活性氧响应型甲氨蝶呤修饰紫杉醇/淫羊藿苷胶束的工艺优化与体外抗肿瘤作用评价-中国药房

活性氧响应型甲氨蝶呤修饰紫杉醇/淫羊藿苷胶束的工艺优化与体外抗肿瘤作用评价

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篇名：	活性氧响应型甲氨蝶呤修饰紫杉醇/淫羊藿苷胶束的工艺优化与体外抗肿瘤作用评价
TITLE：	Technology optimization and in vitro anti-tumor effect evaluation of reactive oxygen species-responsive metho-trexate-modified paclitaxel/icariin micelles
摘要：	目的制备活性氧（ROS）响应型甲氨蝶呤（MTX）修饰紫杉醇（PTX）/淫羊藿苷（ICA）胶束（MTX-oxi-Ms@PTX/ICA），并对其进行工艺优化和体外抗肿瘤作用评价。方法通过协同毒性实验筛选PTX和ICA的协同毒性浓度范围。采用薄膜水合法制备胶束，通过响应面法优化其工艺，并评估按最优工艺制备的胶束的基本特性。考察胶束对小鼠肾癌细胞RENCA的细胞毒性、靶向性以及抑制侵袭和迁移的作用。结果协同毒性实验结果表明，PTX浓度为2.5～10μmol/L、ICA浓度为5～15μmol/L时表现出最强的协同毒性效果。MTX-oxi-Ms@PTX/ICA的最优工艺如下：聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物（So‐luplus®）质量为80mg，Soluplus®和维生素E琥珀酸酯聚乙二醇1000质量比为4∶1（mg/mg），二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-酮缩硫醇-聚乙二醇5000为2mg，二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-甲氨蝶呤为2mg，PTX为1mg，ICA为1.5mg，水合温度35°C，处方量为5mL。最优工艺条件下，3批MTX-oxi-Ms@PTX/ICA中2个药物的平均包封率为92.75%；其临界胶束浓度为0.0079mg/mL，粒径为（62.09±1.68）nm，多分散性指数为0.046±0.032，Zeta电位为（－2.47±0.15）mV；放置30d内，胶束粒度和多分散性指数均未发生明显变化；体外释放结果表明，MTX-oxi-Ms@PTX/ICA能够在氧化环境中更快地响应并释放药物。MTX-oxi-Ms@PTX/ICA对RENCA细胞的半数抑制浓度为（5.170±0.036）μmol/L；体外细胞摄取实验结果表明，与未修饰胶束相比，经MTX修饰的胶束对癌细胞具有更强的靶向效果，且其对RENCA细胞侵袭、迁移的抑制能力显著增强（P＜0.05）。结论成功制备了MTX-oxi-Ms@PTX/ICA胶束，该胶束具有较高的包封率、较低的临界胶束浓度和良好的稳定性；且其对RENCA细胞有较明显的细胞毒性，并具有抑制癌细胞侵袭、迁移的作用。
ABSTRACT：	OBJECTIVE To prepare reactive oxygen species （ROS）-responsive methotrexate （MTX）-modified paclitaxel （PTX）/icariin （ICA） micelles （MTX-oxi-Ms@PTX/ICA）， and perform technology optimization and in vitro anti-tumor effect evaluation. METHODS Synergistic toxicity concentration range of PTX and ICA was screened by synergistic toxicity test. The micelles were prepared by thin film hydration method， and their technology was optimized by response surface methodology. The fundamental characteristics of the micelles prepared by the optimal technology were evaluated. The micelles’ cytotoxicity， targeting ability to renal carcinoma RENCA cells of mice， and their inhibitory effects on invasion and migration were assessed. RESULTS Results of synergistic toxicity experiments demonstrated that the strongest synergistic effect occurred when PTX concentrations ranged from 2.5 to 10 μmol/L and ICA concentrations ranged from 5 to 15 μmol/L. The optimal technology of MTX-oxi-Ms@PTX/ ICA was determined to include 80 mg Soluplus®， Soluplus® and TPGS1000 mass ratio of 4∶1 （mg/mg）， 2 mg DSPE-PEG2000-TK- PEG5000， 2 mg DSPE-PEG2000-MTX， 1 mg PTX， and 1.5 mg ICA， with a hydration temperature of 35 ℃ and a formulation volume of 5 mL. Under the optimal conditions， average encapsulation efficiency of PTX and ICA in 3 batches of MTX-oxi- Ms@PTX/ICA reached 92.75%， the critical micelle concentration （CMC） was 0.007 9 mg/mL， the particle size was （62.09±1.68） nm， the polydispersity index （PDI） was 0.046±0.032， and the Zeta potential was （－2.47±0.15） mV. Within 30 days of placement， there was no significant change E-mail：yingqiang_1126@163.com in particle size and polydispersity index of micelle. In vitro release experiments showed that MTX-oxi-Ms@PTX/ICA released drugs more rapidly in oxidative environments. The half maximal inhibitory concentration of MTX-oxi-Ms@PTX/ICA against RENCA cells was （5.170±0.036） μmol/L. In vitro cellular uptake experiments indicated that compared with unmodified micelles， MTX modified micelles had stronger targeting effects on cancer cells， and also significantly enhanced the inhibitory ability of invasion and migration of RENCA cells （P＜0.05）. CONCLUSIONS MTX-oxi-Ms@PTX/ICA micelles are successfully prepared， which exhibit high encapsulation efficiency， low critical micelle concentration， and good stability. These micelles demonstrate significant cytotoxicity against RENCA cells and effectively inhibit cancer cell invasion and migration.
期刊：	2025年第36卷第03期
作者：	邹乃建；孔亮；常雷；万芃伯；姜晓琳；袁明殿；鹿英强
AUTHORS：	ZOU Naijian，KONG Liang，CHANG Lei，WAN Pengbo，JIANG Xiaolin，YUAN Mingdian，LU Yingqiang
关键字：	活性氧响应型胶束；甲氨蝶呤；靶向药物递送；紫杉醇；淫羊藿苷
KEYWORDS：	reactive oxygen species-responsive micelles； methotrexate； targeted drug delivery； paclitaxel； icariin
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