人参皂苷Rk1修饰的伊曲康唑新型脂质体的构建及抗肿瘤活性初步研究

Construction of a Novel Itraconazole Liposome Modified by Ginsenoside Rk1 and Preliminary Studies on Its Antitumor Activity

关键词:  人参皂苷Rk1  伊曲康唑  脂质体  主动靶向  肿瘤

Key words:  ginsenoside Rk1  itraconazole  liposome  active targeting  tumor

摘要:

目的 制备一种人参皂苷Rk1修饰的伊曲康唑新型脂质体(R-ITZ-Lip)用于肿瘤治疗，并初步考察其体内外抗肿瘤药效。方法 采用逆向蒸发法制备R-ITZ-Lip，对其进行粒径、电位、包封率等表征研究；采用荧光显微镜和流式试验定性定量考察R-ITZ-Lip体外肿瘤细胞靶向性，采用活体和离体成像试验考察其体内肿瘤靶向性；采用MTT试验和肿瘤生长曲线考察其体内外药效。结果R-ITZ-Lip外观呈圆形，平均粒径为(124.67±2.05)nm，包封率为(97.49±1.93)%；体外细胞摄取试验结果表明，R-ITZ-Lip能够被乳腺癌细胞4T1特异性摄取，活体和离体成像结果表明R-ITZ-Lip在4T1异种移植小鼠模型的肿瘤部位分布显著增强；MTT试验表明R-ITZ-Lip对4T1细胞表现出较好的抑制作用，IC₅₀为1.37 μg·mL^-1，低于伊曲康唑胆固醇脂质体(C-ITZ-lip)的3.12 μg·mL^-1，4T1异种移植小鼠模型体内药效结果表明，R-ITZ-Lip有效地抑制了肿瘤的生长，R-ITZ-lip组的抑瘤率为83.54%，优于C-ITZ-lip组(73.87%)和ITZ注射液组(57.86%)。结论 构建了一种用于治疗肿瘤的R-ITZ-Lip，具有改善的制剂学性质，能够实现肿瘤的精准靶向，提高治疗效果。

Abstract:

OBJECTIVE To prepare a novel itraconazole liposome modified by ginsenoside Rk1(R-ITZ-Lip) for tumor therapy and investigate its antitumor efficacy in vitro and in vivo. METHODS R-ITZ-Lip was prepared by reverse evaporation method, and its particle size, Zeta potential, encapsulation efficiency were investigated. The in vitro and in vivo tumor targeting of R-ITZ-Lip was evaluated by fluorescence microscopy, flow cytometry and in vivo and in vitro imaging experiments. MTT cytotoxicity tests and tumor growth inhibitory rate were used to evaluate the antitumor efficacy in vitro and in vivo. RESULTS R-ITZ-Lip showed a rounded morphology with average particle size of (124.67±2.05)nm and encapsulation efficiency of (97.49±1.93)%. The cellular uptake experiments showed that R-ITZ-Lip could be better taken up by mouse triple-negative breast cancer 4T1 cells, and the in vivo and in vitro fluorescence imaging results showed that the distribution of R-ITZ-Lip in tumor sites was significantly enhanced in 4T1 xenograft mouse model. In the MTT cytotoxicity tests, R-ITZ-Lip showed concentration-dependent cytotoxicity to 4T1 cells with IC₅₀ of 1.37 μg·mL^-1, which was much lower than that of 3.12 μg·mL^-1 of the itraconazole cholesterol liposomes(C-ITZ-Lip). In the 4T1 xenograft model, R-ITZ-Lip more effectively inhibited the tumor growth, angiogenesis and malignant proliferation of tumor cells. The tumor inhibition rate of R-ITZ-lip group was 83.54%, which was significantly better than that of C-ITZ-lip group(73.87%) and ITZ injection group(57.86%). CONCLUSION R-ITZ-Lip is constructed for tumor therapy, which exhibits the characteristics of improved pharmacologic properties, precise tumor targeting and enhanced therapeutic effect.