Elsevier

Journal of Controlled Release

Volume 203, 10 April 2015, Pages 126-139
Journal of Controlled Release

Review
Asialoglycoprotein receptor mediated hepatocyte targeting — Strategies and applications

https://doi.org/10.1016/j.jconrel.2015.02.022Get rights and content

Abstract

Hepatocyte resident afflictions continue to affect the human population unabated. The asialoglycoprotein receptor (ASGPR) is primarily expressed on hepatocytes and minimally on extra-hepatic cells. This makes it specifically attractive for receptor-mediated drug delivery with minimum concerns of toxicity. ASGPR facilitates internalization by clathrin-mediated endocytosis and exhibits high affinity for carbohydrates specifically galactose, N-acetylgalactosamine and glucose. Isomeric forms of sugar, galactose density and branching, spatial geometry and galactose linkages are key factors influencing ligand-receptor binding. Popular ligands for ASGPR mediated targeting are carbohydrate polymers, arabinogalactan and pullulan. Other ligands include galactose-bearing glycoproteins, glycopeptides and galactose modified polymers and lipids. Drug-ligand conjugates provide a viable strategy; nevertheless ligand-anchored nanocarriers provide an attractive option for ASGPR targeted delivery and are widely explored. The present review details various ligands and nanocarriers exploited for ASGPR mediated delivery of drugs to hepatocytes. Nanocarrier properties affecting ASGPR mediated uptake are discussed at length. The review also highlights the clinical relevance of ASGPR mediated targeting and applications in diagnostics. ASGPR mediated hepatocyte targeting provides great promise for improved therapy of hepatic afflictions.

Introduction

Liver, a major reticuloendothelial system (RES) organ actively participates in the body's defense process. Liver diseases are cited as the fifth major cause of death and reflect a steady increase. Following drug administration although drugs with molecular weight greater than 300 Da accumulate in the liver, rapid elimination including P-glycoprotein mediated efflux and non-specific target cell accumulation often result in poor success rates. Hepatocellular carcinoma (HCC) the third most mortal cancer in developing countries has a poor survival rate, while the need for improved treatment options in hepatitis is urgent [1], [2]. Malarial deaths often related to relapse, kill almost one child per minute [3]. Interestingly these afflictions affect a specific type of liver cell, the hepatocytes.

Targeted delivery to liver continues to attract immense attention and is a subject of recent reviews. Receptor-mediated endocytosis is an attractive approach to deliver drugs to specific cell types. It enables high drug concentrations within the cell and minimum concentration at off-target sites, thereby amalgamating high efficacy with low toxicity. Selection of an appropriate receptor for targeted delivery could ensure a great degree of success. The asialoglycoprotein receptor (ASGPR) present in abundance on hepatocytes and minimally expressed on extra-hepatic could provide attractive advantage for hepatocyte-mediated delivery. ASGPR mediated targeted delivery to hepatocytes is dealt with, although briefly in a review [4]. Another review focuses on glycosylated nanocarriers for targeted delivery to specific cell types. While hepatocytes are one among a number of targets discussed, the major focus is on galactosylated liposomes [5].

The present review entails a detailed discussion on ASGPR and ASGPR mediated hepatocyte targeted delivery. Ligands for ASGPR mediated targeting, drug-ligand conjugates and ligand-anchored nanocarriers are discussed in detail. The review also focuses on their clinical relevance and diagnostic applications.

Section snippets

Asialoglycoprotein receptor

ASGPR also known as ‘The Ashwell–Morell Receptor’ was the first cellular mammalian lectin discovered [6]. ASGPR clears desialylated glycoproteins with exposed non-reducing D-galactose (Gal) or N-acetylgalactosamine (GalNAc) as end groups. The uptake of cellular fibronectin, pro-thrombotic components, hepatic lipoproteins and serum immunoglobulin-A is another function of ASGPR. Pharmacological functions of ASGPR have been reviewed earlier [7]. The interaction of ASGPR with cellular components of

Ligands for targeting ASGPR

Sugar based ligands exhibit maximum affinity to ASGPR with their physicochemical properties playing a predominant role in ligand binding. Natural and synthetic ligands have been explored.

By-passing reticuloendothelial system (RES)

RES plays a major role in innate immune defense, comprising of mobile and fixed-tissue macrophages, monocytes and special endothelial cells of liver, spleen, bone marrow and lymph node. Liver predominates with almost 80% of macrophages presented as fixed-tissue macrophages, mainly Kupffer cells. They identify, filter and destroy particles, dead cells, abnormal cells, foreign matter, virus, bacteria, etc., preventing their spread in systemic circulation [91]. RES of liver and spleen primarily

Clinical relevance and advances in ASGPR based targeting

Hepatocellular carcinoma, hepatitis and malaria are three major diseases where ASGPR based targeting could provide a major advantage. More specifically using targeted nanocarriers facilitated by receptor-mediated endocytosis coupled with by-pass of P-glycoprotein mediated efflux could ensure high drug localization. Extensive studies using drug-ligand conjugates and ligand-anchored nanocarriers for these conditions are evident and documented in Table 2, Table 3, Table 4. Yet another important

Contradictions

The merits of ASGPR targeting are often circumvented under specialized conditions. The non-specific hepatic accumulation of Lac-HSA conjugated to doxorubicin in HCC, reflects low ASGPR level, which could be attributed to poor maturation and differentiation in initial stages of HCC [235], [236], [237]. Anti-ASGPR antibodies associated with autoimmune hepatitis could neutralize ASGPR in hepatitis, thereby contravening the advantage of ASGPR targeting [220], [238].

Gal-emulsions show greater

Conclusion

Nanocarriers and targeted drug delivery are synonymous. Anchoring nanocarriers with ASGPR ligands can provide a quantum leap in hepatocyte specific targeted delivery. Docking studies support tailor made synthetic ligands incorporating Gal/Gal-NAc as dimers and oligomers, with C3 carbon free, to form multivalent and multiantennary structure covalently coupled to nanocarriers as promising ligands. The use of various spacer arms at 25–30 Å could provide improved benefits. On one hand while such new

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