Drug targeting hepatocytes specifically Asialoglycoprotein receptors
Keywords:
N\AAbstract
The Asialoglycoprotein receptor has been on interest to target the liver for treatment of multiple ailments. Asialoglycoprotein receptors being easy target for carbohydrate molecules, contains a calcium ion channel, type C-lectins and are major on the hepatocyte (the outer covering of liver plasma membrane). This receptor has a great potential, it can help target a drug onto a specific liver site, it can be used for diagnostic and therapeutic purposes.
When we discuss about liver diseases with a very minimal amount of nontargeting drug or a delivery system, is due to the high specificity, effective internalisation rate and also easy access to the blood and lymph vascular system. But then the targeting is not achieved as the drug can be carry forward with the flow of blood. We in this review article draw a conclusive structure of the number of molecules which can impact on targeting liver. Along with its use in liver diagnostics, it also examines the receptor's clinical importance in a variety of liver diseases.
Graphical abstract
Liver with hepatocyte cell on the surface containing ASGPR
Figure 1: Different procedurs or ligands to target Asialoglycoprotein receptor
Downloads
Metrics
References
Mazzanti R, Gramantieri L, Bolondi L. Hepatocellular carcinoma: epidemiology and clinical aspects. Mol Aspects Med 2008;29:130–43.
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11:97–107.
World Health Organization. Malaria: fact sheet N94. Geneva: World Health Organization; 2014.
Poelstra K, Prakash J, Beljaars L. Drug targeting to the diseased liver. J Control Release 2012;161:188–97.
Kawakami S, Hashida M. Glycosylation-mediated targeting of carriers. J Control Release 2014;190:542–55.
Grewal PK. The Ashwell–Morell receptor. In: Minoru F, editor. Methods in enzymology. San Diego: Academic Press; 2010. p. 223–41.
Vishvakrama P, Sharma S. Liposomes: an overview. Journal of Drug Delivery and Therapeutics. 2014 Jun 24:47-55.
Vishvakarma P. Design and development of montelukast sodium fast dissolving films for better therapeutic efficacy. Journal of the Chilean Chemical Society. 2018 Jun;63(2):3988-93.
Dodeur M, Durand D, Dumont J, Durand G, Feger J, Agneray J. Effects of streptozotocin-induced diabetes mellitus on the binding and uptake of asialoorosomucoid by isolated hepatocytes from rats. Eur J Biochem 1982;123:383–87.
Li Y, Huang G, Diakur J, Wiebe LI. Targeted delivery of macromolecular drugs: asialoglycoprotein receptor (ASGPR) expression by selected hepatoma cell lines used in antiviral drug development. Curr Drug Deliv 2008;5:299–302.
Prabhakar Vishvakarma, Jaspreet Kaur, Gunosindhu Chakraborthy, Dhruv Kishor Vishwakarma, Boi Basanta Kumar Reddy, Pampayya Thanthati, Shaik Aleesha, Yasmin Khatoon. Nephroprotective Potential of Terminalia Arjuna Against Cadmium-Induced Renal Toxicity by In-Vitro Study. J. Exp. Zool. India Vol. 28, No. 1, pp. 939-944, 2025
Onizuka T, Shimizu H, Moriwaki Y, Nakano T, Kanai S, Shimada I, et al. NMR study of ligand release from asialoglycoprotein receptor under solution conditions in early endosomes. FEBS J 2012;279:2645–56.
D’Souza AA, Jain P, Galdhar CN, Samad A, Degani MS, Devarajan PV. Comparative in silico-in vivo evaluation of ASGP-R ligands for hepatic targeting of curcumin Gantrez nanoparticles. AAPS J 2013;15:696–706.
Wu J, Nantz MH, Zern MA. Targeting hepatocytes for drug and gene delivery: emerging novel approaches and applications. Front Biosci 2002;7:d717–25.
Mandal S, Vishvakarma P, Verma M, Alam MS, Agrawal A, Mishra A. Solanum Nigrum Linn: an analysis of the Medicinal properties of the plant. Journal of Pharmaceutical Negative Results. 2023 Jan 1:1595-600.
McAbee DD, Jiang X, Walsh KB. Lactoferrin binding to the rat asialoglycoprotein receptor requires the receptor’s lectin properties. Biochem J 2000;348:113–17.
Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. J Control Release 2010;145:182–95.
Tanabe T, Pricer WE Jr, Ashwell G. Subcellular membrane topology and turnover of a rat hepatic binding protein specific for asialoglycoproteins. J Biol Chem 1979;254:1038–43.
Varga CM, Wickham TJ, Lauffenburger DA. Receptor-mediated targeting of gene delivery vectors: insights from molecular mechanisms for improved vehicle design. Biotechnol Bioeng 2000;70:593–605.
Schwartz AL, Bolognesi A, Fridovich SE. Recycling of the asialoglycoprotein receptor and the effect of lysosomotropic amines in hepatoma cells. J Cell Biol 1984;98:732–38.
Schwartz AL, Fridovich SE, Lodish HF. Kinetics of internalization and recycling of the asialoglycoprotein receptor in a hepatoma cell line. J Biol Chem 1982;257:4230–37.
Warren R, Doyle D. Turnover of the surface proteins and the receptor for serum asialoglycoproteins in primary cultures of rat hepatocytes. J Biol Chem 1981;256:1346–55.
Wang HX, Xiong MH, Wang YC, Zhu J, Wang J. N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver. J Control Release 2013;166:106–14.
Kolatkar AR, Leung AK, Isecke R, Brossmer R, Drickamer K, Weis WI. Mechanism of N-acetylgalactosamine binding to a C-type animal lectin carbohydrate-recognition domain. J Biol Chem 1998;273:19502–08.
Ruiz NI, Drickamer K. Differential ligand binding by two subunits of the rat liver asialoglycoprotein receptor. Glycobiology 1996;6:551–59.
Mukthavaram R, Marepally S, Venkata MY, Vegi GN, Sistla R, Chaudhuri A. Cationic glycolipids with cyclic and open galactose head groups for the selective targeting of genes to mouse liver. Biomaterials 2009;30:2369–84.
Franssen EJF, Jansen RW, Vaalburg M, Meijer DKF. Hepatic and intrahepatic targeting of an anti-inflammatory agent with human serum albumin and neoglycoproteins as carrier molecules. Biochem Pharmacol 1993;45:1215–26.
Kawakami S, Yamashita F, Nishida K, Nakamura J, Hashida M. Glycosylated cationic liposomes for cell-selective gene delivery. Crit Rev Ther Drug Carrier Syst 2002;19:171–90.
Stokmaier D, Khorev O, Cutting B, Born R, Ricklin D, Ernst TO, et al. Design, synthesis and evaluation of monovalent ligands for the asialoglycoprotein receptor (ASGP-R). Bioorg Med Chem 2009;17:7254–64.
Nishikawa M. Development of cell-specific targeting systems for drugs and genes. Biol Pharm Bull 2005;28:195–200.
Managit C, Kawakami S, Nishikawa M, Yamashita F, Hashida M. Targeted and sustained drug delivery using PEGylated galactosylated liposomes. Int J Pharm 2003;266:77–84.
Wong TC, Townsend RR, Lee YC. Synthesis of D-galactosamine derivatives and binding studies using isolated rat hepatocytes. Carbohydr Res 1987;170:27–46.
Staud F, Nishikawa M, Takakura Y, Hashida M. Liver uptake and hepato-biliary transfer of galactosylated proteins in rats are determined by the extent of galactosylation. Biochim Biophys Acta 1999;1427:183–92.
Nishikawa M, Takemura S, Takakura Y, Hashida M. Targeted delivery of plasmid DNA to hepatocytes in vivo: optimization of the pharmacokinetics of plasmid DNA/galactosylated poly(L-lysine) complexes by controlling their physicochemical properties. J Pharmacol Exp Ther 1998;287:408–15.
Hashida M, Nishikawa M, Yamashita F, Takakura Y. Cell-specific delivery of genes with glycosylated carriers. Adv Drug Deliv Rev 2001;52:187–96.
Lee RT, Wang MH, Lin WJ, Lee YC. New and more efficient multivalent glyco-ligands for asialoglycoprotein receptor of mammalian hepatocytes. Bioorg Med Chem 2011;19:2494–500.
Biessen EA, Beuting DM, Roelen HC, van de Marel GA, van Boom JH, van Berkel TJ. Synthesis of cluster galactosides with high affinity for the hepatic asialoglycoprotein receptor. J Med Chem 1995;38:1538–46.
Rensen PC, de Vrueh RL, Kuiper J, Bijsterbosch MK, Biessen EA, van Berkel TJ. Recombinant lipoproteins: lipoprotein-like lipid particles for drug targeting. Adv Drug Deliv Rev 2001;47:251–76.
Connolly DT, Townsend RR, Kawaguchi K, Bell WR, Lee YC. Binding and endocytosis of cluster glycosides by rabbit hepatocytes: evidence for a short-circuit pathway that does not lead to degradation. J Biol Chem 1982;257:939–45.
Westerlind U, Westman J, Tornquist E, Smith CI, Oscarson S, Lahmann M, et al. Ligands of the asialoglycoprotein receptor for targeted gene delivery, part 1: synthesis of and binding studies with biotinylated cluster glycosides containing N-acetylgalactosamine. Glycoconj J 2004;21:227–41.
Singh M, Ariatti M. Targeted gene delivery into HepG2 cells using complexes containing DNA, cationized asialoorosomucoid and activated cationic liposomes. J Control Release 2003;92:383–94.
Rice KG, Weisz OA, Barthel T, Lee RT, Lee YC. Defined geometry of binding between triantennary glycopeptide and the asialoglycoprotein receptor of rat hepatocytes. J Biol Chem 1990;265:18429–34.
Lee YC. Biochemistry of carbohydrate-protein interaction. FASEB J 1992;6:3193–200.
Joziasse DH, Lee RT, Lee YC, Biessen EA, Schiphorst WE, Koeleman CA, et al. α3-galactosylated glycoproteins can bind to the hepatic asialoglycoprotein receptor. Eur J Biochem 2000;267:6501–08.
Saunier B, Triyatni M, Ulianich L, Maruvada P, Yen P, Kohn LD. Role of the asialoglycoprotein receptor in binding and entry of hepatitis C virus structural proteins in cultured human hepatocytes. J Virol 2003;77:546–59.
Sliedregt LA, Rensen PC, Rump ET, van Santbrink PJ, Bijsterbosch MK, Valentijn AR, et al. Design and synthesis of novel amphiphilic dendritic galactosides for selective targeting of liposomes to the hepatic asialoglycoprotein receptor. J Med Chem 1999;42:609–18.
Managit C, Kawakami S, Yam8232ashita F, Hashida M. Effect of galactose density on asialoglycoprotein receptor-mediated uptake of galactosylated liposomes. J Pharm Sci 2005;94:2266–75.
McAbee DD, Jiang X. Copper and zinc ions differentially block asialoglycoprotein receptor-mediated endocytosis in isolated rat hepatocytes. J Biol Chem 1999;274:14750–58.
Geffen I, Spiess M. Phorbol ester-induced redistribution of the ASGP receptor is independent of receptor phosphorylation. FEBS Lett 1991;305:209–12.
Kim EM, Jeong HJ, Kim SL, Sohn MH, Nah JW, Bom HS, et al. Asialoglycoprotein-receptor-targeted hepatocyte imaging using 99mTc galactosylated chitosan. Nucl Med Biol 2006;33:529–34.
Debanne MT, Evans WH, Flint N, Regoeczi E. Receptor-rich intracellular membrane vesicles transporting asialotransferrin and insulin in liver. Nature 1982;298:398–400.
Venugopala KN, Venugopala R, Rasool A, Balogun M, Kandeel M, Dharmarajan S, et al. Development of asialoglycoprotein receptor-targeted nanoparticles for selective delivery of gemcitabine to hepatocellular carcinoma. Molecules 2019;24:4566. https://doi.org/10.3390/molecules24244566.
O’Sullivan J, Muñoz-Muñoz J, Turnbull G, Sim N, Penny S, Moschos S. Beyond GalNAc! Drug delivery systems comprising complex oligosaccharides for targeted use of nucleic acid therapeutics. RSC Adv 2022;12:20432–46. https://doi.org/10.1039/D2RA01999J.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
