Molecularly engineered tumor acidity-responsive plant toxin gelonin for safe and efficient cancer therapy  

作　　者：Guo-Bin Ding Chenchen Zhu Qian Wang Huiyan Cao Bin-Chun Li Peng Yang Roland H.Stauber Guangjun Nie Zhuoyu Li 

机构地区：[1]Institute of Biotechnology,The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education,Shanxi University,Taiyuan,030006,China [2]CAS Key Laboratory for Biomedical Effects of Nanomaterials&Nanosafety,National Center for Nanoscience and Technology,Beijing,100190,China [3]Nanobiomedicine Department/ENT,University Medical Center Mainz,Mainz,55131,Germany

出　　处：《Bioactive Materials》2022年第12期42-55,共14页生物活性材料（英文）

基　　金：National Natural Science Foundation of China(No.31500771,31770382);Research Project Supported by Shanxi Scholarship Council of China(No.2021-016);Natural Science Foundation of Shanxi Province(No.201901D111007,201901D111013);foreign experts project of Shanxi Provincial“100 Talents Plan”(Prof.Roland H Stauber);graduate education innovation project of Shanxi Province(2021Y120).

摘　　要：Due to the unsatisfactory therapeutic efficacy and inexorable side effects of small molecule antineoplastic agents,extensive efforts have been devoted to the development of more potent macromolecular agents with highspecificity.Gelonin is a plant-derived protein toxin that exhibits robust antitumor effect via inactivating ribosomesand inhibiting protein synthesis.Nonetheless,its poor internalization ability to tumor cells has compromisedthe therapeutic promise of gelonin.In this study,a tumor acidity-responsive intracellular protein deliverysystem-functional gelonin(Trx-pHLIP-Gelonin,TpG)composed of a thioredoxin(Trx)tag,a pH low insertionpeptide(pHLIP)and gelonin,was designed and obtained by genetic recombination technique for the first time.TpG could effectively enter into tumor cells under weakly acidic conditions and markedly suppress tumor cellproliferation via triggering cell apoptosis and inhibiting protein synthesis.Most importantly,treatment byintravenous injection into subcutaneous SKOV3 solid tumors in a mouse model showed that TpG was much moreeffective than gelonin in curtailing tumor growth rates with negligible toxicity.Collectively,our present worksuggests that the tumor acidity-targeted delivery manner endowed by pHLIP offers a new avenue for efficientdelivery of other bioactive substances to acidic diseased tissues.

关 键 词：GELONIN BIOSYNTHESIS pHLIP Tumor-acidity responsive Apoptosis Cancer therapy 

分 类 号：R730.5[医药卫生—肿瘤]