肿瘤微环境双重响应性水飞蓟宾纳米胶束体外抗乳腺癌活性及转移研究  

pH and GSH dual-responsive silybin nano-micelles for inhibition of breast cancer activity and metastasis in vitro

作　　者：贾玲玉 郝单丽 杨佳颖 谢冉 德格晶 易红[1] 臧琛[1] 赵钰 赵庆贺[1] 陈燕军[1] JIA Ling-yu;HAO Dan-li;YANG Jia-ying;XIE Ran;DE Ge-jing;YI Hong;ZANG Chen;ZHAO Yu;ZHAO Qing-he;CHEN Yan-jun(Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]中国中医科学院中药研究所,北京100700

出　　处：《药学学报》2023年第9期2785-2793,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金(81974461,22005344)。

摘　　要：肿瘤微环境的复杂特征为肿瘤治疗带来考验的同时也为新型治疗策略提供了新的途径。本研究合成了肿瘤微环境pH响应和谷胱甘肽(glutathione,GSH)响应的聚(2-乙基-2噁唑啉)-聚乳酸-二硫键聚β氨基酯[poly(2-ethyl-2-oxazoline)-poly(lactic acid)-SS-poly(β-amino ester),PEOz-PLA-SS-PBAE]三嵌段共聚物,通过薄膜水化法负载水飞蓟宾(silybin)制备胶束,以提高水飞蓟宾抗肿瘤活性。通过芘荧光探针法测定该聚合物的临界胶束浓度(critical micelle concentration,CMC)为1.8μg·mL^(-1)。动态光散射法测定胶束粒径为155.30±1.80 nm,多分散指数(polydispersity index,PDI)为0.168±0.004。HPLC测定胶束的载药量和包封率为(5.48±0.04)%和(68.52±0.48)%。其体外释放结果表现出胶束具有pH与GSH敏感性,具有缓释效果。通过测定空白胶束的溶血率和细胞毒性试验证明材料具有良好的生物相容性。载药胶束组细胞毒性实验和细胞凋亡实验表明PEOz-PLA-SS-PBAE载药胶束对MDA-MB-231细胞具有显著的抑制效果和诱导其凋亡的效果。细胞划痕实验与Transwell侵袭实验结果显示PEOz-PLA-SS-PBAE载药胶束能够显著抑制MDA-MB-231细胞的转移。因此,本研究制备的PEOz-PLA-SS-PBAE载药胶束具有良好的体外抑制肿瘤生长以及抗肿瘤转移的作用,为水飞蓟宾的进一步应用铺垫了基础。The clinical tumor therapy was greatly challenged due to the complex characteristics of tumor microenvironment,however,which also provide arena for novel therapeutic strategies.In this study,poly(2-ethyl-2-oxazoline)-poly(lactic acid)-SS-poly(β-amino ester(PEOz-PLA-SS-PBAE)triblock copolymers with pH and GSH double response were synthesized,polymer micelles were prepared by thin film hydration method for loading of silybin to improve its antitumor activity.The critical micelle concentration was determined by pyrene fluorescence method as 1.8μg·mL-1.The particle size was 155.30±1.80 nm as determined by dynamic light scattering,with polydispersity index of 0.168±0.004.The drug loading and entrapment efficiency of the micelles were determined by HPLC as(5.48±0.04)%and(68.52±0.48)%,respectively.The in vitro drug release profiles showed that the micelles have low pH sensitivity and high GSH responsiveness,and exhibited sustained release profiles.The good biocompatibility of the material was proved by measuring the hemolysis rate and cytotoxicity of the blank micelle.The cytotoxicity and apoptosis rate of tumor cells showed that the drug loaded PEOz-PLA-SS-PBAE micelles had significant inhibitory effect and apoptosis-inducing effect on MDA-MB-231 cells.The results of wounding healing assay and Transwell invasion test showed that the drug loaded PEOz-PLA-SS-PBAE micelles could significantly inhibit the metastasis of MDA-MB-231 cells.The PEOz-PLA-SS-PBAE drug-loaded micelles prepared in this study have good inhibitory effect on tumor growth and anti-tumor metastasis in vitro,which lays the foundation for the further application of silybin.

关 键 词：还原响应 PH敏感 胶束 水飞蓟宾 体外抑制肿瘤转移 

分 类 号：R944[医药卫生—药剂学]