5-氟尿嘧啶—烟酰胺共晶的制备及其抗肿瘤活性研究

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。
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