聚乙二醇修饰的树状大分子负载卡巴他赛的制备工艺优化及抗肿瘤活性研究  

Optimization of preparation and antitumor activity of PEGylated dendrimer loaded cabazitaxel

作　　者：滕艺 韩尚聪 孙勇[1] TENG Yi;HAN Shang-cong;SUN Yong(School of Pharmacy,Qingdao University,Qingdao Shandong 266071)

机构地区：[1]青岛大学药学院,山东青岛266071

出　　处：《中南药学》2024年第6期1470-1478,共9页Central South Pharmacy

基　　金：青岛市关键技术攻关及产业化示范项目(No.23-3-3-hygg-25-hy)。

摘　　要：目的 制备一种高效递送卡巴他赛(CTX)的聚乙二醇(PEG)修饰树状大分子递送胶束(mPEG-PAMAM),优化处方和制备工艺。方法 聚酰胺-胺树状大分子(PAMAM)与PEG发生迈克尔加成反应得到mPEG-PAMAM胶束,经纳米沉淀法进行药物装载,通过红外光谱、核磁共振氢谱鉴定合成材料的结构;通过透射电镜和激光粒度仪观察载药胶束的外貌形态并测定其粒径、电位;高效液相色谱法测定其载药量、包封率等;通过MTT等实验考察其细胞毒性,共聚焦显微镜探究其细胞摄取情况;在动物水平上注射RM-1前列腺癌细胞构建小鼠肿瘤模型,探究其整体抑瘤能力。结果 mPEG-PAMAM@CTX胶束呈较规则的球形,平均粒径(162.8±0.7)nm,载药量6.58%,包封率61.12%,48 h内药物累计释放量达到86.8%;mPEG-PAMAM@CTX具有良好的细胞摄取,能有效地杀伤肿瘤细胞;在体内动物模型中,CTX经体内循环,主要富集在肿瘤部位,表明CTX能够通过mPEG-PAMAM胶束高效递送到RM-1肿瘤组织,且肿瘤抑制率为68.97%。结论 本研究制备的mPEG-PAMAM@CTX胶束能够有效提高CTX溶解度,增强肿瘤抑制效果,为难溶性药物递送的开发提供新的思路。Objective To prepare PEGylated dendrimer delivery micelles(mPEG-PAMAM)with high efficiency delivery of cabazitaxel(CTX),and optimize its formulation and preparation.Methods mPEG-PAMAM micelles were obtained by the Michael addition reaction of polyamide-amine dendrimer(PAMAM)with PEG.After the drug loading by nanoprecipitation method,the structure of mPEG-PAMAM was identified by IR and 1H NMR.The morphology,particle size and potential of the drug-loaded micelles were observed by transmission electron microscope and dynamic light scattering,and the drug loading and encapsulation efficiency were determined by HPLC.The cytotoxicity was determined by MTT assay and the cellular uptake of drug-loaded micelles by confocal microscopy.The mouse tumor model was established by injecting RM-1 prostate cancer cells at the animal level to determine the overall tumor inhibition ability.Results mPEG-PAMAM@CTX micelles had regular sphere with an average particle size of(162.8±0.7)nm,drug loading of 6.58%,and encapsulation efficiency of 61.12%.The drug release reached 86.8%within 48 h.mPEG-PAMAM@CTX had good cell uptake and effectively killed tumor cells.In the in vivo animal models,CTX mainly enriched in the tumor site through in vivo circulation,indicating efficient delivery of CTX to RM-1 tumor tissue by mPEG-PAMAM micelles,with the tumor inhibition rate of 68.97%.Conclusion The mPEG-PAMAM@CTX micellar prepared in this study can effectively improve the solubility of CTX and enhance tumor inhibiton,which provides new ideas for the development of drug delivery with poor solubility.

关 键 词：卡巴他赛 树状大分子 胶束 肿瘤抑制 

分 类 号：R943[医药卫生—药剂学] R96[医药卫生—药学]