DOUBLE TARGETING OF BIODEGRADABLE NANOPARTICLES AS AN ADVANCED APPROACH TO ENHANCE ANTITUMOR EFFECTS

We propose biodegradable core-shell nanoparticles (NPs) made of amphiphilic poly(?-caprolactone)-polyethyleneglycol (PCL-PEG) block copolymers exposing on the surface folic acid (FA) as tumor targeting moiety and the hexapeptide anti-FLT1 (aFLT1) as an anti-angiogenic factor to improve cancer therapy. In nanodelivery, while targeting with FA is a widely used strategy to enhance the selective accumulation of drugs in cancer cells over-expressing FA receptors (FRs), this is the first attempt to exploit a-FLT1 exposed on NPs in order to inhibit the binding of VEGF receptor (VEGFR1 or FLT1R) ligands, negatively affecting VEGF-induced angiogenesis of vascular cells surrounding tumor masses. The hydrophobic PCL core of NPs allowed the entrapment of the poorly water soluble antimitotic agent Docetaxel (DTX) or of the fluorescent dye Nile Red (NR), useful to follow NP cell internalization. The effective exposure of the targeting moiety and it recognition by receptors is ensured by its coupling to a defined percentage of PCL-PEG co-polymer (PCL4000-PEG1500) longer than the majority of di-block (PCL4000-PEG1000) composing the nanovehicles.