Preparation and biological evaluation of tumor-specific Ara-C liposomal preparations containing RGDV motif

Arginine–glycine–aspartate (RGD) has been shown to be essential for the recognition of integrins overexpressed in tumor cells, especially during tumor invasion, angiogenesis, and metasis. In this study, a novel tetrapeptide, RGD–valine (RGDV), was designed and attached to the N position of 1-β-d-arabinofuranosylcytosine (Ara-C) at the valine end, as a homing device for the delivery of Ara-C to tumor cells. Furthermore, fatty acids of various chain lengths (C_nH_2n+1COOH, n = 7, 9, 11, 13, and 15) were attached to the arginine end of RGDV to form a series of C_nH_2n+1CO–RGDV–Ara-C compounds. The structures of C_nH_2n+1CO–RGDV–Ara-C compounds were confirmed using mass spectrometry and nuclear magnetic resonance. The liposomal preparations of the synthesized C_nH_2n+1CO–RGDV–Ara-C compounds were obtained using the film dispersion method in the presence of phospholipids. The particle size, zeta potential, and dispersity index of the liposomes formed were found to be approximately 215 nm (diameter), approximately ?30 mV, and <0.3, respectively. The antitumor activity of the liposomal preparations containing the respective C_nH_2n+1CO–RGDV–Ara-C compounds was evaluated in mice inoculated with sarcoma S₁₈₀. Liposomal Ara-C preparation, liposomal C₁₁H₂₃CO–V–Ara-C preparation, Ara-C, and C₁₁H₂₃CO–V–Ara-C sodium carboxymethyl cellulose (CMC-Na) suspensions were used as controls. C_nH_2n+1CO–RGDV–Ara-C containing liposomal preparations were shown with an enhanced antitumor activity, likely because of the targeting effect of RGDV.