目的 制备高载药量番荔素纳米混悬剂（ACGs-NSPs），并研究其对小鼠乳腺癌4T1移植肿瘤的生长抑制作用，为强效抗肿瘤药物ACGs的临床应用提供可用注射剂型。方法 番荔素、TPGS、SPC（质量比7:5:2）采用超声-沉淀法制备ACGs-NSPs，并用动态光散射法测定ACGs-NSPs的粒径，透射电镜观察其形态；稳定剂TPGS、SPC组成比例对ACGs-NSPs的溶血性考察；透析法考察其体外释放；采用MTT比色法评价ACGs-NSPs对4T1细胞细胞毒性；建立4T1乳腺癌皮下小鼠肿瘤模型，以紫杉醇注射液（PTX）为阳性对照，考察不同剂量ACGs-NSps静脉注射给药对4T1肿瘤的抗肿瘤药效。结果 ACGs-NSPs为表面光滑的球形，平均粒径为(129.03±1.03）nm，多分散指数PDI为0.134±0.03，zeta为（-17.7±0.16）mV，HPLC法测得番荔素线性回归方程为Y=0.157 2 X-0.363 2（R²=0.999），在5~200 μg/mL范围内显性关系良好，载药量高达（45.03±0.72）%；体外释放较为缓慢；MTT试验中，ACGs-NSPs对4T1乳腺癌的细胞毒性显著强于游离药物（IC⁵⁰，3.221 μg/mL vs 4.464 μg/mL，P<0.05）；4T1荷瘤小鼠的药效学实验中，ACGs-NSPs表现出剂量相关性的抑瘤作用，高、中、低剂量组（0.4、0.2、0.1 mg/kg）抑瘤率分别为76.09%、74.34%、42.03%；但高剂量组小鼠有死亡（3/10）。结论 成功制备高载药量的ACGs-NSPs，且其对4T1乳腺癌有显著的抑制作用；从药效和小鼠存活率来看，0.2 mg/kg为合适的给药剂量。

Objective To prepare annonaceous acetogenins (ACGs) nanosuspensions (ACGs-NSps) with high drug loading capacity and to study their anticancer efficacy on 4T1 breast cancer-bearing mice in vivo, so as to provide a suitable dosage form for the potent antitumor agent ACGs. Methods ACGs nanosuspensions were successfully prepared with ACGs, TPGS, and SPC (weight ratio of 7:5:2) using ultrasound-precipitation method. The particle size of ACGs nanosuspension was measured by dynamic light scattering method (DLS) and their morphology was observed by transmission electron microscope (TEM); The hymolysis of resultant ACGs-NSps was assessed; The in vitro drug release was evaluated using dialysis method; The in vitro cytotoxicity of ACGs solution and ACGs nanosuspensions against a breast cancer cell line (4T1 cells) were performed using MTT assay; The in vivo antitumor efficacy of ACGs-NSps was investigated on 4T1 breast cancer modelusing paclitaxel (PTX) as a positive control group. Results ACGs nanosuspensions were spherical with smooth surface and the average particle size of (129.03±1.03) nm. The polydispersity index (PDI) is (0.134±0.03), and Zeta protential was (-17.7±0.16) mV, ACGs linear regression equation was Y=0.157 2 X-0.363 2 (R²=0.999) measured by HPLC, dominant good relations within 5-200 μg/mL, and the average drug loading was (40.67±2.45)%. ACGs-NSPs showed sustained in vitro release with no burst effect. In MTT test, ACGs-NSps displayed significantly higher cytotoicity against 4T1 breast cancer cells than free drug (IC⁵⁰ of 3.221 μg/mL vs 4.464 μg/mL, P<0.05). According to the results of pharmacodynamics experiment on 4T1 breast cancer-bearing mice, ACGs-NSPs demonstrated a dose-dependent tumor inhibitory effect (76.09% for 0.4 mg/kg, 74.34% for 0.2 mg/kg, and 42.03% for 0.1 mg/kg, respectively). But there were three mice (3/10) died in the high dose group. Conclusion ACGs-NSps with high drug loading capacity are successfully prepared and show significant suppression against 4T1 breast cancer in vitro and in vivo. Judging from the in vivo antitumor efficacy and survival rate of mice, the dose of 0.2 mg/kg (iv administration) is recommended for the further in vivo study.

国家自然科学基金委（U1401223，81460734）