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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): 144-152    DOI: 10.3785/j.issn.1008-9292.2017.04.05
专题报道     
抗肿瘤药物瑞戈非尼—环糊精包合物的制备及其生物学性质研究
刘开航(),孙梦莹,汤谷平,胡秀荣*()
浙江大学化学系, 浙江 杭州 310028
Preparation, characterization and antitumor of cyclodextrin inclusion of an anti-cancer drug regorafenib
LIU Kai-hang(),SUN Mengying,TANG Guping,HU Xiurong*()
Department of Chemistry, Zhejiang University, Hangzhou, 310012 China
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摘要：

目的：设计制备三种瑞戈非尼环糊精包合物，以改善瑞戈非尼的溶解度、溶出度和生物利用度。方法：采用重结晶、饱和水溶液等方法对瑞戈非尼—环糊精包合物的制备方法进行研究，通过傅里叶红外光谱、热重分析、X射线粉末衍射、核磁共振、核欧佛豪瑟效应频谱等方法对瑞戈非尼—环糊精包合物进行结构分析。并采用SW620结肠癌细胞荷瘤裸鼠模型考察其体内抑瘤效果。结果：瑞戈非尼被环糊精包合后溶解性能明显改善，溶出度从大到小依次为：瑞戈非尼-β-环糊精包合物>瑞戈非尼—羟丙基-β-环糊精>瑞戈非尼-γ-环糊精包合物。优选包合及溶出效果最好的瑞戈非尼-β-环糊精包合物进行裸鼠体内抑瘤试验，结果表明，瑞戈非尼-β-环糊精包合物抑瘤效果比瑞戈非尼明显提高。结论：难溶性药物瑞戈非尼被环糊精包合后其溶解度和溶出度改善，从而提高瑞戈非尼的生物利用度。
关键词： 蛋白激酶抑制剂;  β环糊精类;  药物调剂;  抗肿瘤药物;  溶解度;  生物利用度    
Abstract:

Objective: In order to improve the drug’s solubility, dissolution and bioavailability, RG-β-CD, RG-γ-CD and RG-Hp-β-CD were prepared by co-crystallization between Regorafenib (RG) and β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and Hydroxypropyl-β-cyclodextrin (Hp-β-CD). Methods: Three inclusion complexes were prepared by recrystallization and solvent evaporation methods and characterized by fourier transform infrared spectroscopy (FT-IR), thermal analysis (TG), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), 1H nuclear magnetic resonance (1H-NMR), nuclear overhauser effect spectroscopy (NOESY). In vivo experiments, tumor suppression assay were made with SW620 colon cancer cell. Results: The ability of solubility and dissolution were improved after inclusion with three kinds of cyclodextrins. The regorafenib-β-cyclodextrin inclusionis proved to have the best stability. The less enhanced was regorafenib-γ-cycl-odextrin inclusion. The best dissolution of regorafenib-β-cyclodextrin inclusion complex was to bring as the tumor suppression assay, the result shows that regorafenib inclusion with β-cyclodextrin is better than regorafenib itself. Conclusion: The bioavailability of regorafenib by inclusion with cyclodextrin can enhance due to the solubility enhancement of RG, which can provide an effective method for improving solubility and dissolution of insoluble drug in clinical medication.
Key words: Protein kinase inhibitors    Beta-cyclodextrins    Drug compounding    Antineoplastic agents    Solubility    Biological availability
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: 胡秀荣     E-mail: liukaihang@zju.edu.cn;huxiurong@zju.edu.cn
作者简介: 刘开航(1991—)，男，硕士研究生，主要从事药物多晶型的研究；E-mail：liukaihang@zju.edu.cn；http://orcid.org/0000-0002-1216-2205
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引用本文:

刘开航,孙梦莹,汤谷平,胡秀荣. 抗肿瘤药物瑞戈非尼—环糊精包合物的制备及其生物学性质研究[J]. 浙江大学学报（医学版）, 2017, 46(2): 144-152.

LIU Kai-hang,SUN Mengying,TANG Guping,HU Xiurong. Preparation, characterization and antitumor of cyclodextrin inclusion of an anti-cancer drug regorafenib. J Zhejiang Univ (Med Sci), 2017, 46(2): 144-152.

链接本文:

http://www.zjujournals.com/xueshu/med/CN/10.3785/j.issn.1008-9292.2017.04.05    或    http://www.zjujournals.com/xueshu/med/CN/Y2017/V46/I2/144

图 1)  瑞戈非尼、环糊精及其包合物的粉末衍射图
图 2  瑞戈非尼、各种环糊精及两者包合物的热重和差示扫描量热图
图 3  瑞戈非尼、环糊精与瑞戈非尼包合物的傅里叶红外图谱
图 4  瑞戈非尼、β-环糊精、γ-环糊精和羟丙基-β-环糊精及与瑞戈非尼包合物的核磁共振氢谱
图 5  瑞戈非尼-β-环糊精包合物、瑞戈非尼-γ-环糊精包合物和瑞戈非尼—羟丙基-β-环糊精包合物的核欧佛豪瑟效应频谱
图 6  瑞戈非尼环糊精包合物示意图
图 7  瑞戈非尼与环糊精包合物在水、酸性溶液和磷酸缓冲液中的体外溶出速率曲线
图 8  瑞戈非尼及瑞戈非尼-β-环糊精包合物组肿瘤生长抑制曲线
图 9  给药21 d后，各组离体肿瘤对比图
图 10  瑞戈非尼及瑞戈非尼-β-环糊精给药后荷瘤裸鼠体质量变化曲线
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