Targeted Delivery of Oligodeoxynucleotides to Parenchymal Liver Cells in Vivo

Overview

Journal Biochem J

Specialty Biochemistry

Date 1999 Jun 9

PMID 10359665

Citations 23

Authors

E A Biessen

H Vietsch

E T Rump

K Fluiter

J Kuiper

M K Bijsterbosch

T J Van Berkel

Affiliations

Soon will be listed here.

Abstract

Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the biosynthesis of clinically relevant proteins. The potential of ODNs for modulating liver-specific genes might be increased by preventing untimely elimination and by improving the local bioavailability of ODNs in the target tissue. In the present study we have assessed whether the local ODN concentration can be enhanced by the targeted delivery of ODNs through conjugation to a ligand for the parenchymal liver cell-specific asialoglycoprotein receptor. A capped ODN (miscellaneous 20-mer sequence) was derivatized with a ligand with high affinity for this receptor, N2-[N2-(N2,N6-bis{N-[p-(beta-d-galactopyranosyloxy) anilino] thiocarbamyl}-L-lysyl)-N6-(N-{p-[beta-D -galactopyranosyloxy] anilino} thiocarbamyl)-L-lysyl]-N6-[N- (p-{beta-D-galactopyranosyloxy}anilino)thiocarbamyl]-L-lysine (L3G4) (Kd 6.5+/-0.2 nM, mean+/-S.D.). Both the uptake studies in vitro and the confocal laser scan microscopy studies demonstrated that L3G4-ODN was far more efficiently bound to and taken up by parenchymal liver cells than underivatized ODN. Studies in vivo in rats showed that hepatic uptake could be greatly enhanced from 19+/-1% to 77+/-6% of the injected dose after glycoconjugation. Importantly, specific ODN accumulation of ODN into parenchymal liver cells was improved almost 60-fold after derivatization with L3G4, and could be attributed to the asialoglycoprotein receptor. In conclusion, the scavenger receptor-mediated elimination pathway for miscellaneous ODN sequences can be circumvented by direct conjugation to a synthetic tag for the asialoglycoprotein receptor. In this manner a crucial requisite is met towards the application of ODNs in vivo to modulate the biosynthesis of parenchymal liver cell-specific genes such as those for apolipoprotein (a), cholesterol ester transfer protein and viral proteins.

Citing Articles

Mammalian cell-based production of glycans, glycopeptides and glycomodules.

Jaroentomeechai T, Karlsson R, Goerdeler F, Teoh F, Gronset M, de Wit D Nat Commun. 2024; 15(1):9668.

PMID: 39516489 PMC: 11549445. DOI: 10.1038/s41467-024-53738-9.

Oligonucleotide therapies for nonalcoholic steatohepatitis.

Li S, Xiong F, Zhang S, Liu J, Gao G, Xie J Mol Ther Nucleic Acids. 2024; 35(2):102184.

PMID: 38665220 PMC: 11044058. DOI: 10.1016/j.omtn.2024.102184.

Tissue pharmacokinetics of antisense oligonucleotides.

Backstrom E, Bonetti A, Johnsson P, Ohlin S, Dahlen A, Andersson P Mol Ther Nucleic Acids. 2024; 35(1):102133.

PMID: 38419941 PMC: 10899043. DOI: 10.1016/j.omtn.2024.102133.

Trials and Tribulations of MicroRNA Therapeutics.

Seyhan A Int J Mol Sci. 2024; 25(3).

PMID: 38338746 PMC: 10855871. DOI: 10.3390/ijms25031469.

Targeted delivery of oligonucleotides using multivalent protein-carbohydrate interactions.

Kumar V, Turnbull W Chem Soc Rev. 2023; 52(4):1273-1287.

PMID: 36723021 PMC: 9940626. DOI: 10.1039/d2cs00788f.

References

Stein C, Cheng Y . Antisense oligonucleotides as therapeutic agents--is the bullet really magical?. Science. 1993; 261(5124):1004-12. DOI: 10.1126/science.8351515. View

Milligan J, Matteucci M, Martin J . Current concepts in antisense drug design. J Med Chem. 1993; 36(14):1923-37. DOI: 10.1021/jm00066a001. View

Tari A, Tucker S, Deisseroth A, Lopez-Berestein G . Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia. Blood. 1994; 84(2):601-7. View

Morishita R, Gibbons G, Kaneda Y, Ogihara T, Dzau V . Pharmacokinetics of antisense oligodeoxyribonucleotides (cyclin B1 and CDC 2 kinase) in the vessel wall in vivo: enhanced therapeutic utility for restenosis by HVJ-liposome delivery. Gene. 1994; 149(1):13-9. DOI: 10.1016/0378-1119(94)90406-5. View

Wagner R . Gene inhibition using antisense oligodeoxynucleotides. Nature. 1994; 372(6504):333-5. DOI: 10.1038/372333a0. View

Zelphati O, Wagner E, Leserman L . Synthesis and anti-HIV activity of thiocholesteryl-coupled phosphodiester antisense oligonucleotides incorporated into immunoliposomes. Antiviral Res. 1994; 25(1):13-25. DOI: 10.1016/0166-3542(94)90090-6. View

Merwin J, Noell G, THOMAS W, Chiou H, DeRome M, McKee T . Targeted delivery of DNA using YEE(GalNAcAH)3, a synthetic glycopeptide ligand for the asialoglycoprotein receptor. Bioconjug Chem. 1994; 5(6):612-20. DOI: 10.1021/bc00030a017. View

Biessen E, Beuting D, Vietsch H, Bijsterbosch M, Van Berkel T . Specific targeting of the antiviral drug 5-iodo 2'-deoxyuridine to the parenchymal liver cell using lactosylated poly-L-lysine. J Hepatol. 1994; 21(5):806-15. DOI: 10.1016/s0168-8278(94)80243-2. View

SANDS H, Ho S, Bao Y, Cocuzza A, Chidester D, Hobbs F . Biodistribution and metabolism of internally 3H-labeled oligonucleotides. II. 3',5'-blocked oligonucleotides. Mol Pharmacol. 1995; 47(3):636-46. View

10.

Hamilton H, Steinbaugh B, STEWART B, Chan O, Schmid H, Schroeder R . Evaluation of physicochemical parameters important to the oral bioavailability of peptide-like compounds: implications for the synthesis of renin inhibitors. J Med Chem. 1995; 38(9):1446-55. DOI: 10.1021/jm00009a005. View

11.

Mizutani T, Kato N, Hirota M, Sugiyama K, Murakami A, Shimotohno K . Inhibition of hepatitis C virus replication by antisense oligonucleotide in culture cells. Biochem Biophys Res Commun. 1995; 212(3):906-11. DOI: 10.1006/bbrc.1995.2055. View

12.

Hangeland J, Levis J, Lee Y, Tso P . Cell-type specific and ligand specific enhancement of cellular uptake of oligodeoxynucleoside methylphosphonates covalently linked with a neoglycopeptide, YEE(ah-GalNAc)3. Bioconjug Chem. 1995; 6(6):695-701. DOI: 10.1021/bc00036a006. View

13.

Lewis J, Lin K, Kothavale A, Flanagan W, Matteucci M, DePrince R . A serum-resistant cytofectin for cellular delivery of antisense oligodeoxynucleotides and plasmid DNA. Proc Natl Acad Sci U S A. 1996; 93(8):3176-81. PMC: 39578. DOI: 10.1073/pnas.93.8.3176. View

14.

Nakazono K, Ito Y, Wu C, Wu G . Inhibition of hepatitis B virus replication by targeted pretreatment of complexed antisense DNA in vitro. Hepatology. 1996; 23(6):1297-303. DOI: 10.1002/hep.510230601. View

15.

Rifai A, Brysch W, Fadden K, Clark J, Schlingensiepen K . Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice. Am J Pathol. 1996; 149(2):717-25. PMC: 1865299. View

16.

Sugano M, Makino N . Changes in plasma lipoprotein cholesterol levels by antisense oligodeoxynucleotides against cholesteryl ester transfer protein in cholesterol-fed rabbits. J Biol Chem. 1996; 271(32):19080-3. DOI: 10.1074/jbc.271.32.19080. View

17.

Biessen E, van Teijlingen M, Vietsch H, Barrett-Bergshoeff M, Bijsterbosch M, Rijken D . Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue plasminogen activator. Circulation. 1997; 95(1):46-52. DOI: 10.1161/01.cir.95.1.46. View

18.

Wagner R, Flanagan W . Antisense technology and prospects for therapy of viral infections and cancer. Mol Med Today. 1997; 3(1):31-8. DOI: 10.1016/S1357-4310(96)10053-8. View

19.

Hangeland J, Flesher J, Deamond S, Lee Y, Tso P, Frost J . Tissue distribution and metabolism of the [32P]-labeled oligodeoxynucleoside methylphosphonate-neoglycopeptide conjugate, [YEE(ah-GalNAc)3]-SMCC-AET-pUmpT7, in the mouse. Antisense Nucleic Acid Drug Dev. 1997; 7(3):141-9. DOI: 10.1089/oli.1.1997.7.141. View

20.

Bijsterbosch M, Manoharan M, Rump E, de Vrueh R, van Veghel R, Tivel K . In vivo fate of phosphorothioate antisense oligodeoxynucleotides: predominant uptake by scavenger receptors on endothelial liver cells. Nucleic Acids Res. 1997; 25(16):3290-6. PMC: 146893. DOI: 10.1093/nar/25.16.3290. View