目的 根据中医治疗肿瘤时提倡的“扶正祛邪”治则，选用中药人参和大黄的主要成分人参皂苷Rg₃（ginsenoside Rg₃，G-Rg₃）和大黄酸（rhein，Rhe）进行组合，制备G-Rg₃/Rhe纳米乳（G-Rg₃/Rhe NE），同时提高G-Rg₃和Rhe溶解度以利于注射给药，并利用该纳米乳联合程序性死亡受体配体1单抗（anti-programmed cell death ligand 1，aPD-L1）治疗三阴性乳腺癌（triple negative breast cancer，TNBC）。方法 采用紫外分光光度法分别测定G-Rg₃和Rhe在不同辅料中的溶解能力，筛选出合适的乳化剂、助乳化剂和油相。利用伪三元相图考察乳化剂与助乳化剂质量比（K_m值）对纳米乳体系的影响，根据形成纳米乳区域面积大小选择适宜的K_m值，优选G-Rg₃/Rhe NE的处方，并对其进行表征和稳定性评价。选用4T1^Fluc原位乳腺肿瘤小鼠模型，评价G-Rg₃/Rhe NE联合aPD-L1抗TNBC的效果。结果 G-Rg₃/Rhe NE的优化组分比为聚氧乙烯氢化蓖麻油EL35-聚乙二醇400-辛癸酸甘油酯-水，其质量比为1.33∶2.67∶2.80∶12.50，K_m值为1∶2，G-Rg₃/Rhe NE的平均粒径为（84.8±1.1）nm，多分散性系数（polydispersity index，PDI）为0.21±0.02，ζ电位为（−11.30±0.43）mV。载药纳米乳中G-Rg₃、Rhe的包封率分别为96.51%、97.47%，两药共载的载药量为0.75%。G-Rg₃/Rhe NE联合aPD-L1，能显著抑制荷4T1^Fluc小鼠的肿瘤生长。结论 G-Rg₃/Rhe NE粒径均一、稳定性好，可联合aPD-L1增强其抗TNBC的效果。

Objective According to the "supporting healthy energy to eliminate evils" treatment principle advocated by traditional Chinese medicine in the treatment of tumors, the main components ginsenoside Rg₃ (G-Rg₃) and rhein (Rhe) in ginseng and rhubarb, respectively, were selected to prepare G-Rg₃/Rhe nanoemulsion. At the same time, the solubility of G-Rg₃ and Rhe was improved to facilitate injection administration, and the nanoemulsion combined with anti-programmed cell death ligand 1 (aPD-L1) was used to treat triple negative breast cancer (TNBC).Methods The solubility of G-Rg₃ and Rhe in different excipients was determined by UV spectrophotometry, and the appropriate emulsifier, co-emulsifier and oil phase were screened out. The pseudo-ternary phase diagram was used to investigate the effect of K_m value on the nanoemulsion system, and the appropriate K_m value was selected according to the size of the nanoemulsion area. The prescription of G-Rg₃/Rhe NE was optimized, and its characterization and stability were evaluated. The 4T1^Fluc in situ mammary tumor mouse model was selected to evaluate the effect of G-Rg₃/Rhe NE combined with aPD-L1 on TNBC. Results The optimized component ratio of G-Rg₃/Rhe NE was as follows:polyoxyethylene hydrogenated castor oil EL35-polyethylene glycol 400-caprylic acid glyceride-water, and the mass ratio was 1.33:2.67:2.80:12.50, the K_m value was 1:2. The average particle size of G-Rg₃/Rhe NE was (84.8 ±1.1) nm, the polydispersity index (PDI) was 0.21 ±0.02, and the ζ potential was (−11.30 ±0.43) mV. The encapsulation rates of G-Rg₃ and Rhe in drug-carrying nanoemulsions were 96.51% and 97.47%, respectively, and the drug loading capacity of the two drugs was 0.75%. G-Rg₃/Rhe NE combined with aPD-L1 could significantly inhibit the tumor growth in 4T1^Fluc-bearing mice. Conclusion The G-Rg₃/Rhe NE was of uniform particle size and good stability, it could synergistically enhance the antitumor effect of aPD-L1 on TNBC.

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国家自然科学基金资助项目（82174095）；浙江省自然科学基金重点项目（Z22H296589）；浙江省医药卫生科技计划项目（2021KY813）；国家级大学生创新创业训练计划（202110344032）