Template Assembled Cyclopeptides as Multimeric System for Integrin Targeting and Endocytosis

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Abstract
The αVβ3 integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. c[-RGDfV-] peptide represents a selective αVβ3 integrin ligand that has been extensively used for research, therapy, and diagnosis of neoangiogenesis. We report here the modular synthesis and biological characterization of template assembled cyclopeptides as a multimeric system for targeting and endocytosis of cells expressing αVβ3 integrin. c[-RGDfK-] was cleanly assembled in a multivalent mode by chemoselective oxime bond formation to a cyclodecapeptides template labeled by different reporter groups. Binding propensity to the αVβ3 receptor and the associated good uptake property displayed by the multivalent molecules demonstrated the interest in the RAFT molecule to design new multimeric system with hitherto unreported properties. These compounds offer an interesting perspective for the reevaluation of integrins as angiogenesis regulators (Hynes, R. O. Nature Med.2003, 9, 918−921) as well as for the design of more sophisticated systems such as molecular conjugate vectors.