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Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates
Locked nucleic acid (LNA) oligonucleotides have been successfully used to efficiently inhibit endogenous small noncoding RNAs in vitro and in vivo. We previously demonstrated that the direct miR-221 inhibition by the novel 13-mer LNA-i-miR-221 induces significant antimyeloma activity and upregulates...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022129/ https://www.ncbi.nlm.nih.gov/pubmed/27327137 http://dx.doi.org/10.1038/mtna.2016.36 |
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author | Gallo Cantafio, Maria Eugenia Nielsen, Boye Schnack Mignogna, Chiara Arbitrio, Mariamena Botta, Cirino Frandsen, Niels M Rolfo, Christian Tagliaferri, Pierosandro Tassone, Pierfrancesco Di Martino, Maria Teresa |
author_facet | Gallo Cantafio, Maria Eugenia Nielsen, Boye Schnack Mignogna, Chiara Arbitrio, Mariamena Botta, Cirino Frandsen, Niels M Rolfo, Christian Tagliaferri, Pierosandro Tassone, Pierfrancesco Di Martino, Maria Teresa |
author_sort | Gallo Cantafio, Maria Eugenia |
collection | PubMed |
description | Locked nucleic acid (LNA) oligonucleotides have been successfully used to efficiently inhibit endogenous small noncoding RNAs in vitro and in vivo. We previously demonstrated that the direct miR-221 inhibition by the novel 13-mer LNA-i-miR-221 induces significant antimyeloma activity and upregulates canonical miR-221 targets in vitro and in vivo. To evaluate the LNA-i-miR-221 pharmacokinetics and pharmacodynamics, novel assays for oligonucleotides quantification in NOD.SCID mice and Cynomolgus monkeys (Macaca fascicularis) plasma, urine and tissues were developed. To this aim, a liquid chromatography/mass spectrometry method, after solid-phase extraction, was used for the detection of LNA-i-miR-221 in plasma and urine, while a specific in situ hybridization assay for tissue uptake analysis was designed. Our analysis revealed short half-life, optimal tissue biovailability and minimal urine excretion of LNA-i-miR-221 in mice and monkeys. Up to 3 weeks, LNA-i-miR-221 was still detectable in mice vital organs and in xenografted tumors, together with p27 target upregulation. Importantly, no toxicity in the pilot monkey study was observed. Overall, our findings indicate the suitability of LNA-i-miR-221 for clinical use and we provide here pilot data for safety analysis and further development of LNA-miRNA-based therapeutics for human cancer. |
format | Online Article Text |
id | pubmed-5022129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50221292016-09-19 Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates Gallo Cantafio, Maria Eugenia Nielsen, Boye Schnack Mignogna, Chiara Arbitrio, Mariamena Botta, Cirino Frandsen, Niels M Rolfo, Christian Tagliaferri, Pierosandro Tassone, Pierfrancesco Di Martino, Maria Teresa Mol Ther Nucleic Acids Original Article Locked nucleic acid (LNA) oligonucleotides have been successfully used to efficiently inhibit endogenous small noncoding RNAs in vitro and in vivo. We previously demonstrated that the direct miR-221 inhibition by the novel 13-mer LNA-i-miR-221 induces significant antimyeloma activity and upregulates canonical miR-221 targets in vitro and in vivo. To evaluate the LNA-i-miR-221 pharmacokinetics and pharmacodynamics, novel assays for oligonucleotides quantification in NOD.SCID mice and Cynomolgus monkeys (Macaca fascicularis) plasma, urine and tissues were developed. To this aim, a liquid chromatography/mass spectrometry method, after solid-phase extraction, was used for the detection of LNA-i-miR-221 in plasma and urine, while a specific in situ hybridization assay for tissue uptake analysis was designed. Our analysis revealed short half-life, optimal tissue biovailability and minimal urine excretion of LNA-i-miR-221 in mice and monkeys. Up to 3 weeks, LNA-i-miR-221 was still detectable in mice vital organs and in xenografted tumors, together with p27 target upregulation. Importantly, no toxicity in the pilot monkey study was observed. Overall, our findings indicate the suitability of LNA-i-miR-221 for clinical use and we provide here pilot data for safety analysis and further development of LNA-miRNA-based therapeutics for human cancer. Nature Publishing Group 2016-06 2016-06-21 /pmc/articles/PMC5022129/ /pubmed/27327137 http://dx.doi.org/10.1038/mtna.2016.36 Text en Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Original Article Gallo Cantafio, Maria Eugenia Nielsen, Boye Schnack Mignogna, Chiara Arbitrio, Mariamena Botta, Cirino Frandsen, Niels M Rolfo, Christian Tagliaferri, Pierosandro Tassone, Pierfrancesco Di Martino, Maria Teresa Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates |
title | Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates |
title_full | Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates |
title_fullStr | Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates |
title_full_unstemmed | Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates |
title_short | Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates |
title_sort | pharmacokinetics and pharmacodynamics of a 13-mer lna-inhibitor-mir-221 in mice and non-human primates |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022129/ https://www.ncbi.nlm.nih.gov/pubmed/27327137 http://dx.doi.org/10.1038/mtna.2016.36 |
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