Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Improved Bioavailability and Hepatoprotective Activity of Baicalein Via a Self-assembled Solutol HS15 Micelles System

Author(s): Shuna Zhang, Ying Wang, Jiaojiao Shan, Xueju Qi and Qun Liu*

Volume 21, Issue 3, 2024

Published on: 15 June, 2023

Page: [461 - 472] Pages: 12

DOI: 10.2174/1567201820666230606163452

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Baicalein (BA) is a flavonoid extract from the root of Scutellaria baicalensis Georgi with excellent biological activities, such as antioxidant and anti-inflammatory activities. However, its poor water solubility limits its further development.

Objective: This study aims to prepare BA-loaded Solutol HS15 (HS15-BA) micelles, evaluate the bioavailability, and explore protective effects on carbon tetrachloride (CCl4) induced acute liver injury.

Methods: The thin-film dispersion method was used to prepare HS15-BA micelles. The physicochemical, in vitro release, pharmacokinetics, and hepatoprotective effects of HS15-BA micelles were studied.

Results: The optimal formulation showed a spherical shape by characterization of the transmission electron microscope (TEM) with an average small size (12.50 nm). The pharmacokinetic results illustrated that HS15-BA increased the oral bioavailability of BA. The in vivo results showed that HS15-BA micelles significantly inhibited the activity of the CCl4-induced liver injury marker enzymes aspartate transaminase (AST) and alanine transaminase (ALT). Also, CCl4 induced oxidative damage to liver tissue, leading to increased L-glutathione (GSH) and superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) activity, while HS15-BA significantly reversed the above changes. Moreover, BA also had a hepatoprotective effect through anti-inflammatory activity; the results of ELISA and RT-PCR revealed that HS15-BA pretreatment significantly inhibited the increase in the expression of inflammatory factors induced by CCl4.

Conclusion: In summary, our study confirmed that HS15-BA micelles enhanced the bioavailability of BA, and showed hepatoprotective effects through antioxidant and anti-inflammatory activities. HS15 could be considered a promising oral delivery carrier in treating liver disease.

Keywords: Acute liver injury, baicalein, solutol hs15, oral delivery, hepatoprotective, CCl4.

« Previous
Graphical Abstract

[1]
Farrington, C.; Wang, W.; Haafiz, A. 344 cellular source and mechanisms of TGFβ1 driven hepatic fibrogenesis in biliary atresia. Gastroenterology, 2010, 138(5), S-785.
[http://dx.doi.org/10.1016/S0016-5085(10)63618-9]
[2]
Yan, S.; Yang, H.; Lee, H.; Yin, M. Protective effects of maslinic acid against alcohol-induced acute liver injury in mice. Food Chem. Toxicol., 2014, 74, 149-155.
[http://dx.doi.org/10.1016/j.fct.2014.09.018] [PMID: 25301236]
[3]
Shi, Y.; Zhang, L.; Jiang, R.; Chen, W.; Zheng, W.; Chen, L.; Tang, L.; Li, L.; Li, L.; Tang, W.; Wang, Y.; Yu, Y. Protective effects of nicotinamide against acetaminophen-induced acute liver injury. Int. Immunopharmacol., 2012, 14(4), 530-537.
[http://dx.doi.org/10.1016/j.intimp.2012.09.013] [PMID: 23059795]
[4]
Zhang, X.; Kuang, G.; Wan, J.; Jiang, R.; Ma, L.; Gong, X.; Liu, X. Salidroside protects mice against CCl4-induced acute liver injury via down-regulating CYP2E1 expression and inhibiting NLRP3 inflammasome activation. Int. Immunopharmacol., 2020, 85, 106662.
[http://dx.doi.org/10.1016/j.intimp.2020.106662] [PMID: 32544869]
[5]
Ma, J.Q.; Li, Z.; Xie, W.R.; Liu, C.M.; Liu, S.S. Quercetin protects mouse liver against CCl4-induced inflammation by the TLR2/4 and MAPK/NF-κB pathway. Int. Immunopharmacol., 2015, 28(1), 531-539.
[http://dx.doi.org/10.1016/j.intimp.2015.06.036] [PMID: 26218279]
[6]
Cong, M.; Zhao, W.; Liu, T.; Wang, P.; Fan, X.; Zhai, Q.; Bao, X.; Zhang, D.; You, H.; Kisseleva, T.; Brenner, D.A.; Jia, J.; Zhuang, H. Protective effect of human serum amyloid P on CCl4-induced acute liver injury in mice. Int. J. Mol. Med., 2017, 40(2), 454-464.
[http://dx.doi.org/10.3892/ijmm.2017.3028] [PMID: 28627620]
[7]
Zhou, H.C.; Wang, H.; Shi, K.; Li, J.M.; Zong, Y.; Du, R. Hepatoprotective Effect of baicalein against acetaminophen-induced acute liver injury in mice. Molecules, 2018, 24(1), 131.
[http://dx.doi.org/10.3390/molecules24010131] [PMID: 30602693]
[8]
Karim, N.; Jia, Z.; Zheng, X.; Cui, S.; Chen, W. A recent review of citrus flavanone naringenin on metabolic diseases and its potential sources for high yield-production. Trends Food Sci. Technol., 2018, 79, 35-54.
[http://dx.doi.org/10.1016/j.tifs.2018.06.012]
[9]
Zeng, Y.; Song, J.; Zhang, M.; Wang, H.; Zhang, Y.; Suo, H. Comparison of In vitro and In vivo antioxidant activities of six flavonoids with similar structures. Antioxidants, 2020, 9(8), 732.
[http://dx.doi.org/10.3390/antiox9080732] [PMID: 32796543]
[10]
Shen, N.; Wang, T.; Gan, Q.; Liu, S.; Wang, L.; Jin, B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem., 2022, 383, 132531.
[http://dx.doi.org/10.1016/j.foodchem.2022.132531] [PMID: 35413752]
[11]
Dinda, B.; Dinda, S.; DasSharma, S.; Banik, R.; Chakraborty, A.; Dinda, M. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur. J. Med. Chem., 2017, 131, 68-80.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.004] [PMID: 28288320]
[12]
Wang, W.; Zhou, P.; Xu, C.; Zhou, X.; Hu, W.; Zhang, J. Baicalein attenuates renal fibrosis by inhibiting inflammation via down-regulating NF-κB and MAPK signal pathways. J. Mol. Histol., 2015, 46(3), 283-290.
[http://dx.doi.org/10.1007/s10735-015-9621-8] [PMID: 25981879]
[13]
Liu, J.H.; Jia, M.; Yao, L.; Wang, Q.; Wang, N.B.; Wang, J.; Chen, W.Y.; Geng, J.J.; Wang, L.; Sun, Z.P. The hepatoprotective effects of baicalein against CCl4-induced acute liver injury in mice. Int. J. Clin. Exp. Med., 2016, 9(12), 23206-23213.
[14]
Ku, S.K.; Bae, J.S. Baicalin, baicalein and wogonin inhibits high glucose-induced vascular inflammation in vitr and in vivo. BMB Rep., 2015, 48(9), 519-524.
[http://dx.doi.org/10.5483/BMBRep.2015.48.9.017] [PMID: 25739393]
[15]
Huang, X.; He, Y.; Chen, Y.; Wu, P.; Gui, D.; Cai, H.; Chen, A.; Chen, M.; Dai, C.; Yao, D.; Wang, L. Baicalin attenuates bleomycin-induced pulmonary fibrosis via adenosine A2a receptor related TGF-β1-induced ERK1/2 signaling pathway. BMC Pulm. Med., 2016, 16(1), 132.
[http://dx.doi.org/10.1186/s12890-016-0294-1] [PMID: 27658704]
[16]
Guo, H.; Liu, D.; Ma, Y.; Liu, J.; Wang, Y.; Du, Z.; Wang, X.; Shen, J.; Peng, H. Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet. Acta Pharmacol. Sin., 2009, 30(11), 1505-1512.
[http://dx.doi.org/10.1038/aps.2009.150] [PMID: 19890358]
[17]
Yang, X.; Yang, J.; Zou, H. Baicalin inhibits IL-17-mediated joint inflammation in murine adjuvant-induced arthritis. Clin. Dev. Immunol., 2013, 2013, 1-8.
[http://dx.doi.org/10.1155/2013/268065] [PMID: 23840239]
[18]
Tran, T.V.A.; Malainer, C.; Schwaiger, S.; Hung, T.; Atanasov, A.G.; Heiss, E.H.; Dirsch, V.M.; Stuppner, H. Screening of Vietnamese medicinal plants for NF-κB signaling inhibitors: Assessing the activity of flavonoids from the stem bark of Oroxylum indicum. J. Ethnopharmacol., 2015, 159, 36-42.
[http://dx.doi.org/10.1016/j.jep.2014.10.012] [PMID: 25456439]
[19]
Kumar, M.; Kasala, E.R.; Bodduluru, L.N.; Dahiya, V.; Lahkar, M. Baicalein protects isoproterenol induced myocardial ischemic injury in male Wistar rats by mitigating oxidative stress and inflammation. Inflamm. Res., 2016, 65(8), 613-622.
[http://dx.doi.org/10.1007/s00011-016-0944-z] [PMID: 27071824]
[20]
Chandrashekar, N.; Selvamani, A.; Subramanian, R.; Pandi, A.; Thiruvengadam, D. Baicalein inhibits pulmonary carcinogenesis-associated inflammation and interferes with COX-2, MMP-2 and MMP-9 expressions in-vivo. Toxicol. Appl. Pharmacol., 2012, 261(1), 10-21.
[http://dx.doi.org/10.1016/j.taap.2012.02.004] [PMID: 22369883]
[21]
Zhang, L.; Yang, S.; Huang, L.; Ho, P.C.L. Poly (ethylene glycol)-block-poly (D, L-lactide) (PEG-PLA) micelles for brain delivery of baicalein through nasal route for potential treatment of neurodegenerative diseases due to oxidative stress and inflammation: An in vitro and in vivo study. Int. J. Pharm., 2020, 591, 119981.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119981] [PMID: 33069896]
[22]
Zhang, X.; Ruan, Q.; Zhai, Y.; Lu, D.; Li, C.; Fu, Y.; Zheng, Z.; Song, Y.; Guo, J. Baicalein inhibits non‐small‐cell lung cancer invasion and metastasis by reducing ezrin tension in inflammation microenvironment. Cancer Sci., 2020, 111(10), 3802-3812.
[http://dx.doi.org/10.1111/cas.14577] [PMID: 32691974]
[23]
Wang, J.; Li, Q.; Chen, Z.; Qi, X.; Wu, X.; Di, G.; Fan, J.; Guo, C. Improved bioavailability and anticancer efficacy of Hesperetin on breast cancer via a self-assembled rebaudioside A nanomicelles system. Toxicol. Appl. Pharmacol., 2021, 419, 115511.
[http://dx.doi.org/10.1016/j.taap.2021.115511] [PMID: 33819459]
[24]
Wang, J.; Yang, H.; Li, Q.; Wu, X.; Di, G.; Fan, J.; Wei, D.; Guo, C. Novel nanomicelles based on rebaudioside A: A potential nanoplatform for oral delivery of honokiol with enhanced oral bioavailability and antitumor activity. Int. J. Pharm., 2020, 590, 119899.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119899] [PMID: 32971177]
[25]
Seo, S.W.; Han, H.K.; Chun, M.K.; Choi, H.K. Preparation and pharmacokinetic evaluation of curcumin solid dispersion using Solutol® HS15 as a carrier. Int. J. Pharm., 2012, 424(1-2), 18-25.
[http://dx.doi.org/10.1016/j.ijpharm.2011.12.051] [PMID: 22226878]
[26]
Illum, L.; Jordan, F.; Lewis, A.L. CriticalSorb™: A novel efficient nasal delivery system for human growth hormone based on Solutol HS15. J. Control. Release, 2012, 162(1), 194-200.
[http://dx.doi.org/10.1016/j.jconrel.2012.06.014] [PMID: 22709592]
[27]
Hou, J.; Sun, E.; Sun, C.; Wang, J.; Yang, L.; Jia, X.; Zhang, Z. Improved oral bioavailability and anticancer efficacy on breast cancer of paclitaxel via Novel Soluplus®—Solutol® HS15 binary mixed micelles system. Int. J. Pharm., 2016, 512(1), 186-193.
[http://dx.doi.org/10.1016/j.ijpharm.2016.08.045] [PMID: 27567930]
[28]
Cho, H.J.; Park, J.H.; Kim, D.D.; Yoon, I.S. Poly(lactic-co-glycolic) Acid/Solutol HS15-based nanoparticles for docetaxel delivery. J. Nanosci. Nanotechnol., 2016, 16(2), 1433-1436.
[http://dx.doi.org/10.1166/jnn.2016.11918] [PMID: 27433600]
[29]
Younes, N.F.; Abdel-Halim, S.A.; Elassasy, A.I. Solutol HS15 based binary mixed micelles with penetration enhancers for augmented corneal delivery of sertaconazole nitrate: Optimization, in vitro, ex vivo and in vivo characterization. Drug Deliv., 2018, 25(1), 1706-1717.
[http://dx.doi.org/10.1080/10717544.2018.1497107] [PMID: 30442039]
[30]
Wang, Y.; Su, Y.; Yang, Y.; Jin, H.; Wu, M.; Wang, Q.; Sun, P.; Zhang, J.; Yang, X.; Shu, X. Increased brain uptake of pterostilbene loaded folate modified micellar delivery system. Drug Deliv., 2022, 29(1), 3071-3086.
[http://dx.doi.org/10.1080/10717544.2022.2126559] [PMID: 36131589]
[31]
Ko, I.G.; Jin, J.J.; Hwang, L.; Kim, S.H.; Kim, C.J.; Han, J.H.; Lee, S.; Kim, H.I.; Shin, H.P.; Jeon, J.W. Polydeoxyribonucleotide exerts protective effect against CCl4-Induced acute liver injury through inactivation of NF-κB/MAPK signaling pathway in mice. Int. J. Mol. Sci., 2020, 21(21), 7894.
[http://dx.doi.org/10.3390/ijms21217894] [PMID: 33114315]
[32]
Peng, X.; Dai, C.; Liu, Q.; Li, J.; Qiu, J. Curcumin attenuates on carbon tetrachloride-induced acute liver injury in mice via modulation of the Nrf2/HO-1 and TGF-β1/Smad3 pathway. Molecules, 2018, 23(1), 215.
[http://dx.doi.org/10.3390/molecules23010215] [PMID: 29351226]
[33]
Dong, K.; Zhang, M.; Liu, Y.; Gao, X.; Wu, X.; Shi, D.; Guo, C.; Wang, J. Pterostilbene-loaded soluplus/poloxamer 188 mixed micelles for protection against acetaminophen-induced acute liver injury. Mol. Pharm., 2023, 20(2), 1189-1201.
[http://dx.doi.org/10.1021/acs.molpharmaceut.2c00881] [PMID: 36647568]
[34]
Bergonzi, M.C.; Vasarri, M.; Marroncini, G.; Barletta, E. Degl’Innocenti, D. Thymoquinone-loaded soluplus®-Solutol® HS15 mixed micelles: Preparation, In vitro characterization, and effect on the SH-SY5Y cell migration. Molecules, 2020, 25(20), 4707.
[http://dx.doi.org/10.3390/molecules25204707] [PMID: 33066549]
[35]
Shen, H.; Liu, Y.; Zhang, H.; Ding, P.; Zhang, L.; Zhang, L.; Ju, J. Enhancing the oral bioavailability of baicalein via Solutol® HS15 and Poloxamer 188 mixed micelles system. J. Pharm. Pharmacol., 2019, 71(5), 765-773.
[http://dx.doi.org/10.1111/jphp.13058] [PMID: 30549042]
[36]
Björnsson, E.S.; Hoofnpagle, J.H. Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports. Hepatology, 2016, 63(2), 590-603.
[http://dx.doi.org/10.1002/hep.28323] [PMID: 26517184]
[37]
Formica, D.; Sultana, J.; Cutroneo, P.M.; Lucchesi, S.; Angelica, R.; Crisafulli, S.; Ingrasciotta, Y.; Salvo, F.; Spina, E.; Trifirò, G. The economic burden of preventable adverse drug reactions: A systematic review of observational studies. Expert Opin. Drug Saf., 2018, 17(7), 681-695.
[http://dx.doi.org/10.1080/14740338.2018.1491547] [PMID: 29952667]
[38]
Cui, Y.; Han, Y.; Yang, X.; Sun, Y.; Zhao, Y. Protective effects of quercetin and quercetin-5′8-disulfonate against carbon tetrachloride-caused oxidative liver injury in mice. Molecules, 2013, 19(1), 291-305.
[http://dx.doi.org/10.3390/molecules19010291] [PMID: 24378968]
[39]
Ullah, H.; Khan, A.; Baig, M.W.; Ullah, N.; Ahmed, N.; Tipu, M.K.; Ali, H.; Khan, S. Poncirin attenuates CCL4-induced liver injury through inhibition of oxidative stress and inflammatory cytokines in mice. BMC Complement Med Ther., 2020, 20(1), 115.
[40]
Pu, W.; Bai, R.; Zhou, K.; Peng, Y.; Zhang, M.; Hottiger, M.O.; Li, W.; Gao, X.; Sun, L. Baicalein attenuates pancreatic inflammatory injury through regulating MAPK, STAT 3 and NF-κB activation. Int. Immunopharmacol., 2019, 72, 204-210.
[http://dx.doi.org/10.1016/j.intimp.2019.04.018] [PMID: 30999210]
[41]
Chao, J.; Xu, M.; Wang, X.; Guo, Z. Baicalein-p-sulfonatocalix[n]arenes inclusion complexes: Characterization, antioxidant ability and stability. Polym. Bull., 2019, 76(2), 989-1006.
[http://dx.doi.org/10.1007/s00289-018-2415-x]
[42]
Dai, C.; Li, H.; Wang, Y.; Tang, S.; Velkov, T.; Shen, J. Inhibition of oxidative stress and ALOX12 and NF-κB pathways contribute to the protective effect of baicalein on carbon tetrachloride-induced acute liver injury. Antioxidants, 2021, 10(6), 976.
[http://dx.doi.org/10.3390/antiox10060976] [PMID: 34207230]
[43]
Xiao, T.; Cui, Y.; Ji, H.; Yan, L.; Pei, D.; Qu, S. Baicalein attenuates acute liver injury by blocking NLRP3 inflammasome. Biochem. Biophys. Res. Commun., 2021, 534, 212-218.
[http://dx.doi.org/10.1016/j.bbrc.2020.11.109] [PMID: 33272570]
[44]
You, G.; Feng, T.; Zhang, G.; Chen, M.; Liu, F.; Sun, L.; Wang, M.; Ren, X. Preparation, optimization, characterization and in vitro release of baicalein-solubilizing glycyrrhizic acid nano-micelles. Int. J. Pharm., 2021, 601, 120546.
[http://dx.doi.org/10.1016/j.ijpharm.2021.120546] [PMID: 33794322]
[45]
Liu, S.; Gao, X.; Wang, Y.; Wang, J.; Qi, X.; Dong, K.; Shi, D.; Wu, X.; Guo, C. Baicalein-loaded silk fibroin peptide nanofibers protect against cisplatin-induced acute kidney injury: Fabrication, characterization and mechanism. Int. J. Pharm., 2022, 626, 122161.
[http://dx.doi.org/10.1016/j.ijpharm.2022.122161] [PMID: 36058409]
[46]
Yeh, Y.H.; Hsieh, Y.L.; Lee, Y.T. Effects of yam peel extract against carbon tetrachloride-induced hepatotoxicity in rats. J. Agric. Food Chem., 2013, 61(30), 7387-7396.
[http://dx.doi.org/10.1021/jf401864y] [PMID: 23841820]
[47]
Cao, M.; Wang, H.; Guo, L.; Yang, S.; Liu, C.; Khor, T.O.; Yu, S.; Kong, A.N. Dibenzoylmethane protects against CCl4-induced acute liver injury by activating Nrf2 via JNK, AMPK, and calcium signaling. AAPS J., 2017, 19(6), 1703-1714.
[http://dx.doi.org/10.1208/s12248-017-0133-1] [PMID: 28828752]
[48]
Cheng, N.; Ren, N.; Gao, H.; Lei, X.; Zheng, J.; Cao, W. Antioxidant and hepatoprotective effects of Schisandra chinensis pollen extract on CCl4-induced acute liver damage in mice. Food Chem. Toxicol., 2013, 55, 234-240.
[http://dx.doi.org/10.1016/j.fct.2012.11.022] [PMID: 23201450]
[49]
Chen, X.; Ding, H.W.; Li, H.D.; Huang, H.M.; Li, X.F.; Yang, Y.; Zhang, Y.L.; Pan, X.Y.; Huang, C.; Meng, X.M.; Li, J. Hesperetin derivative-14 alleviates inflammation by activating PPAR-γ in mice with CCl4-induced acute liver injury and LPS-treated RAW264.7 cells. Toxicol. Lett., 2017, 274, 51-63.
[http://dx.doi.org/10.1016/j.toxlet.2017.04.008] [PMID: 28428136]

Rights & Permissions Print Cite
Article Metrics
17
3
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy