活性氧响应型鬼臼毒素聚合物前药胶束的制备及其抗口腔癌活性  

Preparation of Reactive Oxygen Species Responsive Podophyllotoxin Polymeric Prodrug Micelles and Its Anti-oral Cancer Effect

作　　者：苗健 孙丽[1,2] 高雷[1,2] 王丽丽[1,2] 董振科[3] MIAO Jian;SUN Li;GAO Lei;WANG Lili;DONG Zhenke(Department of Pharmacy,Hefei Stomatological Hospital,Hefei 230000,China;Hefei Stomatological Clinical College,Anhui Medical University,Hefei 230000,China;Beijing Mundipharma Pharmaceutical Company Limited,Hefei 230001,China)

机构地区：[1]合肥市口腔医院药剂科,合肥230000 [2]安徽医科大学合肥口腔临床学院,合肥230000 [3]萌蒂(中国)制药有限公司,合肥230001

出　　处：《医药导报》2024年第11期1782-1790,共9页Herald of Medicine

摘　　要：目的制备基于透明质酸(HA)活性氧(ROS)响应型鬼臼毒素(POD)聚合物前药胶束(HTP-M),并考察其抑制口腔鳞状细胞癌(OSCC)效果。方法采用两步酯化法合成基于HA的ROS响应型POD聚合物前药HA-TK-POD,采用透析法制备聚合物前药胶束HTP-M,并对其形态特征、粒径、电位和载药量进行表征,同时考察ROS响应性药物释放。以SCC-9细胞和荷瘤小鼠为模型,考察HTP-M体内外抗肿瘤效果。结果磁共振氢谱(^(1)H-NMR)证实HA-TK-POD聚合物前药成功合成。所得HTP-M胶束呈类球形,粒径(126.1±3.5)nm,分布均一,Zeta电位(-26.8±1.9)mV。HTP-M载药量(12.3±0.8)%,具有良好ROS响应性。HTP-M可特异性靶向CD44高表达的SCC-9细胞,具有良好的体内外抗肿瘤效果。结论制备了一种基于HA的ROS响应型POD聚合物前药胶束HTP-M,其具有良好的ROS响应性,并可有效抑制OSCC,为临床OSCC的治疗提供了新策略。Objective To prepare hyaluronic acid(HA)-based reactive oxygen species(ROS)responsive podophyllotoxin(POD)polymeric prodrug micelle HTP-M,and to investigate its inhibitory activity on oral squamous cell carcinoma(OSCC)SCC-9 cells.Methods The HA-based ROS-responsive POD polymeric prodrug HA-TK-POD was synthesized by a two-step esterification method.The polymer prodrug micelle HTP-M was prepared by dialysis method,and its morphological characteristics,particle size,Zeta potential,and drug loading efficiency were measured.Meanwhile,the ROS-responsive drug release was also investigated.The in vitro and in vivo antitumor efficiency of HTP-M micelles was evaluated using SCC-9 cells and SCC-9-tumor-bearing mice as the models.Results The successful synthesis of HA-TK-POD polymer prodrug was confirmed by^(1)H-NMR.The obtained HTP-M micelles have a spherical morphology and uniform distribution,and their particle size and zeta potential were(126.1±3.5)nm and(-26.8±1.9)mV,respectively.Moreover,the HTP-M micelles have a high drug loading efficiency(12.3±0.8)%with good ROS responses.HTP-M can specifically target to CD44 overexpression cancer cells,and showed good anticancer effect in vitro and in vivo.Conclusion A ROS-responsive POD polymer prodrug micelle HTP-M based on HA has been prepared in this paper,which has good ROS response and can effectively inhibit the proliferation of OSCC cells and tumor-bearing mice.This work provides a new strategy for the treatment of clinical OSCC.

关 键 词：鬼臼毒素 活性氧响应型 聚合物前药胶束 口腔鳞状细胞癌 药物递送系统 

分 类 号：R979.1[医药卫生—药品] R965[医药卫生—药学] R943