基于石墨烯的药物递送系统和光热治疗试剂的构建

Although the diazotization of rGO (reduced graphene oxide) using the wet-chemical method have been reported, we found that the diazotization of rGO using wet-chemical method was processed in alkaline or neutral solution which is conflicting with the knowledge of textbook which proposed that the diazotization should be processed in acid solution. Otherwise side reaction would occur and by-product would appearance and sometime the stabilizer could also affect the diazotization reaction. Under acid condition, the rGO was functionalized with the p-aminobenzoic acid which formed the diazonium ions thorough the diazotization with the wet-chemical method. In this case, surfactants or stabilizers were not applied during the diazotization.In pre-experiment, we found that the diazotization of rGO was very successful under acid condition without surfactants or stabilizers applied. And the electron conjugation degree of rGO functionalized is higher than GO (graphene oxide), so we think that the efficiency rGO functionalized as the drug delivery system and the photo-thermal therapeutic agents are higher than GO. To our best knowledge, drug (or DNA or protein) delivery systems based on graphene were all based on the graphene oxide (GO) in articles published, and the adsorption of water-insoluble drug on the graphene oxide planar depends mainly on the hydrophobic and π-π stacking interactions. However, according to our pre-experimental results, the degree of conjugate of GO planar is negligible, so we think that the drug delivery system based on GO via π-π stacking interaction is not scientific, and the π-π stacking interaction of GO planar with the water-insoluble drug is negligible and the adsorption of water-insoluble drug on GO planar depends mainly on the weak hydrophobic interactions, which lead lower drug loading ratio.?We plan to systhesis efficient drug delivery system and photo-thermal therapeutic agents based on rGO functionalized, which which will provide us a new vision for functionalizing rGO and for studying drug delivery system based on the graphene materials.

我们发现在已出版的文章中，用wet-chemical方法重氮化rGO（还原氧化石墨烯）是在碱性或中性条件下并在稳定剂存在下进行的，这与教科书中阐述的重氮化反应被严格控制在酸性条件下相矛盾，否则会发生副反应并伴随副产物产生，而且稳定剂的使用也会影响重氮化。我们在预试验中发现，在没有稳定剂存在的酸性环境下，rGO能够被成功的重氮化，而且重氮化后的rGO的电子共轭度高于GO（氧化石墨烯），因此我们认为重氮化的rGO作为药物递送系统和光热治疗试剂的效果要好于GO。在已出版的文章中，基于石墨烯的药物递送系统和光热治疗试剂都是以GO为基础的，由于GO平面的电子共轭度很低以致可以忽略，这导致GO作为药物递送系统及光热治疗试剂的效果不佳。我们拟以重氮化的rGO为基础合成高效的药物递送系统和光热治疗试剂，此研究将为重氮化rGO，为基于石墨烯的药物递送系统和光热治疗试剂提供新思路和新视野。

石墨烯材料在药物递送系统方面的应用已引起了研究者极大的兴趣和研究。由于GO的共轭度很小， GO平面与疏水性药物之间的π-π堆积作用力可忽略不计，疏水药物和GO平面间的吸附主要是疏水作用力，导致GO具有较低的载药率。还原的氧化石墨烯（rGO）作为药物递送系统存在着很大的挑战，主要因为rGO具有很强的疏水性，如果没有稳定剂存在的情况下，在范德华力作用力下，rGO的水溶液会发生不可逆的聚沉或重新堆积生成石墨，使得对rGO的进一步处理变得困难。我们用对氨基苯甲酸对rGO进行重氮化制备了rGO-C6H4-COOH，实验发现，rGO-C6H4-COOH的电子共轭度要明显好于GO，因此，疏水性药物通过π-π堆积相互作用在rGO-C6H4-COOH上的吸附能力要强于GO。以一种新颖的方法制备rGO-C6H4-COOH为突破口，以rGO-C6H4-COOH为基础，通过引入聚乙烯亚胺（PEI）来增加rGO-C6H4-COOH的水溶性,而后通过分别引入卟啉分子，FA， CD制备了rGO-PEI-TCPP光热及光动力治疗试剂，rGO-PEI-FA（PEG正在连入）以及rGO-PEI-CD-Biotin (PEG正准备连入）药物递送系统。分别研究了胶体水溶液的稳定性，细胞毒理性。研究了rGO-PEI-TCPP作为光热及光动力治疗试剂诱导在光照下诱导癌细胞的凋亡情况以及细胞周期情况, 实验发现，制备的光热及光动力系统具有很好的稳定性，作为光热及光动力系统能够有效的杀死癌细胞。同时rGO-PEI-FA（PEG正在连入）以及rGO-PEI-CD-Biotin (PEG正准备连入）药物递送系统的载药率，稳定性，毒理性，细胞周期等与作为药物递送系统相关的一些考察参数也被研究, 实验发现，制备的药物递送系统具有很好的稳定性，药物与药物递送系统连用能够有效的杀死癌细胞。缺点是细胞毒理性较大，正在进一步的将PEG连入上面的两个体系来降低细胞毒理性，这部分的工作正在做。