Preparation of Quercetin Loaded Microparticles and their Antitumor Activity against Human Lung Cancer Cells (A549) in vitro

Author(s): Chen Li*, Liufang Gao, Yi Zhang, Benjamin K. Simpson.

Journal Name: Current Pharmaceutical Biotechnology

Volume 20 , Issue 11 , 2019

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Graphical Abstract:


Abstract:

Background: Novel quercetin-loaded microparticles (QM) were fabricated using coaxial electrospraying, characterized for surface morphology and release profile, and evaluated for antitumor activity in vitro.

Methods: QM exhibited an average diameter of 1.69 ±1.13 mm, which was an appropriate size suitable for respiratory delivery. X-ray diffraction patterns showed that the components in QM existed in an amorphous physical form, leading to favorable interactions between the drug (quercetin), the polymer matrix (polyvinylpyrrolidone, PVP) and other excipients (sodium dodecyl sulfate and sucralose).

Results: QM performed much faster release rate compared with free quercetin powder (Q) in vitro. Furthermore, QM also showed more potent inhibitory effects on A549 cell growth with reduced cell viability, decreased cell migration and induced more G0/G1 phase cell cycle arrest than Q.

Conclusion: Thus, the quercetin loaded microparticles exhibited more potent inhibitory effects than free quercetin on A549 cell. The increased antitumor activity could be attributed to the enhanced accumulation of quercetin in the A549 cells with the QM. However, further studies are necessary to elucidate the exact mechanisms.

Keywords: Quercetin, microparticle, fast-release, anti-tumor activity, lung cancer cells, microparticles.

[1]
Liu, L.; Tang, Y.; Gao, C.; Li, Y.; Chen, S.; Xiong, T.; Li, J.; Du, M.; Gong, Z.; Chen, H.; Liu, L.; Yao, P. Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers. Colloids Surf. B Biointerfaces, 2014, 115, 125-131.
[http://dx.doi.org/10.1016/j.colsurfb.2013.11.029] [PMID: 24333909]
[2]
Kalender, Y.; Kaya, S.; Durak, D.; Uzun, F.G.; Demir, F. Protective effects of catechin and quercetin on antioxidant status, lipid peroxidation and testis-histoarchitecture induced by chlorpyrifos in male rats. Environ. Toxicol. Pharmacol., 2012, 33(2), 141-148.
[http://dx.doi.org/10.1016/j.etap.2011.12.008] [PMID: 22209726]
[3]
Ravichandran, R.; Rajendran, M.; Devapiriam, D. Antioxidant study of quercetin and their metal complex and determination of stability constant by spectrophotometry method. Food Chem., 2014, 146, 472-478.
[http://dx.doi.org/10.1016/j.foodchem.2013.09.080] [PMID: 24176370]
[4]
Kleemann, R.; Verschuren, L.; Morrison, M.; Zadelaar, S.; van Erk, M.J.; Wielinga, P.Y.; Kooistra, T. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis, 2011, 218(1), 44-52.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.04.023] [PMID: 21601209]
[5]
Sani, I.K.; Marashi, S.H.F.; Kalalinia, F. Solamargine inhibits migration and invasion of human hepatocellular carcinoma cells through down-regulation of matrix metalloproteinases 2 and 9 expression and activity. Toxicol. In Vitro, 2015, 29(5), 893-900.
[http://dx.doi.org/10.1016/j.tiv.2015.03.012] [PMID: 25819016]
[6]
Jeong, J.H.; An, J.Y.; Kwon, Y.T.; Rhee, J.G.; Lee, Y.J. Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J. Cell. Biochem., 2009, 106(1), 73-82.
[http://dx.doi.org/10.1002/jcb.21977] [PMID: 19009557]
[7]
Shan, B.E.; Wang, M.X.; Li, R.Q. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest., 2009, 27(6), 604-612.
[http://dx.doi.org/10.1080/07357900802337191] [PMID: 19440933]
[8]
Tanigawa, S.; Fujii, M.; Hou, D.X. Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Biosci. Biotechnol. Biochem., 2008, 72(3), 797-804.
[http://dx.doi.org/10.1271/bbb.70680] [PMID: 18323654]
[9]
Lim, J.H.; Park, J.W.; Min, D.S.; Chang, J.S.; Lee, Y.H.; Park, Y.B.; Choi, K.S.; Kwon, T.K. NAG-1 up-regulation mediated by EGR-1 and p53 is critical for quercetin-induced apoptosis in HCT116 colon carcinoma cells. Apoptosis, 2007, 12(2), 411-421.
[http://dx.doi.org/10.1007/s10495-006-0576-9] [PMID: 17191121]
[10]
Ferraresi, R.; Troiano, L.; Roat, E.; Lugli, E.; Nemes, E.; Nasi, M.; Pinti, M.; Fernandez, M.I.G.; Cooper, E.L.; Cossarizza, A. Essential requirement of reduced glutathione (GSH) for the anti-oxidant effect of the flavonoid quercetin. Free Radic. Res., 2005, 39(11), 1249-1258.
[http://dx.doi.org/10.1080/10715760500306935] [PMID: 16298752]
[11]
Zhang, H.; Zhang, M.; Yu, L.; Zhao, Y.; He, N.; Yang, X. Antitumor activities of quercetin and quercetin-5′,8-disulfonate in human colon and breast cancer cell lines. Food Chem. Toxicol., 2012, 50(5), 1589-1599.
[http://dx.doi.org/10.1016/j.fct.2012.01.025] [PMID: 22310237]
[12]
Srinivas, K.; King, J.W.; Howard, L.R.; Monrad, J.K. Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water. J. Food Eng., 2010, 100, 208-218.
[http://dx.doi.org/10.1016/j.jfoodeng.2010.04.001]
[13]
Alía, M.; Ramos, S.; Mateos, R.; Granado-Serrano, A.B.; Bravo, L.; Goya, L. Quercetin protects human hepatoma HepG2 against oxidative stress induced by tert-butyl hydroperoxide. Toxicol. Appl. Pharmacol., 2006, 212(2), 110-118.
[http://dx.doi.org/10.1016/j.taap.2005.07.014] [PMID: 16126241]
[14]
Windrum, P.; Morris, T.C.; Drake, M.B.; Niederwieser, D.; Ruutu, T. Variation in dimethyl sulfoxide use in stem cell transplantation: A survey of EBMT centres. Bone Marrow Transplant., 2005, 36(7), 601-603.
[http://dx.doi.org/10.1038/sj.bmt.1705100] [PMID: 16044141]
[15]
Mulholland, P.J.; Ferry, D.R.; Anderson, D.; Hussain, S.A.; Young, A.M.; Cook, J.E.; Hodgkin, E.; Seymour, L.W.; Kerr, D.J. Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin. Ann. Oncol., 2001, 12(2), 245-248.
[http://dx.doi.org/10.1023/A:1008372017097] [PMID: 11300332]
[16]
Pralhad, T.; Rajendrakumar, K. Study of freeze-dried quercetin-cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis. J. Pharm. Biomed. Anal., 2004, 34(2), 333-339.
[http://dx.doi.org/10.1016/S0731-7085(03)00529-6] [PMID: 15013147]
[17]
Yuan, Z.P.; Chen, L.J.; Fan, L.Y.; Tang, M.H.; Yang, G.L.; Yang, H.S.; Du, X.B.; Wang, G.Q.; Yao, W.X.; Zhao, Q.M.; Ye, B.; Wang, R.; Diao, P.; Zhang, W.; Wu, H.B.; Zhao, X.; Wei, Y.Q. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res., 2006, 12(10), 3193-3199.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2365] [PMID: 16707620]
[18]
Frijlink, H.W.; Eissens, A.C.; Hefting, N.R.; Poelstra, K.; Lerk, C.F.; Meijer, D.K.F. The effect of parenterally administered cyclodextrins on cholesterol levels in the rat. Pharm. Res., 1991, 8(1), 9-16.
[http://dx.doi.org/10.1023/A:1015861719134] [PMID: 2014215]
[19]
Mu, X.; Zhong, Z. Preparation and properties of poly(vinyl alcohol)-stabilized liposomes. Int. J. Pharm., 2006, 318(1-2), 55-61.
[http://dx.doi.org/10.1016/j.ijpharm.2006.03.016] [PMID: 16624507]
[20]
Bikiaris, D.N. Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs. Expert Opin. Drug Deliv., 2011, 8(12), 1663-1680.
[http://dx.doi.org/10.1517/17425247.2011.618182] [PMID: 21919806]
[21]
Di Martino, P.; Censi, R.; Gigliobianco, M.R.; Zerrillo, L.; Magnoni, F.; Agas, D.; Quaglia, W.; Lupidi, G. Nano-medicine Improving the bioavailability of small molecules for the prevention of neurodegenerative diseases. Curr. Pharm. Des., 2017, 23(13), 1897-1908.
[http://dx.doi.org/10.2174/1381612822666161227154447] [PMID: 28025942]
[22]
Bilia, A.R.; Piazzini, V.; Guccione, C.; Risaliti, L.; Asprea, M.; Capecchi, G.; Bergonzi, M.C. Improving on nature: The role of nanomedicine in the development of clinical natural drugs. Planta Med., 2017, 83(5), 366-381.
[http://dx.doi.org/10.1055/s-0043-102949] [PMID: 28178749]
[23]
Mirza, A.Z.; Siddiqui, F.A. Nanomedicine and drug delivery: A mini review. Int. Nano Lett., 2014, 4, 94-99.
[http://dx.doi.org/10.1007/s40089-014-0094-7]
[24]
Srinivas, K.; King, J.W.; Howard, L.R.; Monra, J.K. Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water. J. Food Eng., 2010, 100, 208-218.
[http://dx.doi.org/10.1016/j.jfoodeng.2010.04.001]
[25]
Agheb, M.; Dinari, M.; Rafienia, M.; Salehi, H. Novel electrospun nanofibers of modified gelatin-tyrosine in cartilage tissue engineering. Mater. Sci. Eng. C, 2017, 71, 240-251.
[http://dx.doi.org/10.1016/j.msec.2016.10.003] [PMID: 27987704]
[26]
Ozcan, F.; Ertul, S.; Maltas, E. Fabrication of protein scaffold by electrospin coating for artificial tissue. Mater. Lett., 2016, 182, 359-362.
[http://dx.doi.org/10.1016/j.matlet.2016.07.010]
[27]
Wong, D.E.; Senecal, K.J.; Goddard, J.M. Immobilization of chymotrypsin on hierarchical nylon 6,6 nanofiber improves enzyme performance. Colloids Surf. B Biointerfaces, 2017, 154, 270-278.
[http://dx.doi.org/10.1016/j.colsurfb.2017.03.033] [PMID: 28351799]
[28]
Ying, B.; Yang, T.; Song, X.; Hu, X.; Fan, H.; Lu, X.; Chen, L.; Cheng, D.; Wang, T.; Liu, D.; Xu, D.; Wei, Y.; Wen, F. Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. Mol. Biol. Rep., 2009, 36(7), 1825-1832.
[http://dx.doi.org/10.1007/s11033-008-9386-1] [PMID: 18982426]
[29]
Nanua, S.; Zick, S.M.; Andrade, J.E.; Sajjan, U.S.; Burgess, J.R.; Lukacs, N.W.; Hershenson, M.B. Quercetin blocks airway epithelial cell chemokine expression. Am. J. Respir. Cell Mol. Biol., 2006, 35(5), 602-610.
[http://dx.doi.org/10.1165/rcmb.2006-0149OC] [PMID: 16794257]
[30]
Tan, B.J.; Liu, Y.; Chang, K.L.; Lim, B.K.W.; Chiu, G.N.C. Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer. Int. J. Nanomedicine, 2012, 7, 651-661.
[PMID: 22334787]
[31]
Zhang, H.T.; Nie, H.L.; Yu, D.G.; Wu, Y.L.; Branford-White, C.J.; Zhu, L.M. Surface modification of electrospun polyacrylonitrile nanofiber towards developing an affinity membrane for bromelain adsorption. Desalination, 2010, 256, 141-147.
[http://dx.doi.org/10.1016/j.desal.2010.01.026]
[32]
Li, C.; Wang, Z.H.; Yu, D.G. Higher quality quercetin sustained release ethyl cellulose nanofibers fabricated using a spinneret with a Teflon nozzle. Colloids Surf. B Biointerfaces, 2014, 114, 404-409.
[http://dx.doi.org/10.1016/j.colsurfb.2013.10.040] [PMID: 24257689]
[33]
Li, Y.; Shen, J.; Fang, M.; Huang, X.; Yan, H.; Jin, Y.; Li, J.; Li, X. The promising antitumour drug disulfiram inhibits viability and induces apoptosis in cardiomyocytes. Biomed. Pharmacother., 2018, 108, 1062-1069.
[http://dx.doi.org/10.1016/j.biopha.2018.09.123] [PMID: 30372806]
[34]
Loo, A.E.K.; Ho, R.; Halliwell, B. Mechanism of hydrogen peroxide-induced keratinocyte migration in a scratch-wound model. Free Radic. Biol. Med., 2011, 51(4), 884-892.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.06.001] [PMID: 21699973]
[35]
Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38. Chem. Biol. Interact., 2012, 195(2), 154-164.
[http://dx.doi.org/10.1016/j.cbi.2011.12.005] [PMID: 22197970]
[36]
Notas, G.; Nifli, A.P.; Kampa, M.; Pelekanou, V.; Alexaki, V.I.; Theodoropoulos, P.; Vercauteren, J.; Castanas, E. Quercetin accumulates in nuclear structures and triggers specific gene expression in epithelial cells. J. Nutr. Biochem., 2012, 23(6), 656-666.
[http://dx.doi.org/10.1016/j.jnutbio.2011.03.010] [PMID: 21782406]
[37]
Mezzena, M.; Scalia, S.; Young, P.M.; Traini, D. Solid lipid budesonide microparticles for controlled release inhalation therapy. AAPS J., 2009, 11(4), 771-778.
[http://dx.doi.org/10.1208/s12248-009-9148-6] [PMID: 19908147]
[38]
Scalia, S.; Salama, R.; Young, P.; Traini, D. Preparation and in vitro evaluation of salbutamol-loaded lipid microparticles for sustained release pulmonary therapy. J. Microencapsul., 2012, 29(3), 225-233.
[http://dx.doi.org/10.3109/02652048.2011.646326] [PMID: 22208706]
[39]
Scalia, S.; Haghi, M.; Losi, V.; Trotta, V.; Young, P.M.; Traini, D. Quercetin solid lipid microparticles: A flavonoid for inhalation lung delivery. Eur. J. Pharm. Sci., 2013, 49(2), 278-285.
[http://dx.doi.org/10.1016/j.ejps.2013.03.009] [PMID: 23541500]
[40]
Moon, H.; Choi, H.H.; Lee, J.Y.; Moon, H.J.; Sim, S.S.; Kim, C.J. Quercetin inhalation inhibits the asthmatic responses by exposure to aerosolized-ovalbumin in conscious guinea-pigs. Arch. Pharm. Res., 2008, 31(6), 771-778.
[http://dx.doi.org/10.1007/s12272-001-1225-2] [PMID: 18563360]
[41]
Shen, X.; Yu, D.; Zhu, L.; Branford-White, C.; White, K.; Chatterton, N.P. Electrospun diclofenac sodium loaded Eudragit® L 100-55 nanofibers for colon-targeted drug delivery. Int. J. Pharm., 2011, 408(1-2), 200-207.
[http://dx.doi.org/10.1016/j.ijpharm.2011.01.058] [PMID: 21291969]
[42]
Alonzo, D.E.; Zhang, G.G.; Zhou, D.; Gao, Y.; Taylor, L.S. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm. Res., 2010, 27(4), 608-618.
[http://dx.doi.org/10.1007/s11095-009-0021-1] [PMID: 20151181]
[43]
Yoshioka, J.; Yoshitomi, T.; Yasukawa, T.; Yoshimoto, K. Alternation of gene expression levels in Mesenchymal stem cells by applying Positive dielectrophoresis. Anal. Sci., 2016, 32(11), 1213-1216.
[http://dx.doi.org/10.2116/analsci.32.1213] [PMID: 27829628]
[44]
Robaszkiewicz, A.; Balcerczyk, A.; Bartosz, G. Antioxidative and prooxidative effects of quercetin on A549 cells. Cell Biol. Int., 2007, 31(10), 1245-1250.
[http://dx.doi.org/10.1016/j.cellbi.2007.04.009] [PMID: 17583542]
[45]
Sun, M.; Nie, S.; Pan, X.; Zhang, R.; Fan, Z.; Wang, S. Quercetin-nanostructured lipid carriers: Characteristics and anti-breast cancer activities in vitro. Colloids Surf. B Biointerfaces, 2014, 113, 15-24.
[http://dx.doi.org/10.1016/j.colsurfb.2013.08.032] [PMID: 24060926]
[46]
Han, Q.; Yang, R.; Li, J.; Liang, W.; Zhang, Y.; Dong, M.; Besenbacher, F.; Wang, C. Enhancement of biological activities of nanostructured hydrophobic drug species. Nanoscale, 2012, 4(6), 2078-2082.
[http://dx.doi.org/10.1039/c2nr12013e] [PMID: 22331105]
[47]
Amorim, C.M.; Couto, A.G.; Netz, D.J.; de Freitas, R.A.; Bresolin, T.M. Antioxidant idebenone-loaded nanoparticles based on chitosan and N-carboxymethylchitosan. Nanomed.-. Nanotechnology, 2010, 6, 745-752.
[48]
Schaffazick, S.R.; Siqueira, I.R.; Badejo, A.S.; Jornada, D.S.; Pohlmann, A.R.; Netto, C.A.; Guterres, S.S. Incorporation in polymeric nanocapsules improves the antioxidant effect of melatonin against lipid peroxidation in mice brain and liver. Eur. J. Pharm. Biopharm., 2008, 69(1), 64-71.
[http://dx.doi.org/10.1016/j.ejpb.2007.11.010] [PMID: 18182281]
[49]
Boulton, D.W.; Walle, U.K.; Walle, T. Fate of the flavonoid quercetin in human cell lines: Chemical instability and metabolism. J. Pharm. Pharmacol., 1999, 51(3), 353-359.
[http://dx.doi.org/10.1211/0022357991772367] [PMID: 10344638]
[50]
Haenen, G.R.; Arts, M.J.; Bast, A.; Coleman, M.D. Structure and activity in assessing antioxidant activity in vitro and in vivo A critical appraisal illustrated with the flavonoids. Environ. Toxicol. Pharmacol., 2006, 21(2), 191-198.
[http://dx.doi.org/10.1016/j.etap.2005.07.010] [PMID: 21783657]
[51]
Makris, D.P.; Rossiter, J.T. Heat-induced, metal-catalyzed oxidative degradation of quercetin and rutin (Quercetin 3-Orhamnosylglucoside) in aqueous model systems J. Agric. Food Chem, 2000, 48(9), 3830-3838.
[http://dx.doi.org/10.1021/jf0001280]] [PMID: 10995278]


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VOLUME: 20
ISSUE: 11
Year: 2019
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DOI: 10.2174/1573407215666190628145902
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