A New N-Acetylgalactosamine Containing Peptide as a Targeting Vehicle for Mammalian Hepatocytes Via Asialoglycoprotein Receptor Endocytosis

Abstract

Galactoside-containing cluster ligands have high affinity for asialoglycoprotein receptors (ASGP-r), which are found in abundance in mammalian parenchymal liver cells. These ligands may be conjugated with a therapeutic drug to improve the efficiency of delivery to diseased liver cells. This report describes a new synthetic route towards clustering glycopeptides containing N-acetyl-D-galactosamine (GalNAc). The building block Fmoc-alpha-(ah-Ac3GalNAc)-L-glutamate allowed access to the target compound YEEE(alpha-ah-GalNAc)(3), a structural mimic of YEE(ah-GalNAc)(3), via solid phase peptide synthesis (SPPS). Fatty acid, poly-lysine, fluorescein and biotin conjugates further demonstrate the facility of the described method. Using fluorescein labeling and 131I labeling, in vitro and in vivo assays confirmed that YEEE(alpha-ah-GalNAc)(3) possesses both specificity and affinity to the liver, similar to the agent YEE(ah-GalNAc)(3), which targets liver lesions. The synthesis described in this report represents a considerable improvement in synthesizing a ligand for ASGP-r by simplifying both the preparation of the starting material and the procedure for conjugating the galactosidase cluster to drugs.

Galactosylated polymeric carriers for liver targeting of sorafenib

“…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 field because 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).…”

Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis

“…These studies were carried out using two test parameters; one by measuring the CTGF protein levels in target cells and second; by studying the reversal of the activation of myofibroblasts which participate in fibrosis. Since attachment of galactosamine to a variety of uncharged polymers can facilitate targeting hepatocytes via asialoglycoprotein receptor interaction [ 33 , 39 ] galactosamine targeting can enhance endocytosis of SSLNP, and increase the amount of siRNA-SSLNP in the cells. This would enable greater gene silencing.…”

Engineered Biological Entities for Drug Delivery and Gene Therapy

“…Many peptides have been described in the literature as receptor-specific ligands so any of them can be added to the multifunctional proteins in order to confer them cell specificity. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] The most natural specific ligands that can also be used for cell targeting are monoclonal antibodies. 32,[63][64][65] In addition, if no specific peptides are available for an intended target, new specific binding peptides can be found by using phage display 66 or combinatorial chemistry.…”