pharmaceutical Technology and Pharmaceutical
Chemistry, Faculty of Pharmacy, Voronezh State
University (Voronezh, Russian Federation).

References

Hou G., Niu J., Song F., Liu Z., Liu S. Studies on the interactions between ginsenosides and liposome by equilibrium dialysis combined with ultrahigh performance liquid chromatography-tandem mass spectrometry. Journal of Chromatography B. 2013;923–924: 1–7. https://doi.org/10.1016/j.jchromb.2013.01.035

Sariev A. K., Abaimov D. A., Seyfulla R. D. Drug bioavailability improvement by means of nanopharmacology: pharmacokinetics of liposomal drugs. Experimental and Clinical Pharmacology. 2010; 11:34–38. (In Russ.). https://doi.org/10.30906/0869-2092-2010-73-11-34-38

Kamchatnov P. R., Salnikova G. S., Mikhailova N. A. Chronic disorders of bran blood circulation and possibilities of their pharmacological correction. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2012;112(6): 72–75. (In Russ.). Available at: https://www.elibrary.ru/item.asp?id=17912111

Dolgova I. N., Starodubtsev A. I. The chronic cerebrovascular pathology in young patients. Medical Bulletin of the North Caucasus. 2011;1:26–29. (In Russ., abstract in Eng.). Available at: https://med-click.ru/uploads/files/docs/hronicheskaya-tserebrovaskulyarnaya-patologiya-u-patsientovmolodogo-vozrasta.pdf

Glukhova O. E. Liposome Drug Delivery System across Endothelial Plasma Membrane: Role of Distance between Endothelial Cells and Blood Flow Rate. Molecules.2020;25:1875. DOI: https://doi.org/10.3390/molecules25081875

Jo S., Kim T., Iyer V.G., Im W. CHARMM-GUI: A Web-based Graphical User Interface for CHARMM. Journal of Computational Chemistry. 2008;29: 1859–1865. https://doi.org/10.1002/jcc.20945

Qi Y., Ingólfsson H. I., Cheng X., Lee J., Marrink S. J., Im W. CHARMM-GUI Martini Maker for Coarse-Grained Simulations with the Martini Force Field. Journal of Chemical Theory and Computation. 2015;1: 4486–4494. https://doi.org/10.1021/acs.jctc.5b00513

Tian Y., Shen S, Gu L., Zhou J., Li Y., Zheng X. Computer-aided design of glucoside brain-targeted molecules based on 4PYP. Journal of Molecular Graphics and Modelling. 2021;103: 107819. https://doi.org/10.1016/j.jmgm.2020.107819

Dar K. B., Bhat A. H., Amin S., … Ganie S. A. Modern computational strategies for designing drugs to curb human diseases: a prospect. Current Topics in Medicinal Chemistry. 2018;18(31): 2702–2719. https://doi.org/10.2174/1568026619666190119150741

Scholtz A. W., Hahn A., Stefflova B., … Weisshaar G. Efficacy and safety of a fixed combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in patients with peripheral vestibular vertigo: a prospective, multinational, multicenter, double-blind, randomized, non-inferiority clinical trial. Clinical Drug Investigation. 2019;39(11): 1045–1056. https://doi.org/10.1007/s40261-019-00858-6

Ivanova L., Nikolov R., Tsikalova P., Nikolova M. Experimental rheoencephalographic studies on the effect of the cinnarizin analogue As2 on cerebral circulation. Acta Physiol Pharmacol Bulg. 1979;5(2):47–52.

Asadi P., Zia Ziabari S. M., Majdi A., Vatanparast K., Naseri Alavi S. A. Cinnarizine/betahistine combination vs. the respective monotherapies in acute peripheral vertigo: a randomized triple-blind placebocontrolled trial. European Journal of Clinical Pharmacology. 2019;75(11): 1513-1519. https://doi.org/10.1007/s00228-019-02741-x

Sethi S., Mangla B., Kamboj S., Rana V. A. QbD approach for the fabrication of immediate and prolong buoyant cinnarizine tablet using polyacrylamide-gcorn fibre gum. International Journal of Biological Macromolecules 2018;117: 350–361. https://doi.org/10.1016/j.ijbiomac.2018.05.178

Maghsoodi M., Nokhodchi A., Oskuei M. A., Heidari S. Formulation of Cinnarizine for stabilization of its physiologically generated supersaturation. AAPS PharmSciTech. 2019;20(3): 139. https://doi.org/10.1208/s12249-019-1338-7

Wang X., Liu W., Du K. Palaeontological evidence of membrane relationship in step-by-step membrane fusion. Molecular Membrane Biology. 2011;28: 115–122. https://doi.org/10.3109/09687688.2010.536169

Hsu P-C., Bruininks B. M. H., Jefferies D., … Im W. CHARMM-GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides. Journal of Computational Chemistry. 2017;15: 38(27):2354–2363. https://doi.org/10.1002/jcc.24895

van Hoogevest P., Wendel P. A. The use of natural and synthetic phospholipids as pharmaceutical excipients. European Journal of Lipid Science and Technology. 2014;116: 1088–1110. https://doi.org/10.1002/ejlt.201400219

Marrink S. J., Risselada H. J., Yefimov S., Tieleman D. P., de Vries, A. H. The MARTINI force field: Coarse grained model for biomolecular simulations. Journal of Physical Chemistry B. 2007;111: 7812–7824. https://doi.org/10.1021/jp071097f

Berendsen H. J. C., Postma J. P. M., van Gunsteren W. F., Di Nola A., Haak J. R. Molecular dynamics with coupling to an external bath. The Journal of Chemical Physics. 1984;81(8): 3684–3690. https://doi.org/10.1063/1.448118

Cansella M., Gouygoub J.-P., Jozefonvicza J., Letourneura D. Lipid composition of cultured endothelial cells in relation to their growth. Lipids. 1997;32: 39–44. https://doi.org/10.1007/s11745-997-0006-3

Published
2023-03-09
How to Cite
Polkovnikova, Y. A. (2023). Simulation of the molecular dynamics of the passage of liposome with cinnarizine through the blood-brain barrier. Condensed Matter and Interphases, 25(1), 95-102. https://doi.org/10.17308/kcmf.2023.25/10982
Section
Original articles

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