基于碳点多功能纳米载药体系的制备及pH响应释药性能研究  

Preparation of a Multifunctional Nano-carrier System Based on Carbon Dots with pH-Triggered Drug Release

作　　者：杜方凯 徐江生 曾钫[1] 吴水珠[1] 

机构地区：[1]华南理工大学发光材料与器件国家重点实验室华南理工大学材料科学与工程学院,广州510640

出　　处：《化学学报》2016年第3期241-250,共10页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.21474031;21174040;21025415);中国博士后科学基金(No.2015M572305);国家重大科学研究计划(No.2013CB834702)资助~~

摘　　要：采用一步微波法成功制备了表面带氨基的荧光纳米碳点CDots,并通过酰胺化反应将靶向基团叶酸接枝到碳点表面,成功获得中间产物CDots-FA.在此基础上,通过已合成四臂端酰肼基化合物2与抗肿瘤药物阿霉素(DOX)连接,实现在碳点表面的阿霉素药物分子的化学键合,最终获得多功能纳米载药体系DOX-CDots-FA.利用原子力显微镜(AFM)、高分辨透射电镜(HR-TEM)和荧光光谱仪对荧光纳米碳点CDots的性能进行表征,并通过核磁共振、紫外-可见吸收光谱对DOX-CDots-FA结构、接枝率进行了表征.同时对纳米载药体系DOX-CDots-FA体外药物释放行为、细胞毒性及细胞摄取成像进行了系统的研究.结果表明,DOX-CDots-FA具有良好的p H响应性.叶酸靶向基团能加速DOX-CDots-FA被He La(FR+)细胞摄取,并表现出更强的细胞毒性.同时细胞摄入成像实验表明,在叶酸靶向作用下,DOX-CDots-FA通过内吞作用进入He La细胞,随后阿霉素被释放出来并进入细胞核区域,抑制细胞的生长,从而实现靶向治疗,降低毒副作用.A folated-functionalized nano-carrier system based on carbon dots was successfully synthesized for cancer cell-targeted drug delivery. In this report, using microwave-assisted assay the fluorescent CDots could be obtained via microwave-assisted pyrolysis of glycerol in the presence of 4,7,10-trioxa-1,13-tridecanediamine. The particle size of the CDots was confirmed by AFM and HR-TEM. The finding showed that the average diameter of CDots is about 4 nm. Incorporating（via a cleavable bond） an anticancer drug, which was Doxorubicin（DOX） in this study, and a targeting ligand（folic acid） onto carbon dot produces a more specific anticancer prodrug DOX-CDots-FA. The structure of the DOX-CDots-FA was characterized by 1H NMR and UV-vis analysis. The loading content of DOX was determined by UV-vis analysis to be 13.5 wt%, and the content of the targeting ligand FA was calculated as 3.13 wt% based on 1H NMR measurement. Particle size parameter of DOX-CDots-FA was determined by HR-TEM. The results showed that the average diameter of DOX-CDots-FA is about 6 nm. In addition, DOX-CDots-FA showed p H-dependent release, that is, the drug releases faster in p H= 5.2 buffer solution than in p H= 7.4 one. The cytotoxicity of DOX-CDots-FA, DOX-CDots nanoparticles and free DOX were evaluated and compared using He La and L929 cell lines. For the FR-positive He La cells, DOX-CDots-FA nanoparticles exhibit superior cytotoxicity as compared to DOX-CDots nanoparticles. These results showed that the FA moieties in DOX-CDots-FA nanoparticles play an important role in enhancing the cytotoxic effect as they increase the binding to FR-expressing cells. This high affinity binding subsequently increases their intracellular uptake as a result of receptor-mediated endocytosis. The FA molecules present on the surface of the nanoparticle prodrug do not have a remarkable effect on cellular uptake and/or cytotoxicity for FR-negative L929 cell lines. The confocal microscope studies revealed that FA-conjugated prodrug DOX-CDots-FA exhibited hi

关 键 词：靶向 荧光 前药 碳点 控制释放 

分 类 号：O613.71[理学—无机化学] TQ460.1[理学—化学]