title: Design, synthesis and biological evaluation of carbohydrate-functionalized cyclodextrins and liposomes for hepatocyte-specific targeting.
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.
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Research Campus-Golm, 14476 Potsdam, Germany.
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Kikkeri
authors.forename: Maha
authors.initials: M
authors.lastname: Maglinao
authors.forename: Paola
authors.initials: P
authors.lastname: Laurino
authors.forename: Mayeul
authors.initials: M
authors.lastname: Collot
authors.forename: Sung You
authors.initials: SY
authors.lastname: Hong
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods; D006017:Glycolipids / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D037263:Asialoglycoprotein Receptor; D002241:Carbohydrates; D050091:Dendrimers; D006017:Glycolipids; D008081:Liposomes; D047392:beta-Cyclodextrins; D004317:Doxorubicin