ReviewAsialoglycoprotein receptor mediated hepatocyte targeting — Strategies and applications
Graphical abstract
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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