Biodistribution and hepatic uptake of triplex-forming oligonucleotides against type α1(1) collagen gene promoter in normal and fibrotic rats

Kun Cheng, Zhaoyang Ye, Ramareddy V. Guntaka, Ram I. Mahato

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Fibrosis is characterized by excessive production of extracellular matrix (ECM) components, predominantly type 1 collagen. Earlier we developed an antigene approach, using a type α1(I) promoter specific TFO to inhibit collagen gene expression. In this report, biodistribution and hepatic cellular and subcellular localization of the 25-mer antiparallel phosphorothioate triplex-forming oligonucleotide (APS TFO) were determined after intravenous injection into rats. TFOs distributed to all the major organs, with higher uptake in the liver, kidney, and spleen. The plasma concentration versus time profile of the 33P-TFO was biphasic, with 4.36 min as t 1/2α of distribution and 34.6 min as t1/2β of elimination. TFO concentrations in the liver increased nonlinearly with increase in its dose from 0.2 to 50 mg/kg, but decreased when injected into fibrotic rats. Competition studies with polyinosinic acid (polyl) and dextran sulfate suggested the involvement of scavenger receptors in the hepatic uptake of the TFO. Intrahepatic cellular distribution by Kupffer, endothelial, and hepatic stellate cells (HSCs) accounted for almost 70% of the liver uptake of 33P-TFO, while only 30% was associated with hepatocytes. The level of liver nuclei-associated TFO was much lower relative to that found in the cytoplasm at 2 and 4 h postinjection, TFO, however, inhibited collagen expression as evidenced by Sirius red staining of the liver section of fibrotic rats. In conclusion, systemic delivery of the TFO against type α1(I) collagen gene promoter may be used for the treatment of liver fibrosis.

Original languageEnglish (US)
Pages (from-to)206-217
Number of pages12
JournalMolecular Pharmaceutics
Issue number3
StatePublished - May 2005


  • Biodistribution
  • Hepatic stellate cells
  • Liver fibrosis
  • Liver perfusion
  • Nuclear localization
  • Triplex-forming oligonucleotide (TFO)

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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