Design of a Targeted Peptide Nucleic Acid Prodrug To Inhibit Hepatic Human Microsomal Triglyceride Transfer Protein Expression in Hepatocytes

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 complementar...

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Bibliographic Details
Published in:Bioconjugate chemistry 2002-03, Vol.13 (2), p.295-302
Main Authors: Biessen, Erik A. L, Sliedregt-Bol, Karen, 'T Hoen, Peter A. Chr, Prince, Perry, Van der Bilt, Erica, Valentijn, A. Rob P. M, Meeuwenoord, Nico J, Princen, Hans, Bijsterbosch, Martin K, Van der Marel, Gijs A, Van Boom, Jacques H, Van Berkel, Theo J. C
Format: Article
Language:English
Subjects:
alpha-Fetoproteins - pharmacology
Animals
Antitumor agents
Asialoglycoproteins - pharmacology
Base Sequence
Biological Transport - drug effects
Carrier Proteins - genetics
Cells, Cultured
Drug Delivery Systems
Drug Design
Fetuins
Gene Expression Regulation - drug effects
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Kinetics
Liver
Mice
Mice, Inbred C57BL
Microsomes
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Molecular Structure
Parenchyma
Peptide Nucleic Acids - chemical synthesis
Peptide Nucleic Acids - chemistry
Peptide Nucleic Acids - genetics
Peptide Nucleic Acids - pharmacology
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Protein biosynthesis
Q1
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tumor Cells, Cultured
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Summary: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.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc015550g