Degradable and Biocompatible Nanoparticles Decorated with Cyclic RGD Peptide for Efficient 1 Drug Delivery to Hepatoma Cells

degradable poly(benzyl malate) derivatives; cyclic RGD peptide; HepaRG hepatoma cells. 14 15 ABSTRACT 16 Amphiphilic derivatives of poly(benzyl malate) were synthesized and characterized with the aim of 17 being used as degradable and biocompatible building blocks for the design of functional nanoparticles 18 (NPs). An anti-cancer model drug, doxorubicin, has been successfully encapsulated into the prepared 19 NPs and its release profile has been evaluated in water and in culture medium. NPs bearing biotin 20 molecules were prepared either for site-specific drug delivery via the targeting of biotin receptors 21 overexpressed on the surface of several cancer cells, or for grafting biotinylated cyclic RGD peptide 22 onto their surface using the strong and highly specific interactions between biotin and the streptavidin 23 protein. We have shown that this binding did not affect dramatically the physico-chemical properties 24 of the corresponding NPs. Cyclic RGD grafted fluorescent NPs were more efficiently uptaken by the 25 2 HepaRG hepatoma cells than biotinylated fluorescent NPs. Furthermore, the targeting of HepaRG 26 hepatoma cells with NPs bearing cyclic RGD was very efficient and much weaker for HeLa and HT29 27 cell lines confirming that cyclic RGD is a suitable targeting agent for liver cells. Our results also 28 provide a new mean for rapid screening of short hepatotropic peptides in order to design NPs showing 29 specific liver targeting properties. 30 31