Therapeutic-oligonucleotides activated by nucleases (TOUCAN): A nanocarrier system for the specific delivery of clinical nucleoside analogues.

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Borsa, Baris Ata,First Research EngineerLinköpings universitet,Biologi,Tekniska fakulteten,Wallenberg Center for Molecular Medicine (WCMM); Nucleic Acid Technologies Laboratory (NAT-Lab) (author)

Therapeutic-oligonucleotides activated by nucleases (TOUCAN) : A nanocarrier system for the specific delivery of clinical nucleoside analogues.

Article/chapterEnglish2023

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ELSEVIER,2023
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LIBRIS-ID:oai:DiVA.org:liu-197102
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-197102URI
https://doi.org/10.1016/j.jconrel.2023.07.057DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:153751442URI

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Language:English
Summary in:English

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Funding: Knut and Alice Wallenberg Foundation [LiU 301097]; Swedish Research Council [2021-05641]; Swedish Research Council [2021-05641] Funding Source: Swedish Research Council
Nucleoside analogues have been in clinical use since 1960s and they are still used as the first therapeutic option for several cancers and viral infections, due to their high therapeutic efficacy. However, their wide clinical acceptance has been limited due to their high toxicity and severe side effects to patients. Herein, we report on a nanocarrier system that delivers nucleosides analogues in a target-specific manner, making nucleoside-based therapeutics safer and with the possibility to be used in other human conditions. This system, named, Therapeutic OligonUCleotides Activated by Nucleases" (TOUCAN) combines: i) the recognition power of oligonucleotides as substrates, ii) the use of nucleases as enzymatic biomarkers and iii) the clinical efficacy of nucleoside analogues, in a single approach. As a proof-of-concept, we report on a TOUCAN that is activated by a specific nuclease produced by bacteria and releases a therapeutic nucleoside, floxuridine. We demonstrate, for the first time, that, by incorporating a therapeutic nucleoside analogue into oligonucleotide probes, we can specifically inhibit bacterial growth in cultures. In this study, Staphylococcus aureus was selected as the targeted bacteria and the TOUCAN strategy successfully inhibited its growth with minimal inhibitory concentration (MIC) values ranging from 0.62 to 40 mg/L across all tested strains. Moreover, our results indicate that the intravenous administration of TOUCANs at a dose of 20 mg/kg over a 24-h period is a highly effective method for treating bacterial infections in a mouse model of pyomyositis. Importantly, no signs of toxicity were observed in our in vitro and in vivo studies. This work can significantly impact the current management of bacterial infections, laying the grounds for the development of a different class of antibiotics. Furthermore, it can provide a safer delivery platform for clinical nucleoside therapeutics in any human conditions, such as cancer and viral infection, where specific nuclease activity has been reported.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi Medicinsk bioteknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology Medical Biotechnology hsv//eng
Therapeutics; Oligonucleotides; Nucleases; Nanocarrier; Drug delivery; Antibiotics

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Hernandez, Luiza I.Linköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,SOMAprobes, Science and Technology Park of Gipuzkoa, Donostia-San Sebastian, Spain(Swepub:liu)luihe46 (author)
Jiménez, TaniaSOMAprobes, Science and Technology Park of Gipuzkoa, Donostia-San Sebastian, Spain (author)
Tellapragada, ChaitanyaKarolinska Institutet (author)
Giske, Christian GKarolinska Institutet (author)
Hernandez, Frank J,1979-Linköpings universitet,Tekniska fakulteten,Biologi,Wallenberg Center for Molecular Medicine (WCMM); Nucleic Acid Technologies Laboratory (NAT-Lab)(Swepub:liu)frahe49 (author)
Linköpings universitetBiologi (creator_code:org_t)

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In:Journal of Controlled Release: ELSEVIER361, s. 260-2690168-36591873-4995

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