Design, synthesis and biological evaluation of carbohydrate-functionalized cyclodextrins and liposomes for hepatocyte-specific targeting

Targeting glycan-binding receptors is an attractive strategy for cell-specific drug and gene delivery. The C-type lectin asialoglycoprotein receptor (ASGPR) is particularly suitable for liver-specific delivery due to its exclusive expression by parenchymal hepatocytes. In this study, we designed and developed an efficient synthesis of carbohydrate-functionalized beta-cyclodextrins (beta CDs) and liposomes for hepatocyte-specific delivery. For targeting of ASGPR, rhodamine B-loaded beta CDs were functionalized with glycodendrimers. Liposomes were equipped with synthetic glycolipids containing a terminal D-GalNAc residue to mediate binding to ASGPR. Uptake studies in the human hepatocellular carcinoma cell line HepG2 demonstrated that beta CDs and liposomes displaying terminal D-Gal/D-GalNAc residues were preferentially endocytosed. In contrast, uptake of beta CDs and liposomes with terminal D-Man or D-GlcNAc residues was markedly reduced. The D-Gal/D-GalNAcfunctionalized beta CDs and liposomes presented here enable hepatocyte-specific targeting. Gal-functionalized beta CDs are efficient molecular carriers to deliver doxorubicin in vitro into hepatocytes and induce apoptosis.