1. Academic Validation
  2. Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes

Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes

  • Bioconjug Chem. 2002 Mar-Apr;13(2):295-302. doi: 10.1021/bc015550g.
Erik A L Biessen 1 Karen Sliedregt-Bol Peter A Chr 'T Hoen Perry Prince Erica Van der Bilt A Rob P M Valentijn Nico J Meeuwenoord Hans Princen Martin K Bijsterbosch Gijs A Van der Marel Jacques H Van Boom Theo J C Van Berkel
Affiliations

Affiliation

  • 1 Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9503, 2300 RA Leiden, The Netherlands. biessen@LACDR.LeidenUniv.nl
Abstract

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.

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