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

Org Biomol Chem. 2010 Nov 7;8(21):4987-96. doi: 10.1039/c0ob00372g. Epub 2010 Sep 2.

Abstract

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 β-cyclodextrins (βCDs) and liposomes for hepatocyte-specific delivery. For targeting of ASGPR, rhodamine B-loaded βCDs 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 βCDs and liposomes displaying terminal D-Gal/D-GalNAc residues were preferentially endocytosed. In contrast, uptake of βCDs and liposomes with terminal d-Man or D-GlcNAc residues was markedly reduced. The d-Gal/d-GalNAc-functionalized βCDs and liposomes presented here enable hepatocyte-specific targeting. Gal-functionalized βCDs are efficient molecular carriers to deliver doxorubicin in vitro into hepatocytes and induce apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / administration & dosage
  • Apoptosis / drug effects
  • Asialoglycoprotein Receptor / metabolism*
  • Carbohydrate Metabolism
  • Carbohydrates / chemistry*
  • Dendrimers / chemistry
  • Dendrimers / metabolism
  • Doxorubicin / administration & dosage
  • Drug Delivery Systems* / methods
  • Glycolipids / chemistry
  • Glycolipids / metabolism
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Liposomes / chemistry*
  • Liposomes / metabolism
  • beta-Cyclodextrins / chemistry*
  • beta-Cyclodextrins / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Asialoglycoprotein Receptor
  • Carbohydrates
  • Dendrimers
  • Glycolipids
  • Liposomes
  • beta-Cyclodextrins
  • Doxorubicin