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Structural features of synthetic glycoconjugates and efficiency of their interaction with glycoprotein receptors on the surface of hepatocytes

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Objectives. Over the last few years, medicinal chemistry research has been focusing on the creation of molecules that can target particular body systems, organs and tissues, thus abating systemic toxicity and side effects, and, most of all, boosting therapeutic potential. This goal can be achieved through the specific interaction of such drugs with active sites of cellular receptors. For example, glycoprotein receptors that can be found on cellular surfaces in neural tissues and liver parenchyma, selectively bind various glycoproteins and glycosides, facilitating their penetration into cells. This review describes how certain parameters of ligand structure (the nature and length of the spacer between carbohydrate and non-carbohydrate fragments of the molecule, number of carbohydrate residues per molecule, etc.) influence the penetration efficiency of synthetic glycoconjugates into liver cells.

Methods. This review article summarizes 75 research papers and discusses data from in vitro and in vivo experiments showing which structures of synthetic carbohydrate derivatives are optimal for targeted drug delivery into liver cells.

Results. The surface of liver cells (hepatocytes) contains a significant number of asialoglycoprotein receptors (ASGP-R) that are almost never found elsewhere. This makes ASGP-R an ideal target for the directed treatment of liver diseases, including such difficult, socially important conditions as hepatocellular carcinoma and Hepatitis C. A number of various ligands and targeted (to ASGP-R) delivery systems have been designed. Such molecules always contain derivatives of mono- and disaccharides, most commonly D-glucose, D-galactose, D-lactose and N-acetylglucosamines. This review contains the chemical structures of carbohydrate-based ligands.

Conclusions. Glycolipids based on D-carbohydrates, when in liposomes, facilitate penetration into liver cells by a receptor-mediated, clathrin-dependent endocytosis mechanism that is activated upon contact of the carbohydrate-containing ligand fragment with the active site of ASGP-R. It can be addressed by the use of monovalent derivatives of carbohydrates as well as polyvalent glycoconjugates. Alterations in the ligand structure and the number of liposomal modifications can boost the therapeutic effect. The distance between the liposomal surface and the carbohydrate residue (spacer length), as well as the hydrophilic-lipophilic balance of the ligand molecule, have a great effect on the affinity and cellular response.

About the Authors

A. S. Nosova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Anastasiya S. Nosova, Master of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

86, Vernadskogo pr., Moscow, 119571, Russia

Competing Interests: The authors declare no conflict of interest.

Yu. A. Budanova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Ulyana A. Budanova, Cand. of Sci. (Chemistry), Assistant of Professor of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

Scopus Author ID 14622352500, ResearcherID E-1659-2014

86, Vernadskogo pr., Moscow, 119571, Russia

Competing Interests: The authors declare no conflict of interest.

Yu. L. Sebyakin
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Yury L. Sebyakin, Dr. of Sci. (Chemistry), Professor, Professor of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

Scopus Author ID 6701455145, ResearcherID T-2835-2019

86, Vernadskogo pr., Moscow, 119571, Russia

Competing Interests: The authors declare no conflict of interest.


1. Farazi P.A., DePinho R.A. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat. Rev. 2006;6:674-687.

2. Llovet J.M., Burroughs A., Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907-1917.

3. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J. Viral Hepat. 2004;11:97-107.

4. Jong Y.P. De, Rice C.M., Ploss A. Editorial evaluation of combination therapy against hepatitis C virus infection in human liver chimeric mice. J. Hepatol. 2011;54(5):848-850.

5. Shulla A., Randall G. Hepatitis C virus-host interactions. In: Hepatitis C Virus I. / T. Miyamura, S.M. Lemon, C.M. Walker, T. Wakita (eds). Springer Japan, 2016; pp. 197-233.

6. Eisenberg C., Seta N., Appel M., Feldmann G. Asialoglycoprotein receptor in human isolated hepatocytes from normal liver and its apparent increase in liver with histological alterations. J. Hepatol. 1991;13:305-309.

7. Poelstra K., Prakash J., Beljaars L. Drug targeting to the diseased liver. J. Control. Release. 2012;161(2):188-197.

8. Grewal P.K. The Ashwell–Morell Receptor. In: Methods in Enzymology. California: Elsevier Inc., 2010. Iss.1; pp. 223-241.

9. Ashwell G., Harford J. Carbohydrate-specific receptors of the liver. Annu. Rev. Biochem. 1982;51(2):531-554.

10. Hubbard A.L., Stukenbrok H. An electron microscope autoradiographic study of the carbohydrate recognition systems in rat liver. J. Cell. Biol. 1979;83:65-81.

11. Hardy M.R., Townsend R.R., Parkhurst S.M., Lee Y.C. Different modes of ligand binding to the hepatic galactose/N-acetylgalactosamine lectin on the surface of rabbit hepatocytes. Biochemistry. 1985;24:22-28.

12. Dotzauer A., Gebhardt U., Bieback K., Göttke U., Kracke A., Mages J., Lemon S.M., Vallbracht A. Hepatitis A virus-specific immunoglobulin A mediates infection of hepatocytes with hepatitis A virus via the asialoglycoprotein receptor. J. Virol. 2002;74(23):10950-10957.

13. Treichel U., Meyer zum Büschenfelde K.H., Stockert R.J., Poralla T. The asialoglycoprotein receptor mediates hepatic binding and uptake of natural hepatitis B virus particles derived from viraemic carriers. J. Gen. Virol. 1994;75(11):3021-3029.

14. Becker S., Spiess M., Klenk H.D. The asialoglycoprotein receptor is a potential liver-specific receptor for Marburg virus. J. Gen. Virol. 1995;76(2):393-399.

15. Treichel U., Meyer zum Büschenfelde K.H., Dienes H.P., Gerken G. Receptor-mediated entry of hepatitis B virus particles into liver cells. Arch. Virol. 1997;142(3):493-498.

16. Weigel P.H., Yik J.H.N. Glycans as endocytosis signals: the cases of the asialoglycoprotein and hyaluronan/chondroitin sulfate receptors. Biochim. Biophys. Acta. 2002;1572:341-363.

17. Cummings R.D., McEver R.P. C-type Lectins. Essentials of Glycobiology. NY: Cold Spring Harbor Labouratory Press, 2009. Iss. 2: 784 p.

18. Bischoffss J., Lodishst H.F. Two asialoglycoprotein receptor polypeptides in human hepatoma cells. J. Biol. Chem. 1987;262(24):11825-11832.

19. Huang X., Leroux J.-C., Castagner B. Well-defined multivalent ligands for hepatocytes targeting via asialoglycoprotein receptor. Bioconjug. Chem. 2017;28(2):283-295.

20. Henis Y.I., Katzir Z., Shia M.A., Lodish H.F. Oligomeric structure of the human asialoglycoprotein receptor: Nature and stoichiometry of mutual complexes containing H1 and H2 polypeptides assessed by fluorescence photobleaching recovery. J. Cell Biol. 1990;111(4):1409-1418.

21. McAbee D.D., Jiang X., Walsh K.B. Lactoferrin binding to the rat asialoglycoprotein receptor requires the receptor’s lectin properties. Biochem. J. 2000;348:113-117.

22. Weis W.I., Taylor M.E., Drickamer K. The C-type lectin superfamily in the immune system. Immunol. Rev. 1998;163:19-34.

23. Shuina E.D., Shchelick I.S., Sebyakin Yu.L. Synthesis and properties of neoglycolipids based on 2-amino-2-hydroxymethylpropane-1,3-diol. Tonkie Khim. Tekhnol. = Fine Chem. Technol. 2017;12(4):65-74 (in Russ.).

24. Kawakami S., Hashida M. Glycosylation-mediated targeting of carriers. J. Control. Release. 2014;190:542-555.

25. Digiacomo L., Cardarelli F., Pozzi D., Palchetti S., Digman M.A., Gratton E., Capriotti A.L., Mahmoudi M., Caracciolo G. An apolipoprotein-enriched biomolecular corona switches the cellular uptake mechanism and trafficking pathway of lipid nanoparticles. Nanoscale. 2017;9(44):17254-17262.

26. Futter C.E., Pearse A., Hewlett L.J., Hopkins C.R. Multivesicular endosomes containing internalized EGF- EGF receptor complexes mature and then fuse directly with lysosomes. J. Cell Biol. 1996;132(6):1011-1023.

27. Luzio J.P., Rous B.A., Bright N.A., Pryor P.R., Mullock B.M., Piper R.C. Lysosome-endosome fusion and lysosome biogenesis. J. Cell Sci. 2000;113:1515-1524.

28. Banizs A.B., Huang T., Nakamoto R.K., Shi W. Endocytosis pathways of endothelial cell derived exosomes. Mol. Pharm. 2018;15(12):5585-5590.

29. Douam F., Lavillette D., Cosset F.L. The mechanism of HCV entry into host cells. Prog. Mol. Biol. Transl. Sci. 2015;129:63-107.

30. Kawasaki T., Ashwell G. Carbohydrate structure of glycopeptides isolated from an hepatic membrane-binding protein specific for asialoglycoproteins. J. Biol. Chem. 1976;251(17):5292-5299.

31. Weis W.I., Drickamer K., Hendrickson W.A. Structure of a C-type mannose-binding protein complexed with an oligosaccharide. Nature. 1992;360:127-134.

32. Drickamer K., Mamon J.F., Binns G., Leung J.O. Primary structure of the rat liver asialoglycoprotein receptor. Structural evidence for multiple polypeptide species. J. Biol. Chem. 1984;259(2):770-778.

33. Hong W., Le A. Van, Doyle D. Identification and characterization of a murine receptor for galactose-terminated glycoproteins. Hepatology. 1988;8(3):553-558.

34. Guan M., Zhou Yi, Zhu Q-L., Liu Y. N-Trimethyl chitosan nanoparticle-encapsulated lactosyl-norcantharidin for liver cancer therapy with high targeting efficacy. Nanomedicine Nanotechnology, Biol. Med. 2012;8(7):1172-1181.

35. D’Souza A.A., Devarajan P. V. Asialoglycoprotein receptor mediated hepatocyte targeting – Strategies and applications. J. Control. Release. 2015;203:126-139.

36. Yoshino K., Nakamura K., Terajima Y., Kurita A. Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochim. Biophys. Acta – Biomembr. 2012; 1818(11):2901-2907.

37. Franssen E.J.F., Jansen R.W., Vaalburg M., Meijer D.K. Hepatic and intrahepatic targeting of an anti-inflammatory agent with human serum albumin and neoglycoproteins as carrier molecules. Biochem. Pharmacol. 1993;45(6):1215-1226.

38. Rensen P.C.N., Sliedregt L.A., Ferns M., Kieviet E., van Rossenberg S.M., van Leeuwen S.H., van Berkel T.J., Biessen E.A. Determination of the upper size limit for uptake and processing of ligands by the asialoglycoprotein receptor on hepatocytes in vitro and in vivo. J. Biol. Chem. 2001;276(40):37577-37584.

39. Engel A., Chatterjee S.K., Al-Arifi A., Reiemann D., Langner J., Nuhn P. Influence of spacer length on interaction of mannosylated liposomes with human phagocytic cells. Pharm. Res. 2003;20(1):51-57.

40. Makky A., Michel J-P., Maillaed P., Rosilio V. Biomimetic liposomes and planar supported bilayers for the assessment of glycodendrimeric porphyrins interaction with an immobilized lectin. Biochim. Biophys. Acta – Biomembr. 2011;1808(3):656-666.

41. Sundler R. Studies on the effective size of phospholipid headgroups in bilayer vesicles using lectin-glycolipid interaction as a steric probe. Biochim. Biophys. Acta. 1984;771:59-67.

42. Sasaki A., Murahashi N., Yamada H., Morikawa A. Syntheses of novel galactosyl ligands for liposomes and their accumulation in the rat liver. Biol. Pharm. Bull. 1994;17(5):680-685.

43. Yoshioka H., Ohmura T., Hasegawa M., Hirota S., Makino M., Kamiya M. Synthesis of galactose derivatives that render lectin-induced agglutinating ability to liposomes. J. Pharm. Sci. 1993;82(3):273-275.

44. Shimada K., Kamps J.A., Regts J., Ikeda K., Shiozawa T., Hirota S., Scherphof G.L. Biodistribution of liposomes containing synthetic galactose-terminated diacylglyceryl-poly(ethyleneglycol)s. Biochim. Biophys. Acta – Biomembr. 1997;1326(2):329-341.

45. Valentijn A.R.P.M., van der Marel G.A., Sliedregt L., van Berkel T. Solid-phase synthesis of lysine-based cluster galactosides receptor with high affinity for the asialoglycoprotein receptor. Tetrahedron. 1997;53(2):759-770.

46. Biessen E.A.L., Broxterman H., van Boom J.H., van Berkel T.J. The cholesterol derivative of a triantennary galactoside with high affinity for the hepatic asialoglycoprotein receptor: A potent cholesterol lowering agent. J. Med. Chem. 1995;38:1846-1852.

47. 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(3):383-394.

48. Nosova A.S., Koloskova O.O., Shilovskiy I.P., Sebyakin Yu.L., Khaitov M.R. Lactose-based glycoconjugates with variable spacers for design of liver-targeted liposomes. Biomeditsinskaya khimiya [Biomedical Chemistry]. 2017;63(5):467-471 (in Russ.)

49. Prakash T.P., Yu J., Migawa M.T., Kinberger G.A., Wan W.B., Østergaard M.E., Carty R.L., Vasquez G. Comprehensive structure activity relationship of triantennary N-acetylgalactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J. Med. Chem. 2016; 59(6):2718-2733.

50. Mukthavaram R., Marepally S., Venkata M.Y., Vegi G.N., 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(12):2369-2384.

51. Sun P., HeY., Lin M., Zhao Y. Glyco-regioisomerism effect on lectin-binding and cell-uptake pathway of glycopolymer-containing nanoparticles. ACS Macro Lett. 2014;3:96-101.

52. Fukuda I., Mochizuki S., Sakurai K. Macrophage-targeting gene delivery using a micelle composed of mannose-modified lipid with triazole ring and dioleoyl trimethylammonium propane. Biomed. Res. Int. 2015;(10):1-8.

53. Monestier M., Charbonnier P., Gateau C., Cuillel M., Robert F., Lebrun C., Mintz E., Renaudet O., Delangle P. ASGPR-mediated uptake of multivalent glycoconjugates for drug delivery in hepatocytes. ChemBioChem. 2016;17:590-594.

54. Grant C.W.M., Peters M.W. Lectin-membrane interactions information from model systems. Biochim. Biophys. Acta – Rev. Biomembr. 1984;779(4):403-422.

55. Koloskova O.O., Budanova U.A., Shchelik I.C.,Shilovskii I.P., Khaitov M.R., Sebyakin Y.L. Examination the properties of lipopeptide liposomes modified by glycoconjugates. Nano Hybrids Compos. 2017;13:82-88.

56. Sliedregt L.A.J.M., Rensen P.C., Rump E.T., van Santbrink P.J., Bijsterbosch M.K., Valentijn A.R., van der Marel G.A., van Boom J.H., van Berkel T.J., Biessen E.A. Design and synthesis of novel amphiphilic dendritic galactosides for selective targeting of liposomes to the hepatic asialoglycoprotein receptor. J. Med. Chem. 1999;42:609-618.

57. Engel A., Chatterjee S.K., Al-Arifi A., Nuhn P. Influence of spacer length on the agglutination of glycolipid-incorporated liposomes by ConA as model membrane. J. Pharm. Sci. 2003;92(11):2229-2235.

58. Narang A.S., Thoma L., Miller D.D., Mahato R.I. Cationic lipids with increased DNA binding affinity for nonviral gene transfer in dividing and nondividing cells. Bioconjug. Chem. 2005;16(1):156-168.

59. Felgner J.H., Kumar R., Sridhar C.N., Wheeler C.J., Tsai Y.J., Border R., Ramsey P., Martin M., Felgner P.L. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J. Biol. Chem. 1994;269(4):2550-2561.

60. Maiti B., Kamra M., Karande A.A., Bhattacharya S. Transfection efficiencies of α-tocopherylated cationic gemini lipids with hydroxyethyl bearing headgroups under high serum conditions. Org. Biomol. Chem. 2018;11:1983-1993.

61. Li H., Hao Y., Wang N., Wang L., Jia S., Wang Y., Yang L., Zhang Y., Zhang Z. DOTAP functionalizing single-walled carbon nanotubes as non-viral vectors for efficient intracellular siRNA delivery. Drug. Deliv. 2016;23(3):840-848.

62. Berchel M., Akhter S., Berthe W., Gonçalves C., Dubuisson M., Pichon C., Jaffrès P-A., Midoux P. Synthesis of α-amino-lipophosphonates as cationic lipids or co-lipids for DNA transfection in dendritic cells. J. Mater. Chem. B. 2017;5(33):6869-6881.

63. Zhao Y., Zhu J., Zhou H., Guo X., Tian T., Cui S., Zhen Y., Zhang S., Xu Y. Sucrose ester based cationic liposomes as effective non-viral gene vectors for gene delivery. Colloids Surfaces B Biointerfaces. 2016;145:454-461.

64. Chesnoy S., Huang L. Structure and function of lipid-DNA complexes for gene delivery. Annu. Rev. Biophys. Biomol. Struct. 2000;29:27-47.

65. Zhao Y., Liu A., Du Y., Cao Y., Zhang E., Zhou Q., Hai H., Zhen Y.,Zhang S. Effects of sucrose ester structures on liposome-mediated gene delivery. Acta Biomater. 2018;72:278-286.

66. Kinberger G.A., Prakash T.P., Yu J., Vasquez G., Low A., Chappell A., Schmidt K., Murray H.M., Gaus H., Swayze E.E., Seth P.P. Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes. Bioorg. Med. Chem. Lett. 2016;26(15):3690-3693.

67. Oh H.R., Jo H.Y., Park J.S., Kim D.E., Cho J.Y., Kim P.H., Kim K.S. Galactosylated liposomes for targeted co-delivery of doxorubicin/vimentin siRNA to hepatocellular carcinoma. Nanomaterials. 2016;6(141).

68. Bansal D., Yadav K., Pandey V., Ganeshpurkar A., Agnihotri A., Dubey N. Lactobionic acid coupled liposomes: An innovative strategy for targeting hepatocellular carcinoma. Drug Deliv. 2016;23(1):140-146.

69. Liu X., Han M., Xu J., Geng S., Zhang Y., Ye X., Gou J., Yin T., He H., Tang X. Asialoglycoprotein receptor-targeted liposomes loaded with a norcantharimide derivative for hepatocyte-selective targeting. Int. J. Pharm. 2017;520(1-2):98-110.

70. Sonoke S.S., Ueda T., Fujiwara K., Kuwabara K., Yano J. Galactose-modified cationic liposomes as a liver-targeting delivery system for small interfering RNA. Biol. Pharm. Bull. 2011;34(8):1338-1342.

71. De Silva A.T.M., Maia A.L.C., de Oliveira Silva J., de Barros A.L.B., Soares D.C.F., de Magalhães M.T.Q., José Alves R., Ramaldes G.A. Synthesis of cholesterol-based neoglycoconjugates and their use in the preparation of liposomes for active liver targeting. Carbohydr. Res. 2018;465:52-57.

72. Gur’eva L.Y., Bol’sheborodova А.K., Sebyakin Y.L. Design, synthesis, and properties of neoglycolipids based on ethylene glycoles conjugated with lactose as components of targeted delivery systems of biologically active compounds. Russ. J. Org. Chem. 2012;48(8):1047-1054.

73. Budanova U.A., Shchelik I., Koloskova O., Sebyakin Y.L. Multivalent glycoconjugate as the vector of target delivery of bioactive compounds. Mendeleev Commun. 2016;26(3):205-206.

74. Koloskova O.O., Nosova A.S., Shchelik I.S., Shilovskiy I., Sebyakin Y.L., Khaitov M.R. Liver-targeted delivery of nucleic acid by liposomes modified with a glycoconjugate. Mendeleev Commun. 2017;27(6):626-627.

75. Sakashita M., Mochizuki S., Sakurai K. Hepatocyte-targeting gene delivery using a lipoplex composed of galactose-modified aromatic lipid synthesized with click chemistry. Bioorg. Med. Chem. 2014;22(19):5212-5219.

Supplementary files

1. Fig. 1. Schematic depiction of ASGP-R that showing a heterooligomer made up of two H1 subunits and one H2 subunit. The figure shows the spatial arrangement of the receptor’s binding sites [19].
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Nosova A.S., Budanova Yu.A., Sebyakin Yu.L. Structural features of synthetic glycoconjugates and efficiency of their interaction with glycoprotein receptors on the surface of hepatocytes. Fine Chemical Technologies. 2019;14(5):7-20.

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