Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa

Autor:	Christopher E. Nichols, James P. Snyder, Jan Pohl, Aiming Sun, Mamoru Shoji, Walter Kisiel, Yang J. Lu, Hyunsuk Shim, Bernard E. McCarey, Dennis C. Liotta, Aaron R. Alizadeh, Ernest T. Parker, Cara Mosley
Rok vydání:	2008
Předmět:	Vascular Endothelial Growth Factor A Angiogenesis medicine.medical_treatment Pharmaceutical Science Antineoplastic Agents Factor VIIa Benzylidene Compounds Thromboplastin Targeted therapy Neovascularization Mice Tissue factor Cell Line Tumor Animals Humans Medicine Piperidones Matrigel Neovascularization Pathologic business.industry Cancer Neoplasms Experimental medicine.disease Xenograft Model Antitumor Assays Endocytosis Targeted drug delivery Immunology Cancer cell Cancer research Rabbits medicine.symptom business
Zdroj:	Journal of Drug Targeting. 16:185-197
ISSN:	1029-2330 1061-186X
DOI:	10.1080/10611860801890093
Popis:	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 fVIIa, 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::becacc13022ac2ff00bbcc866d08b183 https://doi.org/10.1080/10611860801890093 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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