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浙江大学学报（医学版）
浙江大学学报（医学版）  2017, Vol. 46 Issue (2): 160-166    DOI: 10.3785/j.issn.1008-9292.2017.04.07
专题报道     
5-氟尿嘧啶—烟酰胺共晶的制备及其抗肿瘤活性研究
吴敏(),刘馨刚,薛宇,陈琪,胡秀荣,周峻,汤谷平*()
浙江大学化学系, 浙江 杭州 310027
Synthesis, characterization and antitumor activity of 5-fluorouracil-nicotinamide cocrystal
WU Min(),LIU Xingang,XUE Yu,CHEN Qi,HU Xiurong,ZHOU Jun,TANG Guping*()
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
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摘要：

目的：以烟酰胺（NCT）为共晶形成物制备5-氟尿嘧啶—烟酰胺共晶（5-Fu-NCT），对其理化特性和生物学性质进行研究。方法：采用冷却结晶法制备5-Fu-NCT共晶，用X射线粉末衍射法、核磁共振、红外光谱、差示扫描量热法等方法对其结构进行表征，用高效液相色谱法测定其溶解度，用MTT法、HE染色和细胞划痕实验测定其对肿瘤细胞活性的影响。结果：成功制备了5-FU-NCT，其特征衍射峰（2θ/°）为16.4、20.4、22.3、27.9、30.1。共晶溶解度为13.5 g/L。体外细胞试验结果表明，5-Fu和5-Fu-NCT作用于BEL-7402/5-Fu细胞的半数致死浓度值（IC50值）分别是129.6 μg/mL、42.6 μg/mL；细胞划痕试验、HE染色结果表明，5-Fu-NCT对耐5-Fu的BEL-7402/5-Fu细胞的毒性更强。结论：采用冷却结晶法成功制备了5-Fu-NCT。相比5-Fu，5-Fu-NCT对BEL-7402/5-Fu细胞有更强的抗肿瘤活性。
关键词： 工艺学，制药;  晶体;  药用制剂/化学;  烟酰胺/药理学;  5-氟尿嘧啶/药理学;  溶解度;  抗生素类，抗肿瘤/药理学    
Abstract:

Objective: To synthesize 5-fluorouracil-nicotinamide (5-FU-NCT) cocrystal and to investigate its physicochemical and biological properties. Methods: The cocrystal of 5-Fu-NCT was prepared through the cooling technology. PXRD, NMR, FTIR and DSC were used to characterize the structure of 5-FU-NCT cocrystal. Solubility was measured by HPLC method. Drug resistant human liver cancer BEL-7402/5-FU cells were treated with 5-FU-NCT cocrystal, the inhibition effect was tested by MTT and HE staining, and cancer cell migration was determined by scratch test. Results: According to PXRD, NMR, FTIR and DSC results, the cocrystal of 5-Fu-NCT had been synthesized successfully. The characteristic diffraction peaks (2θ/°) of the cocrystal were 16.4, 20.4, 22.3, 27.9 and 30.1. The solubility of 5-FU-NCT was 13.5 g/L as measured by HPLC. The antitumor activity tests showed that 5-FU-NCT cocrystal enhanced anticancer effect of 5-FU, and the IC50 of 5-FU and 5-FU-NCT was 129.6 μg/mL and 42.6 μg/mL, respectively. Conclusion: 5-Fu-NCT cocrystal have been synthesized successfully through the cooling technology and it shows an enhanced anticancer effect in comparison to 5-FU on BEL-7402/5-FU cells.
Key words: Technology, pharmaceutical    Lens, crystalline    Pharmaceutical preparations/chemistry    Niacinamide/pharmacology    Fluorouracil/pharmacology    Solubility    Antibiotics, anti antibiotics, Antineoplastic neoplastic/pharmacology
收稿日期: 2016-11-02 出版日期: 2017-10-31
基金资助: 国家自然科学基金（21374098）
通讯作者: 汤谷平     E-mail: wumin_chem@zju.edu.cn;tangguping@zju.edu.cn
作者简介: 吴敏(1988—)，女，博士研究生，主要从事医用学分子材料和药物在肿瘤治疗方面的研究；E-mail: wumin_chem@zju.edu.cn；http://orcid.org/0000-0002-3956-0107
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引用本文:

吴敏,刘馨刚,薛宇,陈琪,胡秀荣,周峻,汤谷平. 5-氟尿嘧啶—烟酰胺共晶的制备及其抗肿瘤活性研究[J]. 浙江大学学报（医学版）, 2017, 46(2): 160-166.

WU Min,LIU Xingang,XUE Yu,CHEN Qi,HU Xiurong,ZHOU Jun,TANG Guping. Synthesis, characterization and antitumor activity of 5-fluorouracil-nicotinamide cocrystal. J Zhejiang Univ (Med Sci), 2017, 46(2): 160-166.

链接本文:

http://www.zjujournals.com/xueshu/med/CN/10.3785/j.issn.1008-9292.2017.04.07    或    http://www.zjujournals.com/xueshu/med/CN/Y2017/V46/I2/160

图 1  5-Fu-NCT的合成示意图
图 2  5-Fu-NCT、5-Fu/NCT、NCT、和5-Fu的粉末X射线衍射图
图 3  5-Fu-NCT的一维氢谱(D2O)图
图 4  5-Fu-NCT、5-Fu/NCT、NCT及5-Fu的差示扫描量热图和5-Fu-NCT的热重图
图 5  5-Fu-NCT、5-Fu/NCT、NCT、5-Fu的红外光谱图
图 6  5-Fu-NCT、5-Fu/NCT、NCT、5-Fu的液相色谱图
图 7  5-Fu-NCT、5-Fu/NCT、NCT、5-Fu的溶解度曲线
图 8  加入共晶的细胞生存曲线(n=4)
图 9  各组与BEL-7402/5-Fu细胞株共孵育24 h后的HE染色结果
图 10  各组在BEL-7402/5-Fu细胞株划痕实验结果
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