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 highs...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.展开更多
基金National Natural Science Foundation of China(No.31500771,31770382)Research Project Supported by Shanxi Scholarship Council of China(No.2021-016)+2 种基金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).
文摘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.
