紫杉醇脂质体的制备及初步毒性、药效学研究

 目的 制备紫杉醇脂质体并对其理化性质、毒性及药效学进行初步研究。方法 将大豆卵磷脂（soybean Phosphatidylcholine,SPC）、培化磷脂酰乙醇胺（mPEG2000-DSPE）及紫杉醇以100∶0.5∶5（摩尔比）混合并溶解于氯仿中,采用油水相研磨成乳,然后高压均质的方法制备脂质体。采用低速离心法测定包封率,动态光散射法测定粒度分布,KM鼠进行毒性实验,H22/KM小鼠为模型进行药效实验。结果 脂质体平均粒径为（140±10） nm;药脂摩尔比在3%～6%内包封率均大于95%;毒性实验表明,紫杉醇脂质体（Pac-lipo）和紫杉醇游离药（Pac-free）对KM雄性小鼠的最大耐受剂量（MTD）分别为64.8和29.4 mg·kg^-1;药效实验表明,紫杉醇脂质体剂量依赖性的抑制鼠肝癌H22肿瘤生长。结论 紫杉醇脂质体具有较高包封率,与紫杉醇游离药相比可以显著提高治疗指数。

Preparation of Liposomal Paclitaxel and Its Toxicity and Antitumor Effect

Objective To prepare the paclitaxel liposomes and evaluate its physicochemical property,toxicity and pharmacodynamics. METHODS SPC,mPEG2000-DSPE and paclitaxel were dissolved in chloroform in a mole ratio of 100:0.5:5. Oil phase and water phase were mixed and skived. The emulsion was homogenized to form liposomes. The mean diameter of liposomes was determined by dynamic light scattering (DLS) techniques. Low-speed centrifugation was employed to determine encapsulation efficiency (EE). The maximum tolerated doses (MTD) was determined in normal KM mice,and antitumor effect was evaluated in H22/KM mice xenograft tumor model. RESULTS The mean diameter of paclitaxel liposomes was （140±10） nm. The EE was over 95 % when the molar ratio of paclitaxel to SPC ranged from 3% to 6%. The MTDs of Pac-lipo and Pac-free in male KM mice were 64.8 and 29.4 mg·kg^-1,respectively. Pac-lipo inhibited H22 tumor weight dose-dependently．CONCLUSION Pac-lipo had a high EE,and could increase the therapeutic index significantly,compared with Pac-free.