唑来膦酸脂质体的制备及抗肿瘤活性研究

Preparation and antitumor activity of zoledronic acid liposomes

目的提高水溶性药物唑来膦酸脂质体(zoledronic acid liposomes,ZOL-LIPs)的包封率(encapsulation efficiency,EE)和载药量(drug loading,DL),降低给药剂量,增强ZOL-LIPs对乳腺癌细胞的抑制作用。方法采用逆向蒸发法制备ZOL-LIPs,通过Box-Behnken效应面法优化ZOL-LIPs的处方,用MTT法研究ZOL-LIPs对人乳腺癌MCF-7细胞的体外抑制作用。结果得到ZOL-LIPs的最优处方:药物与磷脂的质量比为0.067,磷脂与胆固醇的质量比为5.503,乙醚与PBS的体积比为1.941,其包封率为43.152%,载药量为2.257%,与预测值接近,其平均粒径为(197.3±1.7)nm,PDI为(0.170±0.027),且具有良好的缓释作用,稳定性强,与唑来膦酸水溶液相比,其对MCF-7细胞的抑制作用更强。结论采用Box-Behnken效应面法优化ZOLLIPs的处方所制备的ZOL-LIPs包封率高且粒径小,可使药物充分聚集于肿瘤组织而发挥EPR效应,为乳腺癌的治疗和预防其骨转移提供了新的方法。

Objective To improve the encapsulation efficiency(EE)and drug loading(DL)of water-soluble drug zoledronic acid liposome(ZOL-LIPs),reduce the dose,and improve the inhibitory effect of ZOL-LIPs on breast cancer cells.Methods ZOL-LIPs were prepared by reverse evaporation method,and the formulation conditions of ZOL-LIPs were optimized by Box-Behnken design.The inhibitory effect of ZOL-LIPs on human breast cancer MCF-7 cells in vitro was studied by MTT assay.Results The ratio of drug to lipid 0.067,the ratio of EPC to Chol 5.503,and the volume ratio of Vethyl to VPBS 1.941 were proved to be the optimal conditions of preparing ZOL-LIPs.The EE and DL of ZOL-LIPs prepared according to the optimal prescription were 43.152%and 2.257%,which were equivalent to the predicted values.The average particle size was(197.3±1.7)nm,and the PDI was(0.170±0.027).In addition,the ZOL-LIPs showed a sustained release effect,good stability,and indicated a stronger inhibitory effect on MCF-7 cells compared with zoledronic acid solutions.Conclusion The Box-Behnken design could be used to optimize and predict the formulation conditions of ZOL-LIPs with EE and DL as indicators.The high EE and small particle size of prepared ZOL-LIPs could enable ZOL fully aggregate in tumor tissue to exert EPR effect.Zoledronic acid may become a new approach for breast cancer treatment and prevention of bone metastases.