目的 制备聚多巴胺（PDA）修饰的载榄香烯（ELE）介孔二氧化硅纳米粒（D/MSN-ELE），并对其进行处方工艺优化、质量评价、体外释放、体外抗肿瘤活性及促进细胞凋亡能力研究。方法 通过溶液吸附法制备载榄香烯介孔二氧化硅纳米粒（MSN-ELE），聚合法制备聚多巴胺修饰的介孔二氧化硅纳米粒（D/MSN）和D/MSN-ELE，应用透射电子显微镜表征不同纳米粒的形态，热重分析计算PDA接枝率，HPLC法评价D/MSN-ELE载药量和包封率，透析袋法考察D/MSN-ELE的体外释放特性。采用MTT染色法，分析不同纳米粒对人胚胎成纤维HELF细胞和人非小细胞肺癌A549细胞的细胞毒性。采用流式细胞仪检测D/MSN-ELE活性氧水平和线粒体膜电位水平。结果 最优制备工艺为药物与载体比例6：1，温度为50℃，时间为8 h，此工艺条件下制备的D/MSN-ELE分布均一，粒径为（288.70±3.88）nm。其平均载药量和包封率分别为（11.58±0.73）%和（59.82±0.57）%。体外释药具有pH值响应性，累积释药量随pH值减小而增大。ELE、MSN-ELE和D/MSN-ELE对A549细胞的半数抑制浓度分别为91.29、27.56、6.02 μg/mL。活性氧及线粒体膜电位检测结果进一步表明D/MSN-ELE能促进肿瘤细胞凋亡。结论 优选工艺下的D/MSN-ELE具有较高的药物载药量、pH值响应性药物释放和大幅增强的抗肿瘤活性及促进细胞凋亡能力，为基于MSN的ELE药物靶向递送提供了进一步的实验基础。

Objective To prepare polydopamine-modified elemene-loaded mesoporous silica nanoparticles (D/MSN-ELE), and conduct research on formulation process optimization, quality evaluation, in vitro release, in vitro antitumor activity, and ability to promote apoptosis. Methods Elemene-loaded mesoporous silica nanoparticles (MSN-ELE) were prepared by solution adsorption method, D/MSN-ELE and polydopamine-modified mesoporous silica nanoparticles (D/MSN) were prepared by polymerization. The morphology of the nanoparticles was characterized by transmission electron microscopy. The PDA graft ratio was calculated by thermogravimetric analysis. The loading and encapsulation efficiency of D/MSN-ELE were evaluated using HPLC, the dialysis bag method was used to investigate the release characteristics in vitro of D/MSN-ELE. MTT staining was used to analyze the cytotoxicity of different nanoparticles on HELF and A549 cells. Flow cytometry was used to detect the levels of D/MSN-ELE reactive oxygen species and mitochondrial membrane potential. Results The optimal preparation process was the drug loading ratio of 6:1, the temperature was 50℃, and the time was 8 h. The D/MSN-ELE prepare under the process condition have a were uniform distribution with a particle size of (288.70±3.88) nm. The average drug loading and encapsulation efficiency were (11.58±0.73)% and (59.82±0.57)%, respectively. In vitro drug release was pH-responsive, and cumulative drug release increased with decreasing pH. The half-lethal concentrations of ELE, MSN-ELE and D/MSN-ELE on A549 cells were 91.29, 27.56 and 6.02 μg/mL, respectively. The detection results of reactive oxygen species and mitochondrial membrane potential further indicated that drug-loaded nanoparticles were able to promote tumor target cell apoptosis. Conclusion D/MSN-ELE under the optimized process has a higher drug loading, pH-responsive drug release and greatly enhanced antitumor activity. This study provides further experiments basis for tumor-targeted delivery of elemene drugs based on mesoporous silica nanoparticles.

R283.6

国家自然科学基金重点项目（81730108）；国家自然科学基金面上项目（81973635）；浙江省重大科技专项项目（2015C03055）；杭州市重大科研项目（20162013A07）；杭州市重大科研项目（20142013A63）