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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol

Kun Cheng, Zhaoyang Ye, Ramareddy V. Guntaka and Ram I. Mahato
Journal of Pharmacology and Experimental Therapeutics May 2006, 317 (2) 797-805; DOI: https://doi.org/10.1124/jpet.105.100347
Kun Cheng
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Zhaoyang Ye
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Ramareddy V. Guntaka
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Ram I. Mahato
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Abstract

A triplex-forming oligonucleotide (TFO) specific for type α1(I) collagen promoter is a promising candidate for treating liver fibrosis. Earlier, we determined the pharmacokinetics and biodistribution of TFO after systemic administration into normal and fibrotic rats. In this study, we conjugated cholesterol to the 3′ end of the TFO via a disulfide bond and determined its cellular and nuclear uptake and bioactivity using HSC-T6 cell lines in vitro, followed by biodistribution at whole-body, organ (liver), and subcellular levels. Conjugation with cholesterol had little effect on the triplex-forming ability of the TFO with target duplex DNA, and the cellular uptake of 33P-TFO-cholesterol (Chol) increased by 2- to approximately 4-fold. Real-time reverse transcriptase-polymerase chain reaction analysis after transfection of HSC-T6 cells with TFO-Chol or TFO indicated that TFO-Chol had higher inhibition on type α1(I) collagen primary transcript than naked TFO at low concentration (200 nM) but showed similar inhibition at higher concentration (500 and 1000 nM). There was increase in the inhibition on primary transcript with transfection time. The hepatic uptake of 33P-TFO-Chol after systemic administration was 72.22% of the dose compared with 45.8% of 33P-TFO. There was significant increase in the uptake of 33P-TFO-Chol by hepatic stellate cells and hepatocytes. More importantly, the nuclear uptake of TFO-Chol was higher than TFO in cell culture system and in vivo studies. In conclusion, TFO-Chol is a potential antifibrotic agent.

Footnotes

  • This work was supported by National Institutes of Health Grants R01 DK064633 and USPHS 47379.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.100347.

  • ABBREVIATIONS: APS, antiparallel phosphorothioate; TFO, triplex-forming oligonucleotide; bp, base pair(s); HSC, hepatic stellate cell; ODN, oligodeoxynucleotide; Chol, cholesterol; ESI, electrospray ionization; MS, mass spectrometry; DTT, dithiothreitol; HPLC, high-performance liquid chromatography; 3-HPA, 3-hydroxypicolinic acid; MALDI-TOF, matrix-assisted laser desorption ionization/time of flight; T4-PNK, T4 polynucleotide kinase; PBS, phosphate-buffered saline; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; PCR, polymerase chain reaction; DMN, dimethylnitrosamine.

    • Received December 20, 2005.
    • Accepted January 30, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol

Kun Cheng, Zhaoyang Ye, Ramareddy V. Guntaka and Ram I. Mahato
Journal of Pharmacology and Experimental Therapeutics May 1, 2006, 317 (2) 797-805; DOI: https://doi.org/10.1124/jpet.105.100347

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol

Kun Cheng, Zhaoyang Ye, Ramareddy V. Guntaka and Ram I. Mahato
Journal of Pharmacology and Experimental Therapeutics May 1, 2006, 317 (2) 797-805; DOI: https://doi.org/10.1124/jpet.105.100347
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