以酸敏感腙键为连接子的靶向NGR肽修饰阿霉素的合成与性能研究  

Synthesis and performance study of targeted NGR peptide-modifieddoxorubicin using acid-sensitive hydrazone bond as linker

作　　者：程丹丹 郭虎 黎可 沈鸿雁[1] CHENG Dan-dan;GUO Hu;LI Ke;SHEN Hong-yan(Department of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]沈阳药科大学制药工程学院,沈阳110016

出　　处：《中国新药杂志》2025年第2期205-209,共5页Chinese Journal of New Drugs

摘　　要：目的:合成以NGR(Asn-Gly-Arg)序列为靶向肽,酸敏感腙键为连接子的阿霉素(doxorubicin, DOX)前药,并探究该前药对氨肽酶N过表达的肿瘤细胞的增殖抑制作用和靶向作用。方法:采用固相和液相相结合的方法合成DOX前药,优化其合成工艺并探究腙键的酸敏感性;采用人结肠癌细胞HT29(氨肽酶N不表达)和小鼠乳腺癌细胞4T1(氨肽酶N过表达)对DOX前药的细胞毒性和靶向性进行评价。结果:当肽酰肼和DOX的投料比为4∶1,反应时间为4 h时,可以得到纯度较高的DOX前药;DOX前药在甲醇中的稳定性高于在水中,并且酸性增强、稳定性降低,体现腙键的酸敏感性;DOX前药对氨肽酶N受体过表达的4T1细胞表现出选择性的细胞毒性。结论:合成的DOX前药对肿瘤细胞中过表达的氨肽酶N受体具有靶向作用,其结构中的腙键可在弱酸性的肿瘤微环境中特异性裂解释放DOX,从而赋予DOX双重靶向性,以减轻其对正常细胞的毒副作用。Objective:To synthesize doxorubicin precursor with NGR(Asn-Gly-Arg)sequence as target peptide and acid-sensitive hydrazone bond as linker,and investigate the proliferation inhibitory and targeting effects of doxorubicin(DOX)precursor on tumor cells overexpressing aminopeptidase N.Methods:A combination of solid-phase and liquid-phase methods was used to synthesize the DOX precursor,optimize its synthesis process,and probe the acid sensitivity of the stilbene bond;the cytotoxicity and targeting properties of the DOX precursor were then evaluated using human colon cancer cells HT29(aminopeptidase N non-expression)and mouse breast cancer cells 4T1(aminopeptidase N overexpression).Results:When the feeding ratio of peptidylhydrazine and DOX was 4∶1 and the reaction time was 4 h,DOX precursor with high purity could be obtained;the stability of the DOX precursor in methanol was higher than that in water,and its stability was decreased by the increase of acidity,reflecting the acid sensitivity of the germanium bond;and the DOX precursor displayed selective cytotoxicity to the aminopeptidase N receptor overexpressing 4T1 cells.Conclusion:Synthetic DOX prodrug targets the overexpressed aminopeptidase N receptor in tumor cells and has structural stilbene bonds that can be specifically cleaved to release DOX in the weakly acidic tumor microenvironment,thus conferring dual targeting of DOX to mitigate its toxic side effects on normal cells.

关 键 词：多肽偶联药物 NGR序列 阿霉素 氨肽酶N 抗肿瘤药物 

分 类 号：R914.5[医药卫生—药物化学]