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

被引:35
作者
Biessen, EAL
Sliedregt-Bol, K
Hoen, PACT
Prince, P
Van der Bilt, E
Valentijn, ARPM
Meeuwenoord, NJ
Princen, H
Bijsterbosch, MK
Van der Marel, GA
Van Boom, JH
Van Berkel, TJC
机构
[1] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Biopharmaceut, NL-2300 RA Leiden, Netherlands
[2] Leiden Univ, Dept Organ Chem, NL-2300 RA Leiden, Netherlands
[3] TNO, Gaubius Lab, PG, Leiden, Netherlands
关键词
D O I
10.1021/bc015550g
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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(GaINAc)(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(GaINAc)(2)). The prodrug was avidly bound and rapidly internalized by HepG2s. After iv injection into mice, K(GaINAc)(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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收藏
页码:295 / 302
页数:8
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