The relationship between the cyclic-RGDfK ligand and αvβ3 integrin receptor.

Ever since the finding that αvβ3 integrin receptors are over expressed on the endothelial cell surfaces of tumor vasculatures relative to normal resting vasculatures was disclosed in 1994, αvβ3 integrin receptor selective systems are finding increasing applications both for targeting anti-cancer drugs/genes selectively to tumor vasculatures and for imaging growing tumors. Among the cyclic peptide based integrin antagonists identified through both phage display and structure-activity studies, mainly αvβ3 integrin selective cyclic peptide c(RGDfK-) has found most widespread exploitations for targeting chemotherapeutic drugs/genes to both tumor and tumor vasculatures in anti-angiogenic cancer therapy. Herein we show that a lipopeptide containing widely acclaimed αvβ3 integrin receptor selective cyclic RGDfK ligand in its head-group area can effectively deliver genes into both the endothelial and tumor cells via all the three widely used integrin receptors namely αvβ3, αvβ5 & α5β1 integrins. We demonstrate that intravenous administration of the electrostatic complex of the cationic liposomes of an amphiphiles with cyclic RGDfK head-group and the anti-cancer p53 gene leads to significant tumor growth inhibition in a syngeneic mouse tumor model presumably through inducing apoptosis of tumor neovasculatures. The findings delineated herein provide experimental evidence that cyclic-RGDfK-ligand may not be that highly selective for αvβ3 integrin receptor as is popularly believed.