黄连素衍生物（氟[<sup>19</sup>F]HX-01）体外靶向肝癌的初步研究 _Journal of Biomedical Engineering

Authors：

ZHANG Tong , WU Xiaoai , CAI Huawei , LIANG Meng ,  FAN Chengzhong

Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

FAN Chengzhong, Email: chengzhong.fan@scu.edu.cn

Keywords：

fluoro[¹⁹F] HX-01; berberine; human hepatocellular carcinoma cells; human normal hepatic cells; positron emission tomography imaging

DOI：

10.7507/1001-5515.201604025

Video：

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[¹⁸F]HX-01, a Fluorine-18 labeled berberine derivative, is a potential positron emission tomography (PET) tumor imaging agent, while [¹⁹F]HX-01 is a nonradioactive reference substance with different energy state and has the same physical and chemical properties. In order to collect data for further study of [¹⁸F]HX-01 PET imaging of hepatocellular carcinomain vivo, this study compared the uptake of [¹⁹F]HX-01 by human hepatocellular carcinoma and normal hepatocytesin vitro. The target compound, [¹⁹F]HX-01, was synthesized in one step using berberrubine and 3-fluoropropyl 4-methylbenzenesulfonate. Cellular uptake and localization of [¹⁹F]HX-01 were performed by a fluorescence microscope in human hepatocellular carcinoma HepG2, SMMC-7721 and human normal hepatocyte HL-7702. Cellular proliferation inhibition and cell cytotoxicity assay of the [¹⁹F]HX-01 were conducted using cell counting kit-8 (CCK-8) on HepG2, SMMC-7721 and HL-7702 cells. Fluorescent microscopy showed that the combining ability of [¹⁹F]HX-01 to the carcinoma SMMC-7721 and HepG2 was higher than that to the normal HL-7702. Cellular proliferation inhibition assay demonstrated that [¹⁹F]HX-01 leaded to a dose-dependent inhibition on SMMC-7721, HepG2, and HL-7702 proliferation. Cell cytotoxicity assay presented that the cytotoxicity of [¹⁹F]HX-01 to SMMC-7721 and HepG2 was obviously higher than that to HL-7702. Thisin vitro study showed that [¹⁹F]HX-01 had a higher selectivity on human hepatocellular carcinoma cells (SMMC-7721, HepG2) but has less toxicity to normal hepatocytes (HL-7702). This could set up the idea that the radioactive reference substance [¹⁸F]HX-01 may be worthy of further development as a potential molecular probe targeting human hepatocellular carcinoma using PET.

Citation： ZHANG Tong, WU Xiaoai, CAI Huawei, LIANG Meng, FAN Chengzhong. 黄连素衍生物（氟[¹⁹F]HX-01）体外靶向肝癌的初步研究 . Journal of Biomedical Engineering, 2017, 34(2): 253-259. doi: 10.7507/1001-5515.201604025 Copy

1.	Chen F X, Gao X S. Huanglian single prescriptions and Huanglian therapy. Chinese Traditional Patent Medicine, 1997b(19): 36-37.
2.	Hano K. The carcinostatic effects of some plant components and their related compounds. Acta Unio Int Contra Cancrum, 1959, 15(Suppl 1): 122.
3.	Tang J, Feng Y, Tsao S, et al. Berberine and coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmacol, 2009, 126(1): 5-17.
4.	Sun Y, Xun K, Wang Y, et al. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs, 2009, 20(9): 757-769.
5.	Tillhon M, Guamán Ortiz L M, Lombardi P, et al. Berberine: new perspectives for old remedies. Biochem Pharmacol, 2012, 84(10): 1260-1267.
6.	Zhang Xiaoling, Gu Lubing, Li Jiansha, et al. Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res, 2010, 70(23): 9895-9904.
7.	Liu Q, Jiang H, Liu Z, et al. Berberine Radio sensitizes human esophageal cancer cells by downregulating homologous recombination repair protein RAD51. PLoS One, 2011(6): e23427.
8.	Li J, Gu L, Zhang H, et al. Berberine represses DAXX gene transcription and induces cancer cell apoptosis. Lab Invest, 2013, 93(3): 354-364.
9.	Mei X L, Wu X A, Fan C Z, et al. Radiosynthesis of novel¹⁸F-berberine derivatives as potential tumor imaging agent//The 59th Society of Nuclear Medicine Annual Meeting, Miami Beach, Florida: 2012, 53 (Supplement 1):1680.
10.	梅小莉, 吴小艾, 张彤, 等. 18F-黄连素衍生物:一种潜在的 PET/CT 肿瘤靶向分子显像剂. 生物医学工程学杂志, 2015, 32(2): 460-464.
11.	LIU Bing, WANG Genshu, YANG Jie, et al. Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes. PLoS One, 2011, 6(6): e21416.
12.	Long N M, Smith C S. Causes and imaging features of false positives and false negatives on F-PET/CT in oncologic imaging. Insights Imaging, 2011, 2(6): 679-698.
13.	Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, 2008, 57(5): 712-717.
14.	WEI Wei, ZHAO Hongmin, WANG Aili, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol, 2012, 166(1): 99-105.
15.	Pereira G C, Branco A F, Matos J A, et al. Mitochondrially targeted effects of berberine [Natural Yellow 18, 5, 6-dihydro-9, 10-dimethoxybenzo(g)-1, 3-benzodioxolo(5, 6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. J Pharmacol Exp Ther, 2007, 323(2): 636-649.
16.	Serafim T L, Oliveira P J, Sardao V A, et al. Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line. cancer Chemother Pharmacol, 2008, 61(6): 1007-1018.
17.	Singh I P, Mahajan S. Berberine and its derivatives:a patent review (2009-2012). Expert Opin Ther Pat, 2013, 23(2): 215-231.
18.	Diogo C V, Machado N G, Barbosa I A, et al. Berberine as a promising safe anti-cancer agent-is there a role for mitochondria? Curr Drug Targets, 2011, 12(6): 850-859.

1. Chen F X, Gao X S. Huanglian single prescriptions and Huanglian therapy. Chinese Traditional Patent Medicine, 1997b(19): 36-37.
2. Hano K. The carcinostatic effects of some plant components and their related compounds. Acta Unio Int Contra Cancrum, 1959, 15(Suppl 1): 122.
3. Tang J, Feng Y, Tsao S, et al. Berberine and coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmacol, 2009, 126(1): 5-17.
4. Sun Y, Xun K, Wang Y, et al. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs, 2009, 20(9): 757-769.
5. Tillhon M, Guamán Ortiz L M, Lombardi P, et al. Berberine: new perspectives for old remedies. Biochem Pharmacol, 2012, 84(10): 1260-1267.
6. Zhang Xiaoling, Gu Lubing, Li Jiansha, et al. Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res, 2010, 70(23): 9895-9904.
7. Liu Q, Jiang H, Liu Z, et al. Berberine Radio sensitizes human esophageal cancer cells by downregulating homologous recombination repair protein RAD51. PLoS One, 2011(6): e23427.
8. Li J, Gu L, Zhang H, et al. Berberine represses DAXX gene transcription and induces cancer cell apoptosis. Lab Invest, 2013, 93(3): 354-364.
9. Mei X L, Wu X A, Fan C Z, et al. Radiosynthesis of novel¹⁸F-berberine derivatives as potential tumor imaging agent//The 59th Society of Nuclear Medicine Annual Meeting, Miami Beach, Florida: 2012, 53 (Supplement 1):1680.
10. 梅小莉, 吴小艾, 张彤, 等. 18F-黄连素衍生物:一种潜在的 PET/CT 肿瘤靶向分子显像剂. 生物医学工程学杂志, 2015, 32(2): 460-464.
11. LIU Bing, WANG Genshu, YANG Jie, et al. Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes. PLoS One, 2011, 6(6): e21416.
12. Long N M, Smith C S. Causes and imaging features of false positives and false negatives on F-PET/CT in oncologic imaging. Insights Imaging, 2011, 2(6): 679-698.
13. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, 2008, 57(5): 712-717.
14. WEI Wei, ZHAO Hongmin, WANG Aili, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol, 2012, 166(1): 99-105.
15. Pereira G C, Branco A F, Matos J A, et al. Mitochondrially targeted effects of berberine [Natural Yellow 18, 5, 6-dihydro-9, 10-dimethoxybenzo(g)-1, 3-benzodioxolo(5, 6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. J Pharmacol Exp Ther, 2007, 323(2): 636-649.
16. Serafim T L, Oliveira P J, Sardao V A, et al. Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line. cancer Chemother Pharmacol, 2008, 61(6): 1007-1018.
17. Singh I P, Mahajan S. Berberine and its derivatives:a patent review (2009-2012). Expert Opin Ther Pat, 2013, 23(2): 215-231.
18. Diogo C V, Machado N G, Barbosa I A, et al. Berberine as a promising safe anti-cancer agent-is there a role for mitochondria? Curr Drug Targets, 2011, 12(6): 850-859.

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黄连素衍生物（氟[¹⁹F]HX-01）体外靶向肝癌的初步研究