天津医药

天津医药 ›› 2018, Vol. 46 ›› Issue (5): 499-504.doi: 10.11958/20180134

• 诊断技术 • 上一篇    下一篇

阿霉素修饰纳米银的制备及其体外抗肿瘤活性研究

杨丽军， 禇丽萍， 王婧， 任春华， 王中强， 黄帆   

  1. 北京协和医学院&中国医学科学院放射医学研究所， 天津市放射医学与分子核医学重点实验室 （邮编300192）
  • 收稿日期:2018-01-22 修回日期:2018-03-16 出版日期:2018-05-15 发布日期:2018-05-15
  • 通讯作者: 杨丽军 E-mail:yanglijunly@126.com
  • 基金资助:
    国家自然科学基金;国家自然科学基金;放射性核素标记药物及临床前药代动力学关键技术研发;天津市自然科学基金;“药物毒理与放射损伤药物山西省重点实验室”开放课题

Preparation of doxorubicin modified silver nanoparticle and its anti-tumor activity in vitro

YANG Li-jun, CHU Li-ping, WANG Jing, REN Chun-hua, WANG Zhong-qiang, HUANG Fan   

  1. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
  • Received:2018-01-22 Revised:2018-03-16 Published:2018-05-15 Online:2018-05-15

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摘要： 摘要： 目的 设计合成一类新型的具有pH响应性的阿霉素-纳米银 （DOX-Ag NPs） 联合抗肿瘤药物， 对其理化性质进行表征， 并研究其体外响应性释药行为和抗肿瘤活性。方法 通过硫辛酰肼 （LA-NHNH2 ） 连接纳米银 （Ag NPs） 和阿霉素 （DOX）， 得到DOX-Ag NPs。利用核磁氢谱 （1 H NMR） 和高分辨质谱 （HRMS） 对硫辛酰肼-阿霉素 （LA- NHN=DOX） 进行结构确证； 通过动态光散射 （DLS） 和透射电镜 （TEM） 分析纳米粒的粒径和形貌； 通过紫外-可见吸收光谱和荧光光谱表征纳米粒的光学性质； 通过透析法结合荧光光谱检测DOX-Ag NPs在不同pH下的DOX释放行为； 采用噻唑蓝比色法研究DOX-Ag NPs对HepG2肿瘤细胞的增殖抑制效果。结果 LA-NHN=DOX的1 H NMR数据及HRMS检测到746.275 6处的分子离子峰均证明LA-NHN=DOX成功合成。DOX-Ag NPs为粒径 （40.4±3.8） nm的球形纳米粒； 在弱酸性条件下DOX-Ag NPs能够快速响应性释放DOX； DOX-Ag NPs对HepG2肿瘤细胞增殖抑制呈现浓度依赖性， 当DOX浓度为0.5~20 mg/L （Ag浓度为0.45~18 mg/L） 时， DOX-Ag NPs组细胞生存率均明显低于DOX 组和Ag NPs组 （均P＜0.05）。结论 DOX-Ag NPs是一种具有pH响应性的联合抗肿瘤纳米制剂， 能在肿瘤组织快速释放DOX， 并通过与Ag NPs的协同治疗， 发挥良好的体外抗肿瘤作用。

关键词: 阿霉素, 纳米银, pH响应, 联合治疗, 抗肿瘤

Abstract: Abstract: Objective To design and synthesize a novel type of combined anti-tumor drug-doxorubicin modified silver nanoparticles (DOX-Ag NPs) with pH response, characterize its physical and chemical properties, and investigate its drug responsive release and anti-tumor activity in vitro. Methods DOX-Ag NPs were prepared by coupling silver nanoparticles (Ag NPs) with doxorubicin (DOX) via a LA-NHNH2 linker. The structure of LA-NHN=DOX was confirmed by nuclear magnetic resonance ( 1 H NMR) and high resolution mass spectrometry (HRMS). The particle size and micromorphology of the nanoparticles were detected by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The optical properties of the nanoparticles were characterized by UV-vis absorption spectroscopy and fluorescence spectroscopy. The DOX release kinetics of DOX-Ag NPs under different pH conditions were examined by dialysis method combined with fluorescence spectroscopy. The in vitro anti-tumor effects of DOX-Ag NPs were evaluated by MTT assay. Results DOX-Ag NPs were spherical nanoparticles with a particle size of (40.4 ± 3.8) nm. DOX-Ag NPs could rapidly release DOX under weak acid condition. DOX-Ag NPs significantly inhibited the proliferation and cell viability of HepG2 cells in concentration dependent manner. When DOX concentration was 0.5-20 mg/L (Ag concentration was 0.45-18 mg/L), the cell survival rate was significantly lower in DOX-Ag NPs group than that of DOX group and Ag NPs group (P < 0.05). Conclusion DOX-Ag NPs are a combined anti-tumor nano-drug with pH-responsive ability, which can release DOX rapidly in tumor tissues and play an anti-tumor effect through synergistic treatment with Ag NPs in vitro.

Key words: doxorubicin, silver nanoparticle, pH-responsive, combination therapy, anti-tumor