pH响应纳米载药系统DOX@MIL-101(Fe)-NH2/HA的制备及靶向抗肿瘤作用研究

Preparation and Targeted Antitumor Effect of pH Responsive Nanoscale Drug Delivery System DOX@MIL-101(Fe)-NH2/HA

关键词:  纳米金属有机骨架  环境刺激响应  靶向传输  透明质酸  阿霉素

Key words:  nano-metal organic framework  environmental stimulus response  targeted delivery  hyaluronic acid  doxorubicin

摘要:

目的 制备透明质酸(hyaluronan acid，HA)修饰的纳米金属有机框架MIL-101(Fe)-NH₂载药系统，并进行体外抗肿瘤活性评价。方法 采用溶剂热法制备MIL-101(Fe)-NH₂，通过物理吸附法制备HA修饰载阿霉素的DOX@MIL-101(Fe)- NH₂/HA(DMNH)。并利用扫描电子显微镜、X射线衍射仪、氮气吸附-脱附法等对所合成材料及载药系统进行表征。采用透析法考察了载药系统的体外释药行为，并利用激光共聚焦显微镜观察HepG2细胞对其摄取情况。结果 MIL-101(Fe)-NH₂形貌为规则的正八面体，比表面积和粒径分别为1 061.45 m²·g^-1和200 nm。载药后DMNH的尺寸均一，比表面积为205.84 m²·g^-1，粒径为300 nm。MIL-101(Fe)-NH₂的最佳载药率为65.3%，根据药物释放曲线，从装有阿霉素的MIL-101(Fe)-NH₂载药体系(DMN)、DMNH中释放阿霉素显示出时间和pH依赖性。细胞摄取试验结果显示DMNH较其他组别可以运输更多的阿霉素进入HepG2细胞。细胞毒性的结果证实在相同的药物浓度下，DMNH表现出更高的肿瘤细胞杀伤效率。结论 本研究制备的DMNH载药系统结构稳定、载药量和释药效率高，同时具有优异的肿瘤细胞靶向性及pH响应释放特性，在抗肿瘤药物靶向传输方面具有应用前景。

Abstract:

OBJECTIVE To prepare the drug delivery system of nano metal organic framework MIL-101(Fe)-NH₂ modified by hyaluronan(HA) and evaluate its antitumor activity in vitro. METHODS MIL-101(Fe)-NH₂ was prepared by solvothermal method. HA-modified doxorubicin-loaded DOX@MIL-101(Fe)-NH₂/HA(DMNH) was prepared by physical adsorption. Scanning electron microscopy, X-ray diffraction and nitrogen adsorption desorption method were characterized. In vitro drug release was investigated by dialysis method, and the uptake of HepG2 cells was detected by laser confocal scanning microscopy. RESULTS The morphology of MIL-101(Fe)-NH₂was regular octahedron. The specific surface area and particle size was 1 061.45 m²·g^-1 and 200 nm, respectively. The size of DMNH was uniform and the specific surface area was 205.84 m²·g^-1. The particle size was 300 nm. The optimal drug loading rate of MIL-101(Fe)-NH₂ was 65.3%. According to the drug release curve, the release of doxorubicin from doxorubicin-loaded DOX@MIL-101(Fe)-NH₂ drug delivery system and DMNH showed time and pH dependent pattern. Cell uptake assay showed that DMNH could transport more doxorubicin into HepG2 cells than other groups, and showed higher cytotoxicity at the same concentration. CONCLUSION The as-prepared drug delivery system DMNH exhibit stable structure, high drug loading and releasing efficiency, excellent tumor targeting and pH responsive releasing, and show great promising in targeted delivery of anticancer drugs.