Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa
Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa
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DOI：
10.1080/10611860801890093
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Snyder, James P.
中科院分区：
文献类型：
--
作者：
Shoji, Mamoru;Sun, Aiming;Snyder, James P.
组织因子（TF）在肿瘤血管内皮细胞（VEC）和许多恶性肿瘤的癌细胞上异常表达，但在正常 VEC 上没有异常表达，这使其成为癌症治疗的有希望的靶点。作为凝血因子 VIIa (fVIIa) 的跨膜受体，TF 与其同源配体形成高亲和力复合物，随后通过受体介导的内吞作用内化。因此，我们开发了一种使用 fVIIa 作为药物载体选择性地将 EF24（一种有效的合成姜黄素类似物）递送至表达 TF 的肿瘤脉管系统和肿瘤的方法。 EF24通过三肽-氯甲基酮与fVIIa化学缀合。 EF24通过NIL与表达TF的靶点结合后，将与药物载体一起被内吞并发挥其细胞毒性。我们的结果表明，在兔角膜模型和无胸腺裸鼠的基质胶模型中，该缀合物抑制血管内皮生长因子诱导的血管生成。与未缀合的 EF24 相比，缀合物诱导肿瘤细胞凋亡，并显着减小无胸腺裸鼠人乳腺癌异种移植物中的肿瘤大小。通过将强效药物与 fVIIa 结合，这种靶向药物递送系统有可能增强治疗效果，同时减少毒副作用。除了原发性肿瘤之外，它还可能被证明可用于治疗耐药肿瘤和微转移。
Tissue factor (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by NIL, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors.