目的 以聚丙烯酸（polyacrylic acid，PAA）接枝的介孔二氧化硅纳米粒（mesporous silica nanoparticles，MSN）为核（PAA-MSN），采用薄膜水化法自组装形成Angiopep-2（氨基酸残基序列为TFFYGGSRGKRNNFKTEEY）修饰的功能化MSN脂质囊纳米粒（ANG-LP-PAA-MSN）。通过Angiopep-2与血脑屏障（blood brain barrier，BBB）和脑胶质瘤细胞上高表达的低密度脂蛋白相关受体1（LRP-1）特异性地识别、结合，旨在增加水溶性药物三氧化二砷（arsenic trioxide，As₂O₃）跨血脑屏障并靶向脑胶质瘤能力。方法 采用透射电子显微镜（TEM）、热重分析仪（TGA）等考察递药系统的理化性质和载药量，透析袋法考察其不同pH（pH 6.0、7.4）环境下的释药特征；噻唑蓝（MTT）比色法考察递药系统对人脑微毛细血管内皮细胞（HBMEC）和脑胶质瘤细胞（C6）毒性；通过构建体外BBB细胞模型研究载体对As₂O₃跨膜转运能力的影响。结果 该载药纳米粒（ANG-LP-PAA-MSN@As₂O₃）呈圆整的"核-壳"结构，分散性与稳定性良好，载药量为6.32%；PAA接枝后的递药系统突释现象显著改善并表现出pH响应特性；脂质囊包裹以后的递药系统显著提高了生物安全性，同时增加了药物的跨BBB转运率；体外抗肿瘤活性结果表明ANG-PAA-LP-MSN@As₂O₃具有较好的体外抗脑胶质瘤效果。结论 该智能靶向递药系统能够有效增加As₂O₃跨BBB转运，增加药物在脑胶质瘤部位的聚集，并实现肿瘤部位pH响应释放药物。

Objective To enhance the blood-brain barrier (BBB) penetration and glioma targeting ability of arsenic trioxide (As₂O₃), the lipid-coated mesoporous silica nanoparticles (MSN) modified with Angiopep-2 and polyacrylic acid (ANG-PAA-LP-MSN) is prepared by thin-film hydration method. This complex is specifically recognized and bound between ANG and low-density lipoprotein receptor-related protein-1 (LRP-1) which is highly expressed on BBB and glioma cells. Methods The drug delivery system characterization were analysed by transmission electron microscopy (TEM) and thermogravimetric analysis (TGA). Dialysis bag method was used to analyse the drug release characteristics at different pH conditions (pH 6.0 and 7.4, respectively). Cytotoxicity of nanocarriers and the antitumor activity in vitro of this drug delivery system were measured on human brain micro-capillary endothelial cells (HBMEC) and glioma cells (C6) by MTT assay. Moreover, in vitro cells model of BBB was established to study the effect of vehicle on the transmembrane transport of As₂O₃. Results The drug delivery system (ANG-PAA-LP-MSN@As₂O₃) was constructed successfully, it showed a rounded "core-shell" structure with good dispersibility and stability. The drug loading efficency was 6.32%. After PAA modification, this drug delivery system showed higher pH responsiveness to release medium, and the burst release of As₂O₃ was significantly reduced compared with that of unmodified group. Lipid coating could significantly improve the biosafety and penetration ability of BBB. The antitumor activity study showed that ANG-PAA-LP-MSN@As₂O₃ exhibited an ideal glioma inhibition effect in vitro. Conclusion This smart targeting drug delivery system enhance the BBB penetration ability of As₂O₃, and the special pH responsiveness demonstrated antitumor ability through increasing its accumulation in the tumor site.

国家自然科学基金资助项目："协同靶向"策略构建两性寡肽脂质体介导三氧化二砷前药脑胶质瘤胞药及机理研究（81673607），砒霜活性成分三氧化二砷脂质囊纳米粒脑胶质瘤深部渗透靶向递药系统研究（81473361），双重血栓靶向定位释放水蛭素融合蛋白基因给药系统的研究（81603303）；老年病中药新产品湖北省协同创新中心项目：基于LRP受体介导载三氧化二砷金属钯中空介孔二氧化硅脂质囊纳米粒的研究（15111903）；浙江省教育厅科研项目：阿霉素自组装纳米粒的制备及其脑内递药特性研究（Y201431480）；浙江省中医药优秀青年人才基金项目：马钱子总碱柔性传递体的制备及其透皮靶向递药研究（2018ZQ013）