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.