Construction of nanostructured DNA harbouring phosphorodiamidate morpholino oligonucleotide for controlled tissue distribution in mice / Yosuke Takahashi, Yuki Araie, Daiki Nomura, Yuki Takahashi, Kohei Sano, Hideo Saji, Yoshinobu Takakura, Makiya Nishikawa
Abstract Phosphorodiamidate morpholino oligonucleotides (PMOs) are a class of antisense oligonucleotides used in the treatment of neuromuscular diseases. Their major drawbacks are high blood clearance and poor cellular delivery. Previously, we demonstrated that tripod-like nanostructured DNA, or tripodna, was efficiently taken up by macrophages and dendritic cells. In this study, we used iodine-125( 125 I)-labelled PMOs, designed a tripodna harbouring an 125 I-PMO ( 125 I-PMO/tripodna), and evaluated whether this tripodna could control the pharmacokinetic properties of PMO. Gel electrophoresis showed that 125 I-PMO was almost completely incorporated into the tripodna. Compared to 125 I-PMO, 125 I-PMO/tripodna was more efficiently taken up by macrophage-like RAW264.7 cells. Moreover, after intravenous injection into mice, the area under the plasma concentration–time curve of 125 I-PMO/tripodna was significantly larger than that of 125 I-PMO. The distribution of 125 I-PMO/tripodna in the liver and spleen at 24 h was 32- and 51-fold higher than that of 125 I-PMO, respectively. The fractionation of liver cells revealed that non-parenchymal cells were the major cells contributing to the hepatic uptake of 125 I-PMO/tripodna. These results indicate that tripodna has the potential to deliver PMO, particularly to the liver and spleen.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Journal of drug targeting - 26(2018), 4, Seite 373-381 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Takahashi, Yosuke [VerfasserIn] |
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| Links: |
FID Access [lizenzpflichtig] |
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| Themen: |
Drug targeting |
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| Umfang: |
1 Online-Ressource (9 p) |
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| doi: |
10.1080/1061186X.2017.1387789 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Construction of nanostructured DNA harbouring phosphorodiamidate morpholino oligonucleotide for controlled tissue distribution in mice |c Yosuke Takahashi, Yuki Araie, Daiki Nomura, Yuki Takahashi, Kohei Sano, Hideo Saji, Yoshinobu Takakura, Makiya Nishikawa |
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| 520 | |a Abstract Phosphorodiamidate morpholino oligonucleotides (PMOs) are a class of antisense oligonucleotides used in the treatment of neuromuscular diseases. Their major drawbacks are high blood clearance and poor cellular delivery. Previously, we demonstrated that tripod-like nanostructured DNA, or tripodna, was efficiently taken up by macrophages and dendritic cells. In this study, we used iodine-125( 125 I)-labelled PMOs, designed a tripodna harbouring an 125 I-PMO ( 125 I-PMO/tripodna), and evaluated whether this tripodna could control the pharmacokinetic properties of PMO. Gel electrophoresis showed that 125 I-PMO was almost completely incorporated into the tripodna. Compared to 125 I-PMO, 125 I-PMO/tripodna was more efficiently taken up by macrophage-like RAW264.7 cells. Moreover, after intravenous injection into mice, the area under the plasma concentration–time curve of 125 I-PMO/tripodna was significantly larger than that of 125 I-PMO. The distribution of 125 I-PMO/tripodna in the liver and spleen at 24 h was 32- and 51-fold higher than that of 125 I-PMO, respectively. The fractionation of liver cells revealed that non-parenchymal cells were the major cells contributing to the hepatic uptake of 125 I-PMO/tripodna. These results indicate that tripodna has the potential to deliver PMO, particularly to the liver and spleen | ||
| 653 | |a Word | ||
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| 700 | 1 | |a Araie, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Nomura, Daiki |e verfasserin |4 aut | |
| 700 | 1 | |a Takahashi, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Sano, Kohei |e verfasserin |4 aut | |
| 700 | 1 | |a Saji, Hideo |e verfasserin |4 aut | |
| 700 | 1 | |a Takakura, Yoshinobu |e verfasserin |4 aut | |
| 700 | 1 | |a Nishikawa, Makiya |e verfasserin |4 aut | |
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