青蒿琥酯-转铁蛋白复合物抑制癌细胞增殖的初步研究

Proliferation inhibition study of artesunate-transferrin adduct on cancer cells

采用简单、快捷的药物配体自识别的方式制备了青蒿琥酯(ATS)-转铁蛋白(Tf)复合物(ATS-Tf).紫外-可见光谱分析表明:在正常生理条件(pH=7.4)下,ATS与Tf易自组装形成稳定的ATS-Tf复合物(结合常数K f为3.4×105L/mol);而在酸性条件(pH=5.5)下,结合能力相对变弱(K f=1.7×104L/mol),ATS易与Tf分离,具有良好的pH敏感性.同时研究了该复合物对细胞增殖的抑制作用,结果表明:ATS-Tf复合物对正常肝细胞L-02的毒性较低,而对人肺腺癌细胞A549、肝癌细胞HepG2和胃癌细胞MGC-803的增殖具有显著的抑制作用,表现出良好的靶向杀伤性,有望开发成新型靶向抗肿瘤药物.液相色谱法证实Tf增强了癌细胞对ATS的摄取能力.进一步通过分子对接模拟和荧光光谱分析对ATS与Tf的结合模式和机理进行了研究,提出了ATS-Tf靶向抑制癌细胞增殖的可能机理.研究为青蒿琥酯靶向抗肿瘤药物的研发提供了理论支持和实验依据,在癌症治疗领域具有良好的应用前景.

Artesunate-transferrin（ATS- Tf） adduct was prepared through drug-ligand self-assembly. UV-vis spectrum analysis showed that ATS- Tf adduct can be easily formed with relatively high binding constant at neutral pH（3.4 × 10^5 L/mol at pH = 7.4）. However, the adduct became less stable with low binding constant at acidic condition（ 1.7 ×10^4 L/mol at pH = 5.5 ）. Proliferation inhibition studies of ATS - Tf adduct on cancer cells and normal cells showed that the ATS - Tf adduct had better antitu- mor activity on human to hepatoeellular carcinoma cell （HepG2） ,lung adenoearcinoma cell （ A549 ）, and gastric carcinoma cell （ MGC -803 ）, while it had low toxicity on normal human liver cell（ L -02 ）. HPLC analysis confirmed that the incorporation of Tf increased the uptake of ATS by cancer cells. The interactive model and mechanism of ATS with Tf were further studied by molecu- lar docking and fluorescence spectroscopy analysis. The possible inhibition mechanism of ATS - Tf adduct on cancer cells was also proposed.