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

邹乃建; 孔亮; 常雷; 万芃伯; 姜晓琳; 袁明殿; 鹿英强

doi:10.6039/j.issn.1001-0408.2025.03.05

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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

药学研究 | 更新时间：2025-02-10

- 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
- Technology optimization and in vitro anti-tumor effect evaluation of reactive oxygen species-responsive methotrexate-modified paclitaxel/icariin micelles
- 中国药房 2025年36卷第3期页码：285-292
- 作者机构：
  
  1.辽宁中医药大学附属医院泌尿外科，沈阳　110032
  2.辽宁中医药大学药学院，辽宁大连　116600
- 作者简介：
  
  主治医师，硕士。研究方向：中西医结合治疗肾病。E-mail：zounaijian@126.com
  副主任医师。研究方向：中西医结合治疗肾病。 E-mail：yingqiang_1126@163.com
- 基金信息：
  
  国家自然科学基金项目(82204629)
- DOI：10.6039/j.issn.1001-0408.2025.03.05
  中图分类号： R943;R73-3
- 纸质出版日期：2025-02-15，
  
  收稿日期：2024-07-10，
  
  修回日期：2024-12-23，
  
  录用日期：2024-12-23
- 稿件说明：
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邹乃建,孔亮,常雷等.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 ^Δ[J].中国药房,2025,36(03):285-292.

ZOU Naijian,KONG Liang,CHANG Lei,et al.Technology optimization and in vitro anti-tumor effect evaluation of reactive oxygen species-responsive methotrexate-modified paclitaxel/icariin micelles[J].ZHONGGUO YAOFANG,2025,36(03):285-292.
邹乃建,孔亮,常雷等.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 ^Δ[J].中国药房,2025,36(03):285-292. DOI： 10.6039/j.issn.1001-0408.2025.03.05.

ZOU Naijian,KONG Liang,CHANG Lei,et al.Technology optimization and in vitro anti-tumor effect evaluation of reactive oxygen species-responsive methotrexate-modified paclitaxel/icariin micelles[J].ZHONGGUO YAOFANG,2025,36(03):285-292. DOI： 10.6039/j.issn.1001-0408.2025.03.05.

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2.5～10 μmol/L、ICA浓度为5～15 μmol/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（Soluplus

）质量为80 mg，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2 mg，二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-甲氨蝶呤为2 mg，PTX为1 mg，ICA为1.5 mg，水合温度35 °C，处方量为5 mL。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0.007 9 mg/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30 d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（

＜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 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 （

＜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.

关键词

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

methotrexatetargeted drug deliverypaclitaxelicariin

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