高载药量斑蝥素聚合物胶束递送系统制备及其抗乳腺癌研究

刘丝露; 白云; 王建华; 张可青; 孙艳雪; 张可欣; 徐鹏程

doi:10.11665/j.issn.1000-5048.2023102501

高载药量斑蝥素聚合物胶束递送系统制备及其抗乳腺癌研究

Preparation of high-drug-loading cantharidin polymer micelle delivery system and its anti-breast cancer activity

摘要

摘要: 为制备高载药量的斑蝥素聚合物胶束给药系统（CTD@Sol），并初步探讨该给药系统抗乳腺癌的可行性。首先，以聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物（Sol）为载体材料，以斑蝥素（CTD）为模型药物，采用溶剂注入法制备得到CTD@Sol，并对其外观形貌、粒径、电位、体外释放度等药剂学属性进行评价。通过MTT法、Annexin V-FITC/PI双染法考察了CTD@Sol对乳腺癌（4T1）细胞的生长抑制及凋亡情况；利用流式细胞术研究了4T1对该给药系统的摄取效率；通过小动物活体成像考察了给药系统在体内的组织分布及对肿瘤组织的靶向性。结果表明，CTD@Sol外观呈微弱淡蓝色乳光，平均粒径为（159.73 ± 1.96）nm、PDI为0.198 ± 0.006、Zeta电位为 –（47.60 ± 1.77）mV、包封率为（90.29 ± 1.69）%、载药量为（45.00 ± 0.84）%；体外释放及溶血实验表明，相较于中性环境（pH 7.4）下，CTD@Sol在酸性环境（pH 5.5）下药物明显加速释放，提示该体系具有细胞内吞体pH条件下的酸敏感性和良好的生物安全性。细胞摄取、细胞毒、凋亡实验表明，CTD@Sol对4T1细胞更具有杀伤力，且Sol聚合物胶束作为药物递送载体能显著增强细胞对药物的摄取效率；体内实验表明该递送系统对肿瘤组织具有显著的靶向性。综上，本研究成功制备了高载药量（> 45%）CTD@Sol给药系统，该系统药剂学性能良好，靶向性强，生物安全性良好，具有应用于乳腺癌治疗的潜力。

Abstract: The aim of this study was to prepare a high drug-carrying capacity micellar drug delivery system (CTD@Sol) of the polymer zebra tetracycline and to preliminarily investigate the feasibility of this drug delivery system for the treatment of breast cancer. Firstly, CTD@Sol was prepared using sol as the carrier material and CTD as the model drug, and its pharmacological properties such as appearance and morphology, particle size, potential and in vitro release were evaluated. The growth inhibitory and apoptotic effects of CTD@Sol on breast cancer (4T1) cells were investigated by MTT assay and Annexin V-FITC/PI double staining assay; the uptake efficiency of 4T1 to this delivery system was investigated by flow cytometry; and the in vivo tissue distribution of the delivery system and the targeting of tumour tissues were investigated by small animal in vivo imaging technique. The results showed that CTD@Sol appeared as a light pale blue creamy white colour, with an average particle size of (159.73 ± 1.96) nm, a PDI of 0.198 ± 0.006, Zeta potential of –(47.60 ± 1.77) mV, an encapsulation rate of (90.29 ± 1.69)% and a drug loading capacity of (45.00 ± 0. 84)%; the in vitro release and haemolysis experiments showed that the drug release rate of CTD@Sol in acidic environment (pH 5.5) was significantly faster than that in neutral environment (pH 7.4), suggesting that the system is acid-sensitive and has good biosafety under endocytosed pH conditions. Cellular uptake, cytotoxicity and apoptosis experiments showed that CTD@Sol was more lethal to 4T1 cells, and the sol-gel polymer micelles as a drug delivery vehicle could significantly improve the cellular uptake efficiency of the drug; in vivo experiments showed that the delivery system had a significant targeting effect on tumour tissues.In conclusion, this study has successfully produced a CTD@Sol drug delivery system with high drug loading capacity (>45%), good pharmacological performance, strong targeting and biosafety, which has the potential to be used in the treatment of breast cancer.

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