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Hybridisation of 76Br-labelled antisense oligonucleotides to Chromogranin A mRNA verified by RT-PCR
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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2004 In: Nuclear Medicine and Biology, Vol. 31, 1073-1078 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 31, 1073-1078 p.
URN: urn:nbn:se:uu:diva-96298OAI: oai:DiVA.org:uu-96298DiVA: diva2:170828
Available from: 2007-10-18 Created: 2007-10-18Bibliographically approved
In thesis
1. Radiolabelled Oligonucleotides for Evaluation of in vivo Hybridisation Utilising PET Methodology
Open this publication in new window or tab >>Radiolabelled Oligonucleotides for Evaluation of in vivo Hybridisation Utilising PET Methodology
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antisense oligonucleotides (ODN) may interfere in gene expression on the basis of hybridising to its complementary messenger RNA (mRNA) sequence in the cell thereby preventing the synthesis of the peptide. Therefore, these ODNs may be potential drugs to treat human diseases by “knocking down” the expression of responsible genes or correcting the maturation process of mRNA in the field called antisense therapy. Moreover, antisense ODNs upon labelling are also potential imaging agents to monitor gene expression in vivo, i.e. to accomplish in vivo hybridisation. This would provide a non-invasive tool compared to present methods, which require tissue samples.

This goal may be reached using positron emission tomography (PET) methodology. PET is a most advanced in vivo imaging technology, which would allow exploring the fate of radionuclide-labelled antisense ODNs in the body; thereby providing information about biodistribution and quantitative accumulation in tissues to assess pharmacokinetic properties of ODNs. This kind of evaluation is important as part of the characterisation of antisense therapeutics but also as part of the development of antisense imaging agents.

The present study aimed to investigate 76Br- and 68Ga-labelled ODNs of five different modifications: phosphodiester, phosphorothioate, 2'-O-methyl phosphodiester, locked nucleic acid (LNA), and peptide nucleic acid. The study included exploration of the hybridisation abilities of these ODNs after labelling; furthermore, the biodistribution, metabolite analysis and uptake of the ODNs in rats regarding non-hybridisation and hybridisation specific uptake was conducted. Among the ODNs studied, LNA-DNA mixmer (LNA and DNA nucleotides in alternation along the sequence) displayed the most promising characteristics considering a higher retention in tissues, stability and longer plasma residence. However, biodistribution data demonstrated a non-hybridisation specific distribution in rat tissues with kidney, liver, spleen and bone marrow being the organs of high uptake. Scavenger receptors or other saturable processes unrelated to hybridisation may play a role in tissue uptake and in clearance of antisense ODNs through these organs. These processes may be sequence dependent suggesting that proof of in vivo hybridisation through imaging needs much more elaborate evaluations than just comparison of sense and antisense sequences and proving dose-dependency.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 90 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 279
Molecular medicine, Gene expression, Antisense oligonucleotides, Positron emission tomography, In vivo hybridisation, In vivo biodistribution, Chromogranin-A, 68Ga, RT-PCR, Scavenger receptors, Molekylärmedicin
urn:nbn:se:uu:diva-8262 (URN)978-91-554-6990-0 (ISBN)
Public defence
2007-11-09, Skoogsalen, University Hospital, Ingång 78/79, Uppsala, 09:15
Available from: 2007-10-18 Created: 2007-10-18Bibliographically approved

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