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

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.

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

Tumor targeting can be achieved by combining a chemotherapeutic agent with a targeting moiety, which recognizes tumor-specific or highly expressed receptors on cancer cells. GnRH receptor is over-expressed on various tumor cells but is barely expressed in healthy visceral organs which makes it possible to use GnRH analogues(GnRHa) as the targeting moieties to deliver cytotoxic agents. Two conjugates were synthesized by incorporating paclitaxel(PTX) into GnRH analogue which was synthesized in the solid phase, the conjugation of PTX with GnRH analogs was performed by thio-ether bond and disulfide bond as a linker. The purity of the conjugates was analyzed by high performance liquid chromatography(HPLC) and the structures of the conjugates were confirmed by high resolution mass spectrum(HRMS). The resulting conjugates 1 and 2 both preserved the cytotoxic activity of PTX and also retained the high binding affinity of the peptide hormone portion of the conjugates. The high affinity indicated that the conjugates might be specifically delivered to tumor tissues or cells via endocytosis mediated by GnRH receptor. The results showed that more than 50% prototypes of conjugate 1 remained with incubating in human serum for 24 h which indicating a favorable stability.