title: RGD-avidin-biotin pretargeting to alpha v beta 3 integrin enhances the proapoptotic activity of TNF alpha related apoptosis inducing ligand (TRAIL).
abstract: Recombinant TNF-related apoptosis-inducing ligand (TRAIL) is considered a powerful and selective inducer of tumor cell death. We hypothesize that TRAIL's potential as anticancer agent can be enhanced further by promoting its accumulation in tumor tissue. For this purpose, we developed TRAIL complexes that bind to angiogenic endothelial cells. We employed an avidin-biotin pretargeting approach, in which biotinylated TRAIL interacted with RGD-equipped avidin. The assembled complexes killed tumor cells (Jurkat T cells) via apoptosis induction. Furthermore, we demonstrated that the association of the RGD-avidin-TRAIL complex onto endothelial cells enhanced the tumor cell killing activity. Endothelial cells were not killed by TRAIL nor its derived complexes. Our approach can facilitate the enrichment of TRAIL onto angiogenic blood vessels, which may enhance intratumoral accumulation. Furthermore, it offers a versatile technology for the complexation of targeting ligands with therapeutic recombinant proteins and by this a novel way to enhance their specificity and activity.
authors: Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, Groningen, The Netherlands.
authors: Marc
authors: M
authors: Tarrus
authors: Almer M
authors: AM
authors: van der Sloot
authors: Kai
authors: K
authors: Temming
authors: Marie
authors: M
authors: Lacombe
authors: Frank
authors: F
authors: Opdam
authors: Wim J
authors: WJ
authors: Quax
authors: Grietje
authors: G
authors: Molema
authors: Klaas
authors: K
authors: Poelstra
authors: Robbert J
authors: RJ
authors: Kok
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001360:Avidin / Q000378:metabolism; D001710:Biotin / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D019169:Jurkat Cells; D009842:Oligopeptides / Q000494:pharmacology*; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D001360:Avidin; D001710:Biotin; C047981:arginyl-glycyl-aspartic acid