【摘要】 目的:制备靶向肿瘤细胞促性腺激素释放激素（GnRH）受体的多肽-药物偶联物。方法:将GnRH的6位甘氨酸（Gly⁶）用半胱氨酸（Cys）替代,10位的甘氨酰胺(Gly¹⁰-NH₂)分别用乙胺和氨基脲取代,合成了2个GnRH类似物。以硫醚键将上述GnRH类似物与阿霉素（Dox）偶联,得到了2个多肽-药物偶联物[Cys⁶-desGly¹⁰-Pro⁹-NHEt]-GnRH-Dox（偶联物1）和[Cys⁶-α-azaGly¹⁰-NH₂]-GnRH-Dox（偶联物2）。MTT实验考察2个偶联物对GnRH受体过表达的MCF-7人乳腺癌细胞的体外增殖抑制活性,GnRH受体抑制实验评价偶联物2的靶向性。结果:2个偶联物对MCF-7细胞的增殖抑制活性均低于阿霉素,偶联物2对MCF-7细胞的增殖抑制活性高于偶联物1。结论:偶联物2的抗肿瘤活性可能是由[Cys⁶-α-azaGly¹⁰-NH₂]-GnRH与GnRH受体的靶向结合而介导的细胞内吞摄取作用而实现。更多还原

【Abstract】 Objective:To prepare peptide-drug conjugates targeting gonadotropin-releasing hormone（GnRH）receptor on tumor cells.Methods:Two new GnRH analogs were synthesized by replacing the Gly⁶ with Cys and substitution of C-terminal Gly¹⁰-NH₂ by ethylamide andα-azaGly¹⁰-NH₂,respectively.The GnRH analogs were conjugated with doxorubicin（Dox）through a linker containing thioether bond to afford two GnRH-Dox conjugates,named[Cys⁶-desGly¹⁰-Pro⁹-NHEt]-GnRH-Dox（conjugate 1）and[Cys⁶-α-azaGly¹⁰-NH₂]-GnRH-Dox（conjugate2）,respectively.The direct in vitro growth inhibitory effect of these two conjugates on MCF-7 human breast cancer cells which overexpress GnRH recepter was examined by MTT assay,and the targeting effect of conjugate 2 was evaluated by GnRH receptor inhibition test.Results:Both of the two conjugates exhibited lower antiproliferative activity against MCF-7 cell line in comparison with Dox,and the antiproliferative activity of conjugate 2 was higher than that of conjugate 1.Conclusion:The antiproliferative effect of conjugate 2 on MCF-7 cells might be due to the cellular uptake mediated by the target binding of[Cys⁶-α-azaGly¹⁰-NH₂]-GnRH to GnRH receptors.更多还原