Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes
| Autor: | Theo J.C. Van Berkel, Erik A.L. Biessen, Hans M.G. Princen, Peter A C 't Hoen, Jacques H. van Boom, Perry Prince, Martin K. Bijsterbosch, Erica Van der Bilt, A. Rob P. M. Valentijn, Karen Sliedregt-Bol, Nico J. Meeuwenoord, Gijs A. van der Marel |
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| Rok vydání: | 2002 |
| Předmět: |
Peptide Nucleic Acids
Biodistribution Biomedical Engineering Pharmaceutical Science Asialoglycoproteins Bioengineering Microsomal triglyceride transfer protein chemistry.chemical_compound Mice Drug Delivery Systems Tumor Cells Cultured Animals Humans Prodrugs Hepatic Asialoglycoprotein Receptor RNA Messenger Fetuins Cells Cultured Pharmacology Peptide nucleic acid biology Base Sequence Molecular Structure Organic Chemistry Biological Transport Prodrug Molecular biology Mice Inbred C57BL Kinetics chemistry Biochemistry Gene Expression Regulation Drug Design Microsome biology.protein Hepatocytes Microsomes Liver Asialoglycoprotein receptor alpha-Fetoproteins Carrier Proteins Intracellular Biotechnology |
| Zdroj: | Bioconjugate chemistry. 13(2) |
| ISSN: | 1043-1802 |
| Popis: | In this study, we present the design and synthesis of an antisense peptide nucleic acid (asPNA) prodrug, which displays an improved biodistribution profile and an equally improved capacity to reduce the levels of target mRNA. The prodrug, K(GalNAc)(2)-asPNA, comprised of a 14-mer sequence complementary to the human microsomal triglyceride transfer protein (huMTP) gene, conjugated to a high-affinity tag for the hepatic asialoglycoprotein receptor (K(GalNAc)(2)). The prodrug was avidly bound and rapidly internalized by HepG2s. After iv injection into mice, K(GalNAc)(2)-asPNA accumulated in the parenchymal liver cells to a much greater extent than nonconjugated PNA (46% +/- 1% vs 3.1% +/- 0.5% of the injected dose, respectively). The prodrug was able to reduce MTP mRNA levels in HepG2 cells by 35-40% (P < 0.02) at 100 nM in an asialoglycoprotein receptor- and sequence-dependent fashion. In conclusion, hepatocyte-targeted PNA prodrugs combine a greatly improved tropism with an enhanced local intracellular availability and activity, making them attractive therapeutics to lower the expression level of hepatic target genes such as MTP. |
| Databáze: | OpenAIRE |
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