Galactosylated polymeric carriers for liver targeting of sorafenib Emanuela F. Craparo a , Carla Sardo a , Rosa Serio b , Maria G. Zizzo b , Maria L. Bondì c , Gaetano Giammona a, d , Gennara Cavallaro a, * a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Sezione di Chimica e Tecnologie Farmaceutiche, Università di Palermo, via Archirafi 32, 90123 Palermo, Italy b Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Sezione di Biologia Cellulare, Università di Palermo, viale delle Scienze, edificio 16, 90128 Palermo, Italy c Istituto per lo Studio dei Materiali Nanostrutturati (ISMN), U.O.S. Palermo, CNR, via Ugo La Malfa, 153, 90146 Palermo, Italy d IBF-CNR, via Ugo La Malfa, 153, 90146 Palermo, Italy A R T I C L E I N F O Article history: Received 10 January 2014 Received in revised form 26 February 2014 Accepted 28 February 2014 Available online 04 March 2014 Keywords: Galactosylation Polymeric micelles Hepatic cell-targeted carriers Active targeting A B S T R A C T In this paper, we describe the preparation of liver-targeted polymeric micelles potentially able to carry sorafenib to hepatocytes for treatment of hepatocarcinoma (HCC), exploiting the presence of carbohydrate receptors, ASGPR. These micelles were prepared starting from a galactosylated polylactide-polyaminoacid conjugate. This latter was obtained by chemical reaction of a,b-poly(N-2- hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) with polylactic acid (PLA), and subsequent reaction with lactose, leading to PHEA-EDA-PLA-GAL copolymer. Liver-targeted sorafenib- loaded micelles were obtained in aqueous media at low PHEA-EDA-PLA-GAL copolymer concentration value with nanometer size and slightly positive zeta potential. Biodistribution studies on mice demonstrated, after oral administration of sorafenib loaded PHEA-EDA-PLA-GAL micelles, the preferential sorafenib accumulation into the liver. This finding raises hope in terms of future drug delivery strategy of sorafenib-loaded micelles targeted to the liver for the HCC treatment. ã 2014 Elsevier B.V. All rights reserved. 1. Introduction Liver diseases are the major causes of disability and mortality worldwide (Li et al., 2010). In the absence of a satisfactory curative option, the pursuit of alternative pharmacological interventions, therefore, remains extremely pressing. Many potent drugs are often not effective enough in vivo or exhibit adverse effects. Although they accumulate rapidly in the liver, they do not accumulate in the proper intrahepatic cell-type; thus drug targeting to the liver may represent a new promising strategy (Poelska et al., 2012). For several diseases, hepatocytes represent the most relevant target cell, playing a crucial role in viral hepatitis, steatohepatitis, some genetic diseases and several other metabolic disorders. However, the major issue is not drug uptake by hepatocytes; but other competing processes such as the first pass effect or drug uptake by other cell-types may occur. Many efforts have been dedicated to the targeted delivery of drugs and genes in particular to hepatocytes by the development of galactosylated polymeric or lipid carriers in order to enhance the therapeutic effects (in case of hepatocellular carcinoma, viral hepatitis or gene-based therapies) or to reduce side-effects of drugs (in case of antiviral or anticancer drugs) (Poelska et al., 2012). Galactosylation is a speculated strategy in this fieldbecause targeting via galactosylated carriers exploit highly specific interactions of galactose ligands with endogenous lectin receptors such as asialoglycoprotein receptor (ASGPR), which is specifically and abundantly present on hepatocytes (Jain et al., 2012; Rensen et al., 2001; Wu et al., 2004). This receptor has been used to deliver to hepatocytes all kinds of therapeutic compounds ranging from therapeutic proteins, antiviral agents (Di Stefano et al., 1997) to anticancer drugs (Di Stefano et al., 2006; Fiume et al., 2005). Active targeting by coupling galactose (GAL) residues or lactose moieties to proteins and polymers or by their introduction on the colloidal surface of nanoparticles or polymeric micelles, allow enhancing the uptake of drug-loaded systems into hepatocytes with high degree of selectivity (Fiume and Di Stefano, 2010; Li et al., 2010; Poelstra et al., 2012; Suo et al., 2010; Suriano et al., 2010; Wu et al., 2010; Yang et al., 2011; Zheng et al., 2011). In well-differentiated forms of hepatocel- lular carcinoma (HCC), hepatocytes over-express on the surface the ASGP-R (Hyodo et al., 1993) and many drug delivery systems have been already developed to deliver drugs to this receptor using lactosaminated or galactosaminated substituted drug carriers, * Corresponding author at: Lab of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università degli Studi di Palermo, via Archirafi 32, Palermo 90123, Italy. Tel.: +39 091 23891931; fax: +39 091 6100627. E-mail address: gennara.cavallaro@unipa.it (G. Cavallaro). http://dx.doi.org/10.1016/j.ijpharm.2014.02.047 0378-5173/ ã 2014 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 466 (2014) 172–180 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l home page : www.e lsevier.com/loca te/ijpharm