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Molecularly engineered truncated tissue factor with therapeutic aptamers for tumor-targeted delivery and vascular infarction
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2020-11-24 , DOI: 10.1016/j.apsb.2020.11.014
Bozhao Li 1, 2 , Jingyan Wei 1 , Chunzhi Di 2, 3 , Zefang Lu 2, 3 , Feilong Qi 2, 3 , Yinlong Zhang 2, 3 , Wei Sun Leong 4 , Lele Li 2 , Guangjun Nie 2, 3 , Suping Li 2, 3
Affiliation  

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.



中文翻译:

具有治疗性适体的分子工程截短组织因子用于肿瘤靶向递送和血管梗塞

肿瘤血管系统的选择性闭塞已被证明是癌症治疗的有效策略。在血管凝血剂中,凝血诱导蛋白组织因子的细胞外结构域截短组织因子(tTF)应用最广泛。由于截短的蛋白质不表现出凝血活性并在循环中迅速清除,游离 tTF 不能单独用于癌症治疗,而必须与其他部分结合。我们在这里通过将 tTF 与 DNA 适体 AS1411 偶联开发了一种新型的肿瘤特异性 tTF 递送系统,AS1411 选择性地结合在肿瘤血管内皮细胞表面过表达的核仁蛋白受体,并且对靶细胞具有特异性细胞毒性。将 tTF-AS1411 偶联物全身给药至荷瘤动物体内,仅在肿瘤中诱导血管内血栓形成,从而减少肿瘤血供并诱导肿瘤坏死,且无明显副作用。这种结合物代表了一种独特的有吸引力的候选药物,可用于癌症治疗的血管闭塞剂的临床转化。

更新日期:2020-11-24
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