Molecular Dynamics Simulations of Glycyrrhizic Acid Aggregates as Drug-Carriers for Paclitaxel

Author(s): Mumtaz Hussain*.

Journal Name: Current Drug Delivery

Volume 16 , Issue 7 , 2019

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Graphical Abstract:


Abstract:

Background: Glycyrrhizic acid (GA) is a glycoside that has shown considerable promise as a penetration enhancer and drug carrier to improve the absorption of poorly water-soluble drugs. The aggregation behavior of GA and its ability to form large micelles at higher solution concentrations are thought to contribute to these bioavailability enhancing properties. The oral absorption of Paclitaxel (PTX) for example, an anti-cancer agent which exhibits poor oral bioavailability, has been found to significantly increase in the presence of GA.

Methods: In an attempt to visualize the aggregation behavior of GA and its subsequent association with PTX, 100 ns molecular dynamics simulation of a 5 mM aqueous solution of GA with 10 molecules of PTX was conducted using GROMACS and an all-atom forcefield.

Results: Aggregation of GA molecules was found to occur quickly at this level of saturation leading to two stable aggregates of 13 and 17 GA molecules with an effective radius of 10.17 nm to 10.92 nm. These aggregates form not in isolation, but together with PTX molecule embedded within the structures, which reduces the number of interactions and hydrogen-bonding with water.

Conclusion: GA aggregation occurs around PTX molecules in solution, forming co-joined GA-PTX cluster units at a ratio of 3:1. These clusters remain stable for the remainder of the 100ns simulation and serve to isolate and protect PTX from the aqueous environment.

Keywords: Molecular dynamics simulation, glycyrrhizic acid, paclitaxel, aggregation, solubilization, gromacs.

[1]
Fiore, C.; Eisenhut, M.; Ragazzi, E.; Zanchin, G.; Armanini, D. A history of the therapeutic use of liquorice in Europe. J. Ethnopharmacol., 2005, 99(3), 317-324.
[http://dx.doi.org/10.1016/j.jep.2005.04.015] [PMID: 15978760]
[2]
Van Wyk, B.E.; Wink, M. Medicinal Plants of the World, 2nd ed; CABI: Wallingford, UK, 2017.
[3]
Yu, J.Y.; Ha, J.Y.; Kim, K.M.; Jung, Y.S.; Jung, J.C.; Oh, S. Anti-Inflammatory activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver. Molecules, 2015, 20(7), 13041-13054.
[http://dx.doi.org/10.3390/molecules200713041] [PMID: 26205049]
[4]
Shibata, S. A drug over the millennia: Pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi, 2000, 120(10), 849-862.
[http://dx.doi.org/10.1248/yakushi1947.120.10_849] [PMID: 11082698]
[5]
Selyutina, O.Y.; Polyakov, N.E.; Korneev, D.V.; Zaitsev, B.N. Influence of glycyrrhizin on permeability and elasticity of cell membrane: Perspectives for drugs delivery. Drug Deliv., 2014, 1-8.
[PMID: 24870200]
[6]
Kuang, Y.; Li, B.; Fan, J.; Qiao, X.; Ye, M. Antitussive and expectorant activities of licorice and its major compounds. Bioorg. Med. Chem., 2018, 26(1), 278-284.
[http://dx.doi.org/10.1016/j.bmc.2017.11.046] [PMID: 29224994]
[7]
Cai, Y.; Xu, Y.; Chan, H.F.; Fang, X.; He, C.; Chen, M. Glycyrrhetinic Acid Mediated Drug Delivery Carriers for Hepatocellular Carcinoma Therapy. Mol. Pharm., 2016, 13(3), 699-709.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00677] [PMID: 26808002]
[8]
Su, X.; Wu, L.; Hu, M.; Dong, W.; Xu, M.; Zhang, P. Glycyrrhizic acid: A promising carrier material for anticancer therapy. Biomed. Pharmacother., 2017, 95, 670-678.
[http://dx.doi.org/10.1016/j.biopha.2017.08.123] [PMID: 28886526]
[9]
Narvekar, M.; Xue, H.Y.; Eoh, J.Y.; Wong, H.L. Nanocarrier for poorly water-soluble anticancer drugs--barriers of translation and solutions. AAPS PharmSciTech, 2014, 15(4), 822-833.
[http://dx.doi.org/10.1208/s12249-014-0107-x] [PMID: 24687241]
[10]
Zhao, M.X.; Ji, L.N.; Mao, Z.W. β-Cyclodextrin/glycyrrhizic acid functionalised quantum dots selectively enter hepatic cells and induce apoptosis. Chemistry, 2012, 18(6), 1650-1658.
[http://dx.doi.org/10.1002/chem.201102795] [PMID: 22213427]
[11]
Chen, L.; Yang, J.; Davey, A.K.; Chen, Y.X.; Wang, J.P.; Liu, X.Q. Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. Xenobiotica, 2009, 39(12), 955-963.
[http://dx.doi.org/10.3109/00498250903271997] [PMID: 19831503]
[12]
Radwant, M.A.; Aboul-Enein, H.Y. The effect of oral absorption enhancers on the in vivo performance of insulin-loaded poly(ethylcyanoacrylate) nanospheres in diabetic rats. J. Microencapsul., 2002, 19(2), 225-235.
[http://dx.doi.org/10.1080/02652040110081406] [PMID: 11837977]
[13]
Zhou, J.X.; Wink, M. Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites. Medicines (Basel), 2018, 5(4), 123.
[http://dx.doi.org/10.3390/medicines5040123] [PMID: 30428619]
[14]
James, K.C.; Stanford, J.B. The solubilising properties of liquorice. J. Pharm. Pharmacol., 1962, 14, 445-450.
[http://dx.doi.org/10.1111/j.2042-7158.1962.tb11122.x] [PMID: 14451014]
[15]
Kornievskaya, V.S.; Kruppa, A.I.; Polyakov, N.E.; Leshina, T.V. Effect of glycyrrhizic acid on lappaconitine phototransformation. J. Phys. Chem. B, 2007, 111(39), 11447-11452.
[http://dx.doi.org/10.1021/jp0739770] [PMID: 17824688]
[16]
Vervaet, C.; Byron, P.R. Drug-surfactant-propellant interactions in HFA-formulations. Int. J. Pharm., 1999, 186(1), 13-30.
[http://dx.doi.org/10.1016/S0378-5173(99)00134-9] [PMID: 10469920]
[17]
Fu-Heng, Y.; Qing, Z. †, Qian-Ying, L.; Sheng-Qi, W.; Bo-Xin, Z.; Ya-Tian, W.; Yun Cai, L.; Guo-Feng, L. Bioavailabil-ity Enhancement of Paclitaxel via a Novel Oral Drug Delivery System: Paclitaxel-Loaded Glycyrrhizic Acid Micelles. Molecules, 2015, 20, 4337-4356.
[http://dx.doi.org/10.3390/molecules20034337] [PMID: 25756651]
[18]
Zelikman, M.V.; Kim, A.V.; Medvedev, N.N.; Selyutina, O.Yu.; Polyakov, N.E. Structure of dimers of glyceryzzic acid in water and their complexes with cholesterol: molecular dynamics simulations. J. Struct. Chem., 2015, 56, 67-76.
[http://dx.doi.org/10.1134/S0022476615010102]
[19]
Oda, M.; Kuroda, M. Molecular dynamics simulations of inclusion complexation of glycyrrhizic acid and cyclodextrins (1:1) in water. J. Incl. Phenom. Macrocycl. Chem., 2016, 85, 271.
[http://dx.doi.org/10.1007/s10847-016-0626-z]
[20]
Malde, A.K.; Zuo, L.; Breeze, M.; Stroet, M.; Poger, D.; Nair, P.C.; Oostenbrink, C.; Mark, A.E. An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0. J. Chem. Theory Comput., 2011, 7(12), 4026-4037.
[http://dx.doi.org/10.1021/ct200196m] [PMID: 26598349]
[21]
Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.E.; Berendsen, H.J.C. GROMACS: fast, flexible, and free. J. Comput. Chem., 2005, 26(16), 1701-1718.
[http://dx.doi.org/10.1002/jcc.20291] [PMID: 16211538]
[22]
Hoover, W.G. Phys. Rev. A, 1985, 31, 1695-1697.
[http://dx.doi.org/10.1103/PhysRevA.31.1695]
[23]
Parrinello, M.; Rahman, A. J. Appl. Phys., 1981, 52, 7182.
[http://dx.doi.org/10.1063/1.328693]
[24]
Essmann, U.; Perera, L.M.; Berkowitz, L.; Darden, T.A.; Lee, H.; Pedersen, L.G. J. Chem. Phys., 1995, 103, 8577-8593.
[http://dx.doi.org/10.1063/1.470117]


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Article Details

VOLUME: 16
ISSUE: 7
Year: 2019
Page: [618 - 627]
Pages: 10
DOI: 10.2174/1567201816666190313155117
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