Comparative Characterization of Hepatic Distribution and mRNA Reduction of Antisense Oligonucleotides Conjugated with Triantennary N-Acetyl Galactosamine and Lipophilic Ligands Targeting Apolipoprotein B
| Autor: | Kei Mayumi, Takeshi Kasuya, Tatsuya Ikehara, Naohisa Kitade, Ayahisa Watanabe, Reina Onishi, Akira Kugimiya, Mado Nakajima |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Acetylgalactosamine Apolipoprotein B Ligands 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Pharmacokinetics Animals RNA Messenger Locked nucleic acid Transaminases Apolipoproteins B Pharmacology biology Oligonucleotide Cholesterol Ligand Gene Transfer Techniques Oligonucleotides Antisense Molecular biology Lipids Mice Inbred C57BL 030104 developmental biology chemistry Biochemistry Liver 030220 oncology & carcinogenesis Galactosamine Phosphodiester bond biology.protein Hepatocytes Molecular Medicine RNA Interference Half-Life |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 357(2) |
| ISSN: | 1521-0103 |
| Popis: | TriantennaryN-acetyl galactosamine (GalNAc, GN3) and lipophilic ligands such as cholesterol andα-tocopherol conjugations dramatically improve the distribution and efficacy of second-generation antisense oligonucleotides (ASOs) in the whole liver. To characterize ligands for delivery to liver cells based on pharmacokinetics and efficacy, we used a locked nucleic acid gapmer of ASO targeting apolipoprotein B as a model compound and evaluated the amount of ASO and apolipoprotein B mRNA in the whole liver, hepatocytes, and nonparenchymal (NP) cells as well as plasma total cholesterol after administration of ASO conjugated with these ligands to mice. Compared with unconjugated ASO, GN3 conjugation increased the amount (7-fold) and efficacy (more than 10-fold) of ASO in hepatocytes only and showed higher efficacy than the increased rate of the amount of ASO. On the other hand, lipophilic ligand conjugations led to increased delivery (3- to 5-fold) and efficacy (5-fold) of ASO to both hepatocytes and NP cells. GN3 and lipophilic ligand conjugations increased the area under the curve of ASOs and the pharmacodynamic duration but did not change the half-life in hepatocytes and NP cells compared with unconjugated ASO. In the liver, the phosphodiester bond between ASO and these ligands was promptly cleaved to liberate unconjugated ASO. These ligand conjugations reduced plasma total cholesterol compared with unconjugated ASO, although these ASOs were well tolerated with no elevation in plasma transaminases. These findings could facilitate ligand selection tailored to liver cells expressed in disease-related genes and could contribute to the discovery and development of RNA interference-based therapy. |
| Databáze: | OpenAIRE |
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