Pharmacokinetics of 111In-labeled triplex-forming oligonucleotide targeting human N-myc gene

Jae-Gol Choe, Meyoung-Kon Kim, Eun Jung Oh, Eun Jeong Yoon, Jeongwon Sohn, Min Kyu Park, Gil-Hong Park

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The radiolabeled triplex-forming oligonucleotide (TFO) demonstrated the potential for sequence-specific DNA binding and destruction. In this study, by selecting the polypurine-polypyrimidine stretch (2950-2978) in the human N-myc gene as a target, the 111In-labeled TFO targeting human N-myc gene (N-mycTFO111In) was tested for its cellular uptake and nuclear localization in vitro and in vivo. This is because the deregulated N-myc expression is strongly implicated in the pathogenesis of several important human malignancies, including breast carcinoma and neuroblastoma. N-mycTFO 111In was bound selectively to the N-myc sequence in vitro. The total cellular uptake of TFO after the incubation of various normal and cancer cells with TFO for 24 h was 20-54.8% of the injected dose (%ID), and the nuclear localization was 6.59-30.0% ID, depending on cell lines. The highest cellular uptake was found in the human neuroblastoma SK-N-DZ (54.8%ID), human mammary ductal carcinoma T47-D (54%ID), human acute T cell leukemia Jurkat (54%ID), and multidrug-resistant human breast adenocarcinoma MCF7/TH (49.5%ID). The lowest was in the human normal mammary epithelium MCF10A (20.0%ID). The highest nuclear localization was found in MCF7/TH (30%ID) and SK-N-DZ (28.7%ID). The lowest was in MCF10A (6.59%ID). We next injected TFO into human mammary tumor-xenografted Balb/c nude mice. Tumor targeting of TFO in vivo reached its maximum peak 5 h after the intravenous injection in three types of tumor models. They are 21.0 ± 3.23%ID per gram of tissue (%ID/g) for MCF7/TH, 7.77 ± 2.11%ID/g for MCF7, and 4.53 ± 1.20%ID/g for MCF10A. The TFO blood level decreased from 8.00 ± 0.90%ID/g 15 min after the injection, to 1.30 ± 0.30%ID/g after 19 h. The kidney TFO level increased rapidly from 5.93 ± 0.94%ID/g after 15 min, to 25.1 ± 5.60%ID/g after 19 h. A high TFO level (19.7-24.5%ID/g) in the liver was maintained until 19 h after the injection. Therefore, we suggest that the 111In-labeled N-myc-targeting TFO, a promising modality for nanoexplosive gene therapy, could effectively target the nucleus of the multidrug-resistant breast carcinoma MCF7/TH in vitro and in vivo. It has approximately 130 min of half-life of blood TFO.

Original languageEnglish
Pages (from-to)93-100
Number of pages8
JournalMolecules and Cells
Volume14
Issue number1
Publication statusPublished - 2002 Aug 1

Fingerprint

myc Genes
Oligonucleotides
Pharmacokinetics
Breast Neoplasms
Neuroblastoma
Neoplasms
Carcinoma, Ductal, Breast
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Injections
Human Mammary Glands
Nude Mice
Intravenous Injections
Genetic Therapy
Half-Life
Adenocarcinoma
Breast

Keywords

  • In
  • Breast Carcinoma
  • N-myc
  • Pharmacokinetics
  • Triplex-forming Oligonucleotide (TFO)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Pharmacokinetics of 111In-labeled triplex-forming oligonucleotide targeting human N-myc gene. / Choe, Jae-Gol; Kim, Meyoung-Kon; Oh, Eun Jung; Yoon, Eun Jeong; Sohn, Jeongwon; Park, Min Kyu; Park, Gil-Hong.

In: Molecules and Cells, Vol. 14, No. 1, 01.08.2002, p. 93-100.

Research output: Contribution to journalArticle

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title = "Pharmacokinetics of 111In-labeled triplex-forming oligonucleotide targeting human N-myc gene",
abstract = "The radiolabeled triplex-forming oligonucleotide (TFO) demonstrated the potential for sequence-specific DNA binding and destruction. In this study, by selecting the polypurine-polypyrimidine stretch (2950-2978) in the human N-myc gene as a target, the 111In-labeled TFO targeting human N-myc gene (N-mycTFO111In) was tested for its cellular uptake and nuclear localization in vitro and in vivo. This is because the deregulated N-myc expression is strongly implicated in the pathogenesis of several important human malignancies, including breast carcinoma and neuroblastoma. N-mycTFO 111In was bound selectively to the N-myc sequence in vitro. The total cellular uptake of TFO after the incubation of various normal and cancer cells with TFO for 24 h was 20-54.8{\%} of the injected dose ({\%}ID), and the nuclear localization was 6.59-30.0{\%} ID, depending on cell lines. The highest cellular uptake was found in the human neuroblastoma SK-N-DZ (54.8{\%}ID), human mammary ductal carcinoma T47-D (54{\%}ID), human acute T cell leukemia Jurkat (54{\%}ID), and multidrug-resistant human breast adenocarcinoma MCF7/TH (49.5{\%}ID). The lowest was in the human normal mammary epithelium MCF10A (20.0{\%}ID). The highest nuclear localization was found in MCF7/TH (30{\%}ID) and SK-N-DZ (28.7{\%}ID). The lowest was in MCF10A (6.59{\%}ID). We next injected TFO into human mammary tumor-xenografted Balb/c nude mice. Tumor targeting of TFO in vivo reached its maximum peak 5 h after the intravenous injection in three types of tumor models. They are 21.0 ± 3.23{\%}ID per gram of tissue ({\%}ID/g) for MCF7/TH, 7.77 ± 2.11{\%}ID/g for MCF7, and 4.53 ± 1.20{\%}ID/g for MCF10A. The TFO blood level decreased from 8.00 ± 0.90{\%}ID/g 15 min after the injection, to 1.30 ± 0.30{\%}ID/g after 19 h. The kidney TFO level increased rapidly from 5.93 ± 0.94{\%}ID/g after 15 min, to 25.1 ± 5.60{\%}ID/g after 19 h. A high TFO level (19.7-24.5{\%}ID/g) in the liver was maintained until 19 h after the injection. Therefore, we suggest that the 111In-labeled N-myc-targeting TFO, a promising modality for nanoexplosive gene therapy, could effectively target the nucleus of the multidrug-resistant breast carcinoma MCF7/TH in vitro and in vivo. It has approximately 130 min of half-life of blood TFO.",
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T1 - Pharmacokinetics of 111In-labeled triplex-forming oligonucleotide targeting human N-myc gene

AU - Choe, Jae-Gol

AU - Kim, Meyoung-Kon

AU - Oh, Eun Jung

AU - Yoon, Eun Jeong

AU - Sohn, Jeongwon

AU - Park, Min Kyu

AU - Park, Gil-Hong

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N2 - The radiolabeled triplex-forming oligonucleotide (TFO) demonstrated the potential for sequence-specific DNA binding and destruction. In this study, by selecting the polypurine-polypyrimidine stretch (2950-2978) in the human N-myc gene as a target, the 111In-labeled TFO targeting human N-myc gene (N-mycTFO111In) was tested for its cellular uptake and nuclear localization in vitro and in vivo. This is because the deregulated N-myc expression is strongly implicated in the pathogenesis of several important human malignancies, including breast carcinoma and neuroblastoma. N-mycTFO 111In was bound selectively to the N-myc sequence in vitro. The total cellular uptake of TFO after the incubation of various normal and cancer cells with TFO for 24 h was 20-54.8% of the injected dose (%ID), and the nuclear localization was 6.59-30.0% ID, depending on cell lines. The highest cellular uptake was found in the human neuroblastoma SK-N-DZ (54.8%ID), human mammary ductal carcinoma T47-D (54%ID), human acute T cell leukemia Jurkat (54%ID), and multidrug-resistant human breast adenocarcinoma MCF7/TH (49.5%ID). The lowest was in the human normal mammary epithelium MCF10A (20.0%ID). The highest nuclear localization was found in MCF7/TH (30%ID) and SK-N-DZ (28.7%ID). The lowest was in MCF10A (6.59%ID). We next injected TFO into human mammary tumor-xenografted Balb/c nude mice. Tumor targeting of TFO in vivo reached its maximum peak 5 h after the intravenous injection in three types of tumor models. They are 21.0 ± 3.23%ID per gram of tissue (%ID/g) for MCF7/TH, 7.77 ± 2.11%ID/g for MCF7, and 4.53 ± 1.20%ID/g for MCF10A. The TFO blood level decreased from 8.00 ± 0.90%ID/g 15 min after the injection, to 1.30 ± 0.30%ID/g after 19 h. The kidney TFO level increased rapidly from 5.93 ± 0.94%ID/g after 15 min, to 25.1 ± 5.60%ID/g after 19 h. A high TFO level (19.7-24.5%ID/g) in the liver was maintained until 19 h after the injection. Therefore, we suggest that the 111In-labeled N-myc-targeting TFO, a promising modality for nanoexplosive gene therapy, could effectively target the nucleus of the multidrug-resistant breast carcinoma MCF7/TH in vitro and in vivo. It has approximately 130 min of half-life of blood TFO.

AB - The radiolabeled triplex-forming oligonucleotide (TFO) demonstrated the potential for sequence-specific DNA binding and destruction. In this study, by selecting the polypurine-polypyrimidine stretch (2950-2978) in the human N-myc gene as a target, the 111In-labeled TFO targeting human N-myc gene (N-mycTFO111In) was tested for its cellular uptake and nuclear localization in vitro and in vivo. This is because the deregulated N-myc expression is strongly implicated in the pathogenesis of several important human malignancies, including breast carcinoma and neuroblastoma. N-mycTFO 111In was bound selectively to the N-myc sequence in vitro. The total cellular uptake of TFO after the incubation of various normal and cancer cells with TFO for 24 h was 20-54.8% of the injected dose (%ID), and the nuclear localization was 6.59-30.0% ID, depending on cell lines. The highest cellular uptake was found in the human neuroblastoma SK-N-DZ (54.8%ID), human mammary ductal carcinoma T47-D (54%ID), human acute T cell leukemia Jurkat (54%ID), and multidrug-resistant human breast adenocarcinoma MCF7/TH (49.5%ID). The lowest was in the human normal mammary epithelium MCF10A (20.0%ID). The highest nuclear localization was found in MCF7/TH (30%ID) and SK-N-DZ (28.7%ID). The lowest was in MCF10A (6.59%ID). We next injected TFO into human mammary tumor-xenografted Balb/c nude mice. Tumor targeting of TFO in vivo reached its maximum peak 5 h after the intravenous injection in three types of tumor models. They are 21.0 ± 3.23%ID per gram of tissue (%ID/g) for MCF7/TH, 7.77 ± 2.11%ID/g for MCF7, and 4.53 ± 1.20%ID/g for MCF10A. The TFO blood level decreased from 8.00 ± 0.90%ID/g 15 min after the injection, to 1.30 ± 0.30%ID/g after 19 h. The kidney TFO level increased rapidly from 5.93 ± 0.94%ID/g after 15 min, to 25.1 ± 5.60%ID/g after 19 h. A high TFO level (19.7-24.5%ID/g) in the liver was maintained until 19 h after the injection. Therefore, we suggest that the 111In-labeled N-myc-targeting TFO, a promising modality for nanoexplosive gene therapy, could effectively target the nucleus of the multidrug-resistant breast carcinoma MCF7/TH in vitro and in vivo. It has approximately 130 min of half-life of blood TFO.

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