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Therapeutic-oligonucleotides activated by nucleases (TOUCAN): A nanocarrier system for the specific delivery of clinical nucleoside analogues.
Borsa, Baris A; Hernandez, Luiza I; Jiménez, Tania; Tellapragada, Chaitanya; Giske, Christian G; Hernandez, Frank J.
Afiliación
  • Borsa BA; Wallenberg Center for Molecular Medicine (WCMM), Linköping, Sweden; Department of Physics, Chemistry and Biology (IFM), Linköping University, Sweden; Nucleic Acid Technologies Laboratory (NAT-Lab), Linköping, Sweden.
  • Hernandez LI; Department of Clinical and Experimental Medicine (IKE), Linköping University, Sweden; SOMAprobes, Science and Technology Park of Gipuzkoa, Donostia-San Sebastian, Spain.
  • Jiménez T; SOMAprobes, Science and Technology Park of Gipuzkoa, Donostia-San Sebastian, Spain.
  • Tellapragada C; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
  • Giske CG; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
  • Hernandez FJ; Wallenberg Center for Molecular Medicine (WCMM), Linköping, Sweden; Department of Physics, Chemistry and Biology (IFM), Linköping University, Sweden; Nucleic Acid Technologies Laboratory (NAT-Lab), Linköping, Sweden. Electronic address: frank.hernandez@liu.se.
J Control Release ; 361: 260-269, 2023 09.
Article en En | MEDLINE | ID: mdl-37541593
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias / Nucleósidos Límite: Animals / Humans Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Suecia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias / Nucleósidos Límite: Animals / Humans Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Suecia
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