title: New multifunctional molecular conjugate vector for targeting, imaging, and therapy of tumors.
abstract: We report the in vitro and in vivo characteristics of a new molecular conjugate vector for targeting and imaging of tumors. Its core is a cyclodecapeptide platform named RAFT, onto which two spatially independent functional domains can be covalently and stereospecifically linked: a cell-targeting domain for tumor targeting and a labeling domain able to carry two drugs and/or labeling agents. To prove the interest of this carrier, we used a well-known cRGD cyclopeptide, a ligand for the alphavbeta3 integrin. We demonstrate that this vector presenting four cRGD motifs very efficiently prevents alphavbeta3-mediated cell adhesion to vitronectin. Furthermore, it is actively endocytosed because of the multivalent cRGD presentation, a major advantage for drug delivery. In vivo experiments in nude mice reveal that repeated intratumoral injections of low doses of RAFT(cRGD)4 reduce tumor growth. Furthermore, RAFT(cRGD)4 significantly improves the targeting specificity of subcutaneous tumor masses as well as that of disseminated metastasis after intravenous injection. Thus, RAFT(cRGD)4 is specific, internalized, and perfectly controlled and can carry multiple biological functions on a single, spatially defined backbone, making it a powerful and versatile synthetic vector for drug delivery, molecular imaging, or both.
authors.affiliation: Groupe de Recherche sur le Cancer du Poumon, INSERM U578, Institut Albert Bonniot, La Tronche 38706 Cedex, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Garanger
authors.forename: Didier
authors.initials: D
authors.lastname: Boturyn
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Jin
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Favrot
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis* / Q000473:pathology* / Q000628:therapy*; D009842:Oligopeptides / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D013237:Stereoisomerism; D019096:Vitronectin / Q000737:chemistry
chemical_list: D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D011108:Polymers; C574552:RAFT-RGD; D019096:Vitronectin; C047981:arginyl-glycyl-aspartic acid