基于大环多胺[12]aneN_(3)多功能非病毒基因载体的合成及性质  

Synthesis and property of multifunctional non-viral gene vectors based on[12]aneN_(3)

作　　者：王倩 刘旭英 唐芳 卢忠林 Qian Wang;Xu-Ying Liu;Fang Tang;Zhong-Lin Lu(Key Laboratory of Radiopharmaceuticals,Ministry of Education,College of Chemistry,Beijing Normal University,Beijing 100875,China)

机构地区：[1]北京师范大学化学学院,放射性药物教育部重点实验室,北京100875

出　　处：《科学通报》2022年第20期2298-2317,共20页Chinese Science Bulletin

基　　金：国家自然科学基金(21778012,21372032,20972019)资助。

摘　　要：基因治疗的提出为人类遗传疾病和重大疾病的治愈带来了重要机遇,经过几十年曲折的发展,基因治疗逐渐得到人们的认可,且相关药品开始进入市场.但与人们的预期相比,基因治疗的发展比较缓慢,一个关键的因素就是缺乏安全高效的基因载体,尤其是非病毒基因载体.在过去十多年,各种各样的非病毒基因载体得到了极大的发展.我们课题组以大环多胺[12]aneN_(3)为正电单元,利用非病毒基因载体的结构可调性,引入单光子、双光子及聚集诱导和近红外荧光显像单元、酯酶和谷胱甘肽刺激响应单元以及胆酸、生物素靶向单元,设计合成了一系列多功能非病毒基因载体,通过凝胶电泳实验、细胞毒性、细胞摄取、细胞器逃逸、定性定量转染实验以及各种荧光成像技术,研究了它们对质粒DNA和siRNA的递送转染性能及其转染过程,发展了一些生物相容性好、基因转染效率高的非病毒基因载体,进一步研究了它们在诊疗一体化、联合治疗等方面的潜力.本文从结构设计与性质研究两个方面介绍了我们在多功能型非病毒基因载体方面的工作进展,概括总结了各种结构的设计与合成,系统总结了基因转染效率提升与机理探究.最后,对非病毒基因载体未来的发展方向进行了展望.In 1972,Theodore Friedmann formally proposed the concept of gene therapy in the journal of Science.The proposal of gene therapy brought important opportunities for the complete cure of human genetic diseases and major diseases.The process from concept to clinical application was long and tortuous.Until the early 1990 s,the NIH of the USA conducted the first clinical study of a rare immunodeficiency disease,which resulted in the explosive expansion of gene therapy.Unfortunately,a patient with ornithine carbamyltransferase deficiency produced an immune response during the treatment of gene therapy,and he eventually died.Since then,gene therapy has entered a cold winter.These setbacks have propelled basic research in immunology,virology,cell biology and targeted diseases.In the early 2000 s,m RNA and si RNA have been developed rapidly for gene therapy,and the 2006 Nobel Prize in Physiology or Medicine was awarded to Andrew Fire and Craig Mello for their discovery of RNA interference.These accelerated the development of gene therapy again.In the following years,viral gene vectors began to enter clinical trials.In 2012,the world’s first gene therapy drug came out,which was called Glybera.It enlarged the application prospect of gene therapy.Gene editing technology won the 2020 Nobel Prize in Chemistry,and the clinical application of gene therapy has received more and more attention.So far,more than 2000 clinical studies have been carried out,it is widely used in diseases ranging from single gene diseases to complex neurodegenerative diseases.By the beginning of 2021,18 gene therapy drugs have been launched around the world,with a market value of over$7 billion.However,compared with people’s expectations,the development of gene therapy is relatively slow,and a key factor is the lack of safe and efficient gene carriers,especially non-viral gene carriers.Their low transfection efficiency is due to their inability to effectively overcome the multiple physiological barriers in the process of gene delivery.Therefore,scie

关 键 词：基因治疗 非病毒基因载体 aneN_(3) 基因转染 荧光显像 

分 类 号：R450[医药卫生—治疗学]