Tritium labeling of antisense oligonucleotides via different conjugation agents

Abstract A novel approach to tritium-labeled antisense oligonucleotides (ASO) was established by conjugating N-succinimidyl propionate, as well as maleimide-derivatives, to the 3′-end of ASOs targeting metastasis-associated lung adenocarcinoma transcript 1 (Malat1) containing amino- or sulfhydryl-li...

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Autores principales:	Martin R. Edelmann, Christophe Husser, Martina B. Duschmalé, Guy Fischer, Claudia Senn, Erich Koller, Andreas Brink
Formato:	article
Lenguaje:	EN
Publicado:	SpringerOpen 2021
Materias:	Antisense oligonucleotide Radiolabeling Malat1 Pharmacokinetics Tritium Therapeutics. Pharmacology RM1-950 Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/6e1253d853d5484ab910488c12140b07
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spelling	oai:doaj.org-article:6e1253d853d5484ab910488c12140b072021-11-21T12:15:48ZTritium labeling of antisense oligonucleotides via different conjugation agents10.1186/s41120-021-00040-32364-9534https://doaj.org/article/6e1253d853d5484ab910488c12140b072021-11-01T00:00:00Zhttps://doi.org/10.1186/s41120-021-00040-3https://doaj.org/toc/2364-9534Abstract A novel approach to tritium-labeled antisense oligonucleotides (ASO) was established by conjugating N-succinimidyl propionate, as well as maleimide-derivatives, to the 3′-end of ASOs targeting metastasis-associated lung adenocarcinoma transcript 1 (Malat1) containing amino- or sulfhydryl-linkers. In vitro stability and Malat1 RNA reduction studies demonstrated that N-ethylmaleimide (NEM) could be used as a stable tag while maintaining the desired target interaction. The corresponding radioactive label conjugation using [3H]-NEM resulted in tritium-labeled ASOs with a high molar specific activity of up to 17 Ci/mmol. Single-dose in vivo studies in mice were carried out to compare [3H]-ASOs with their unlabeled counterpart ASOs, with and without conjugation to N-acetylgalactosamine (GalNAc), for tissue and plasma concentrations time profiles. Despite the structural modification of the labeled ASOs, in vitro target interaction and in vivo pharmacokinetic behaviors were similar to that of the unlabeled ASOs. In conclusion, this new method provides a powerful technique for fast and safe access to tritium-labeled oligonucleotides, e.g., for pharmacokinetic, mass balance, or autoradiography studies. Graphical abstractMartin R. EdelmannChristophe HusserMartina B. DuschmaléGuy FischerClaudia SennErich KollerAndreas BrinkSpringerOpenarticleAntisense oligonucleotideRadiolabelingMalat1PharmacokineticsTritiumTherapeutics. PharmacologyRM1-950Pharmacy and materia medicaRS1-441ENAAPS Open, Vol 7, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Antisense oligonucleotide Radiolabeling Malat1 Pharmacokinetics Tritium Therapeutics. Pharmacology RM1-950 Pharmacy and materia medica RS1-441
spellingShingle	Antisense oligonucleotide Radiolabeling Malat1 Pharmacokinetics Tritium Therapeutics. Pharmacology RM1-950 Pharmacy and materia medica RS1-441 Martin R. Edelmann Christophe Husser Martina B. Duschmalé Guy Fischer Claudia Senn Erich Koller Andreas Brink Tritium labeling of antisense oligonucleotides via different conjugation agents
description	Abstract A novel approach to tritium-labeled antisense oligonucleotides (ASO) was established by conjugating N-succinimidyl propionate, as well as maleimide-derivatives, to the 3′-end of ASOs targeting metastasis-associated lung adenocarcinoma transcript 1 (Malat1) containing amino- or sulfhydryl-linkers. In vitro stability and Malat1 RNA reduction studies demonstrated that N-ethylmaleimide (NEM) could be used as a stable tag while maintaining the desired target interaction. The corresponding radioactive label conjugation using [3H]-NEM resulted in tritium-labeled ASOs with a high molar specific activity of up to 17 Ci/mmol. Single-dose in vivo studies in mice were carried out to compare [3H]-ASOs with their unlabeled counterpart ASOs, with and without conjugation to N-acetylgalactosamine (GalNAc), for tissue and plasma concentrations time profiles. Despite the structural modification of the labeled ASOs, in vitro target interaction and in vivo pharmacokinetic behaviors were similar to that of the unlabeled ASOs. In conclusion, this new method provides a powerful technique for fast and safe access to tritium-labeled oligonucleotides, e.g., for pharmacokinetic, mass balance, or autoradiography studies. Graphical abstract
format	article
author	Martin R. Edelmann Christophe Husser Martina B. Duschmalé Guy Fischer Claudia Senn Erich Koller Andreas Brink
author_facet	Martin R. Edelmann Christophe Husser Martina B. Duschmalé Guy Fischer Claudia Senn Erich Koller Andreas Brink
author_sort	Martin R. Edelmann
title	Tritium labeling of antisense oligonucleotides via different conjugation agents
title_short	Tritium labeling of antisense oligonucleotides via different conjugation agents
title_full	Tritium labeling of antisense oligonucleotides via different conjugation agents
title_fullStr	Tritium labeling of antisense oligonucleotides via different conjugation agents
title_full_unstemmed	Tritium labeling of antisense oligonucleotides via different conjugation agents
title_sort	tritium labeling of antisense oligonucleotides via different conjugation agents
publisher	SpringerOpen
publishDate	2021
url	https://doaj.org/article/6e1253d853d5484ab910488c12140b07
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Tritium labeling of antisense oligonucleotides via different conjugation agents

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