目的 制備高載藥量番荔素納米混懸劑（ACGs-NSPs），并研究其對小鼠乳腺癌4T1移植腫瘤的生長抑制作用，為強效抗腫瘤藥物ACGs的臨床應用提供可用注射劑型。方法 番荔素、TPGS、SPC（質(zhì)量比7:5:2）采用超聲-沉淀法制備ACGs-NSPs，并用動態(tài)光散射法測定ACGs-NSPs的粒徑，透射電鏡觀察其形態(tài)；穩(wěn)定劑TPGS、SPC組成比例對ACGs-NSPs的溶血性考察；透析法考察其體外釋放；采用MTT比色法評價ACGs-NSPs對4T1細胞細胞毒性；建立4T1乳腺癌皮下小鼠腫瘤模型，以紫杉醇注射液（PTX）為陽性對照，考察不同劑量ACGs-NSps靜脈注射給藥對4T1腫瘤的抗腫瘤藥效。結(jié)果 ACGs-NSPs為表面光滑的球形，平均粒徑為(129.03±1.03）nm，多分散指數(shù)PDI為0.134±0.03，zeta為（-17.7±0.16）mV，HPLC法測得番荔素線性回歸方程為Y=0.157 2 X-0.363 2（R²=0.999），在5~200 μg/mL范圍內(nèi)顯性關系良好，載藥量高達（45.03±0.72）%；體外釋放較為緩慢；MTT試驗中，ACGs-NSPs對4T1乳腺癌的細胞毒性顯著強于游離藥物（IC⁵⁰，3.221 μg/mL vs 4.464 μg/mL，P<0.05）；4T1荷瘤小鼠的藥效學實驗中，ACGs-NSPs表現(xiàn)出劑量相關性的抑瘤作用，高、中、低劑量組（0.4、0.2、0.1 mg/kg）抑瘤率分別為76.09%、74.34%、42.03%；但高劑量組小鼠有死亡（3/10）。結(jié)論 成功制備高載藥量的ACGs-NSPs，且其對4T1乳腺癌有顯著的抑制作用；從藥效和小鼠存活率來看，0.2 mg/kg為合適的給藥劑量。

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.

國家自然科學基金委（U1401223，81460734）