Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tis...Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.展开更多
基金supported by grants from the National R&D Program of China(2018YFE0205300,2018YFA0208900)the National Natural Science Foundation of China(81871489,91859118,31730032,31700870,31470969,31661130152)+2 种基金the National Distinguished Young Scientist program(31325010,China)the K.C.Wong Education Foundation(GJTD-2018-03,China)the Beijing Municipal Natural Science Foundation(7182126,China)
文摘Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.
