【摘要】 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.更多还原

【Abstract】 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 × 105L / mol at pH = 7. 4). However,the adduct became less stable with low binding constant at acidic condition(1. 7 ×104L / 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 antitumor activity on human to hepatocellular carcinoma cell(HepG2),lung adenocarcinoma 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 molecular docking and fluorescence spectroscopy analysis. The possible inhibition mechanism of ATS- Tf adduct on cancer cells was also proposed.更多还原