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

Preparation,characterization and antitumor effects of cyclodextrin inclusion complexes of regorafenib

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一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一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,从而瑞戈非尼的生物利用度提高。

Objective： To prepare and characterize cyclodextrin inclusion complexes of regorafenib and to investigated their antitumor effects. Methods： Three inclusion complexes （RG-β-CD, RG-γ-CD, RG-Hp-β-CD） were prepared by reerystallization and solvent evaporation methods between regorafenib （RG） and γ-cyclodextrin （β- CD ）, γ-cyclodextrin （ γ-CD ） and hydroxypropyl-β-cyclodextrin （ Hp-β-CD ）,respectively. The compounds were characterized by Fourier transform infrared spectroscopy （FT-IR）, thermogravimetric analysis （TG）, differential scanning calorimetry （DSC）, powder X-ray diffraction （PXRD）, ^1H nuclear magnetic resonance （^1H-NMR）, nuclear overhauser effect spectroscopy （NOESY）. Human colon cancer SW620 cells were inoculated to Balb/c-nu nude mice, PBS, RG or RG-β-CD were given orally for 3 weeks, and the volumes of tumor were determined and compared among 3 groups. Results： The solubility and dissolution were improved after inclusion with 3 kinds of cyclodextrins. RG-β-CD had the best stability, followed by RG-β-CD inclusion. The in vivo study showed that the tumor suppressive effect of RG-β-CD was stronger than that of regorafenib. Conclusion： The bioavailability of regorafenib by inclusion with cyclodextrin is enhanced due to the increased solubility, which can provide an effective method for improving solubility and dissolution of antitumor agents.