title: Tumor targeting with RGD peptide ligands-design of new molecular conjugates for imaging and therapy of cancers.
abstract: Development of molecular devices endowed with tumor-targeting functions and carrying cytotoxic components should enable the specific delivery of chemotherapeutics to malignant tissues, thus increasing their local efficacy while limiting their peripheral toxicity. Such molecular vectors can pave the way for the development of new classes of therapeutics, fighting against protagonists of neoplastic development. In line with this concept, peptide ligands containing the Arginine-Glycine-Aspartate (RGD) triad, which display a strong affinity and selectivity to the alpha(V)beta(3) integrin, have been developed to target the tumor-associated cells expressing the alpha (V)beta (3) receptors. Among the validated ligands, the leader compound is the cyclic pentapeptide c[-RGDf(NMe)V-] (Cilengitide) developed by kessler et al. (J. Med. Chem., 1999, 42, 3033-3040). This compound has entered phase II clinical trials as an anti-angiogenic agent. Further studies have been directed to develop molecular conjugates of the parent c[-RGDfK-] with conventional chemotherapeutics or with labels for non-invasive imaging technologies. More recently, multimeric RGD containing compounds have been exploited to improve the targeting potential as well as cell-membrane breaching, through receptor-mediated endocytosis. The latter have been constructed on various scaffolds (polylysines or polyglutamates, liposomes, nanoparticles...). Our group has developed a chemical system combining all these properties where multivalent RGD targeting functions are associated with functional molecules through a cyclopeptide template. The latter represents a relevant non-viral vector for tumor targeting, imaging and therapy. This review describes the considerations for the design of the diverse RGD ligands developed so far and reports an overview of the main applications of these structures in cancer research.
authors: DCM, UMR CNRS 5250, ICMG FR-2607, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
authors: Elisabeth
authors: E
authors: Garanger
authors: Didier
authors: D
authors: Boturyn
authors: Pascal
authors: P
authors: Dumy
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D009369:Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid