促性腺激素释放激素类似物-紫杉醇靶向抗肿瘤缀合物的合成及评价

Synthesis and Evaluation of GnRHa-paclitaxel Tumor-targeting Conjugates

以促性腺激素释放激素类似物(GnRHa)为靶向配体,以紫杉醇为抗癌因子,分别以硫醚键和二硫键为连接臂,设计合成了2个靶向抗肿瘤缀合物.研究了缀合物的肿瘤细胞增殖抑制活性和GnRH受体结合活性,结果表明,2个缀合物均具有较强的抗肿瘤活性和GnRH受体亲和力;另外,血浆稳定性实验结果显示,以硫醚键偶联的缀合物1在血浆中孵育24 h,原型保留仍在50%以上,具有较高的稳定性.

AgrC is a membrane-embedded histidine kinase in Staphylococcus aureus that is thought to act as a sensor for the recognition of environmental signals and the transduction of signals into the cytoplasm so as to regulate and control a series of related pathogenic gene expression. However, for the complexity of cell mem-brane, it turns to be difficult to study AgrC on bacterial cell membrane directly. Many researches tried to take advantage of proteoliposome which could provide an approximate natural membrane environment and keep the protein activity to study the structure and function of membrane proteins. In order to build a transmembrane protein incorporation system with a relatively high incorporation efficiency, function activity and stability, various factors were considered, such as the impact of different charge polarity head on protein transmembrane incorporation efficiency. Here, four kinds of different charged liposomes were prepared by changing the phos-pholipid components in liposome and a detergent-mediated method was used to reconstitute truncated AgrC protein（AgrCTM6-7C） into them. The results showed that negatively charged liposomes leaded to a higher incor-poration efficiency compared with the positively charged one and about 60%-70% C-terminal cytoplasmic do-main of AgrCTM6-7C protein reconstituted into negatively charged liposomes were outside-orientated which re-mained a highly kinase activity. Furthermore, from circular dichroism detection result, we can draw a conclu-sion that liposome has certain protective effect on AgrCTM6-7C protein secondary structure and improve the