目的 制备番荔素亚微乳，并进行体内外抗肿瘤作用研究，为番荔素的口服给药提供可行方案。方法 以离心稳定常数（Ke）为指标，采用正交试验对注射用大豆油的用量、混合乳化剂总量和混合乳化剂的质量比进行考察，优化最佳处方配比。考察纳米乳匀机的运转压力和运转次数对番荔素亚微乳的粒径大小和分布的影响，优化工艺参数。透射电镜观察最佳工艺所得番荔素亚微乳，考察其在生物介质中的稳定性。采用噻唑蓝（MTT）比色法评价番荔素亚微乳对鼠乳腺癌4T1、人黑色素瘤A875细胞和人肝癌细胞HepG2的细胞毒性。建立鼠源肝癌H22细胞实体瘤模型，小鼠ig番荔素亚微乳、番荔素油溶液，计算抑瘤率。结果 番荔素亚微乳的最佳处方配比和制备工艺为：注射用大豆油用量为10%，乳化剂总量为3%，其中精制蛋黄卵磷脂与聚山梨酯80质量比为8：2；均质压力为1 500 bar，均质次数为9次。番荔素亚微乳在人工胃肠液中稳定，呈球形，粒径较小，主要在100 nm左右。番荔素亚微乳对4T1、A875、HepG2细胞IC₅₀值分别为3.082、2.001、1.762μg/mL；ig给药1 mg/kg番荔素亚微乳与4 mg/kg油溶液对H22荷瘤鼠的抑瘤效果相当（65.0% vs 56.5%）。结论 番荔素亚微乳可以解决番荔素难溶于水、难于给药的问题，能在不降低疗效的同时将用药剂量降低到传统油溶液的1/4，在一定程度上具有增效减毒作用。

Objective To prepare annonaceous acetogenins submicroemulsion and study its anti-tumor activities in vitro and in vivo, so as to provide a feasible solution for oral administration of annonaceous acetogenins. Methods Centrifugal stability constant (Ke) was used as indexes, factors of formulation, such as the amount of soybean oil for injection, the total amount of mixed emulsifier, and the mass ratio of mixed emulsifier were optimized by orthogonal test. Effect of process parameters operation pressure and operation frequency on particle size and distribution of annonaceous acetogenins submicroemulsion were investigated. Annonaceous acetogenins submicroemulsion obtained by the best parameters was observed with TEM, and its stability in biological media was also investigated. MTT assay was used to evaluate the in vitro anticancer cytotoxic activity against mice breast cancer 4T1, human melanoma A875, and human hepatic cancer HepG2 cell lines. Solid tumor model on basis of murine hepatic cancer H22 cell were established and mice were ig administrated with annonaceous acetogenins submicroemulsion and oil solution to obtain the tumor inhibition rate. Results The optimal formulation was as following:10% injectable soy oil, 3% combinatorial emulsifier (the weight ratio of purified SPE:Tween 80 being 8:2 in the composition of the combinatorial emulsifier). The optimal homogenization condition was 1 500 bar for 9 cycles. Annonaceous acetogenins submicronemulsion showed good stability in artificial gastric and intestinal juice, and waas spherical, with smaller particle size, mainly around 100 nm. Annonaceous acetogenins submicronemulsion showed strong cytotoxicity against 4T1, AB75, and HepG2 cell lines with IC₅₀ values 3.082, 2.001, and 1.762 μg/mL, respectively. Annonaceous acetogenins submicronemulsion ig administration of 1 mg/kg achieved the same anti-tumor efficacy as that of 4 mg/kg of oil solution on H22 tumor-bearing mice (65.0% vs 56.5%). Conclusion Annonaceous acetogenins submicronemulsion effectively resolves poor solubility and difficulty to be delivered in vivo, and can reduce the dose to 1/4 in contrast to oil solution, and meanwhile maintain similar aiti-tumor efficacy.

国家自然科学基金资助项目（U1401223，81460734）