Département de chimie moléculaire

RGD peptides recognize the $\alpha$$\alpha$v$\beta$$\beta$3 integrin, a receptor that is overexpressed on the surface of both tumor blood vessels and cancerous cells. These peptides are powerful tools that act as single antiangiogenic mols., but recently also have been used for tumor imaging and drug targeting. We designed the mol. RAFT-(c[-RGDfK-])4, a constrained and chem. defined entity that can be produced at clin.-grade quality. This scaffold was covalently coupled via a labile bridge to the proapoptotic peptide (KLAKLAK)2 (RAFT-RGD-KLA). A fluorescent, activatable probe was also introduced, allowing intracellular localization. At 2.5 $μ$M, this mol. induced the intracellular release of an active KLA peptide, which in turn caused mitochondrial depolarization and cell death in vitro in tumor cells. In a mouse model, the RAFT-RGD-KLA peptide was found to prevent the growth of remote s.c. tumors. This study demonstrated that the antitumor peptide is capable of killing tumor cells in an RGD-dependent manner, thus lowering the nonspecific cytotoxic effects expected to occur when using cationic cytotoxic peptides. Thus, this chem. is suitable for the design of complex, multifunctional mols. that can be used for both imaging and therapeutics, representing the next generation of perfectly controlled, targeted drug-delivery systems. [on SciFinder(R)]