靶向IGF1R mRNA的反义寡核苷酸修饰物新型制剂体外抗肝癌活性研究  

Investigation on efficacy against hepatocellular carcinoma of novel antisense oligonucleotide targeting IGF1R mRNA encapsulated with neutral cytidinyl/cationic lipid in vitro

作　　者：蒲洋 管静 何仟一 朱月洁 潘德林 关注 杨振军[2,3] PU Yang;GUAN Jing;HE Qian-yi;ZHU Yue-jie;PAN De-lin;GUAN Zhu;YANG Zhen-jun(School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China;State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China;College of Pharmaceutical Sciences,Guizhou University of Traditional Chinese Medicine,Guiyang 550025,China)

机构地区：[1]成都中医药大学药学院,四川成都611137 [2]北京大学药学院/天然药物及仿生药物全国重点实验室,北京100191 [3]贵州中医药大学药学院,贵州贵阳550025

出　　处：《药学学报》2024年第5期1441-1448,共8页Acta Pharmaceutica Sinica

基　　金：北大医学-哈药核酸药物协同创新实验室及国家科技部重大新药创制科技重大专项资助项目(2017ZX09303013)。

摘　　要：反义寡核苷酸是一类靶向沉默mRNA后抑制蛋白翻译的基因疗法,已在多种疾病治疗中应用,但依然缺乏合适的体内递送载体、存在酶稳定性差及使用剂量高等问题。胰岛素样生长因子1型受体(IGF1R)是一种具有酪氨酸激酶活性的细胞表面受体,在多种恶性肿瘤中异常高表达,通过多种途径介导肿瘤细胞的恶性增殖、迁移及侵袭。本研究设计合成了靶向IGF1R mRNA的反义寡核苷酸(N04),利用中性胞苷脂材DNCA联合胱氨酸骨架阳离子脂材CLD对其进行包载递送,并结合化学修饰策略(PS,2’-OMOE),得到稳定且高效的反义寡核苷酸修饰物新型制剂。制剂粒径理想(151 nm)、大小均一(多分散系数0.18)、呈近电中性(ζ电位-3.9 mV)、可被肝癌细胞(HepG-2、Huh-7)高效摄取,明显沉默靶mRNA、导致细胞S期阻滞、促进细胞凋亡,进而抑制细胞增殖。本研究为抗肝细胞癌新型反义寡核苷酸制剂药物的研发提供了工作基础。Antisense oligonucleotides are a type of gene therapy that targets mRNA and inhibits gene expression.They have been applied in the treatment of various diseases,but there are still problems with poor enzyme stability and high dosage in vivo,due to the shortage of appropriate delivery system.Insulin-like growth factor 1 receptor(IGF1R)is a cell surface receptor with tyrosine kinase activity.Its expression is abnormal in a variety of malignant tumors.It mediates the malignant proliferation,migration and invasion of tumor cells through a variety of ways.In this study,an antisense oligonucleotide(ASO,N04)targeting IGF1R mRNA was designed and chemically modified(PS,2'-OMOE),then neutral cytidine lipid DNCA and cystine backbone cationic lipid CLD(Mix)were used to encapsulate ASOs.The particle size,polymer dispersity index andζpotential of the formulations were 151 nm,0.18 and-3.9 mV.The nanoparticles entered liver cancer cells(HepG-2,Huh-7),silenced target mRNA,arrested cell cycle in S phase,promoted apoptosis,and inhibited the proliferation efficiently.These results indicate that Mix/N04MOE5 has great potential in tumor treatment,which provides a basis for further research on novel agents against hepatocellular carcinoma.

关 键 词：反义寡核苷酸 中性胞苷脂材 胱氨酸骨架阳离子脂材 胰岛素样生长因子1型受体 肝细胞癌 

分 类 号：R943[医药卫生—药剂学]