In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel
A recently developed inhibitor of retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens, such as toxins, parasites, intracellular bacteria and viruses. To circumvent its low aqueous solubility, a formulation in poly(ethylene gl...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14611 |
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| author | Robin Vinck Laetitia Anvi Nguyen Mathilde Munier Lucie Caramelle Diana Karpman Julien Barbier Alain Pruvost Jean-Christophe Cintrat Daniel Gillet |
| author_facet | Robin Vinck Laetitia Anvi Nguyen Mathilde Munier Lucie Caramelle Diana Karpman Julien Barbier Alain Pruvost Jean-Christophe Cintrat Daniel Gillet |
| author_sort | Robin Vinck |
| collection | DOAJ |
| description | A recently developed inhibitor of retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens, such as toxins, parasites, intracellular bacteria and viruses. To circumvent its low aqueous solubility, a formulation in poly(ethylene glycol)-<i>block</i>-poly(D,L)lactide micelle nanoparticles was developed. This formulation enabled the study of the pharmacokinetic parameters of Retro-2.1 in mice following intravenous and intraperitoneal injections, revealing a short blood circulation time, with an elimination half-life of 5 and 6.7 h, respectively. To explain the poor pharmacokinetic parameters, the metabolic stability of Retro-2.1 was studied in vitro and in vivo, revealing fast cytochrome-P-450-mediated metabolism into a less potent hydroxylated analogue. Subcutaneous injection of Retro-2.1 formulated in a biocompatible and bioresorbable polymer-based thermosensitive hydrogel allowed for sustained release of the drug, with an elimination half-life of 19 h, and better control of its metabolism. This study provides a guideline on how to administer this promising lead in vivo in order to study its efficacy. |
| first_indexed | 2024-03-09T17:46:22Z |
| format | Article |
| id | doaj.art-4d1c727497204737901a29c2a55eb4c6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:22Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4d1c727497204737901a29c2a55eb4c62023-11-24T11:04:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231461110.3390/ijms232314611In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive HydrogelRobin Vinck0Laetitia Anvi Nguyen1Mathilde Munier2Lucie Caramelle3Diana Karpman4Julien Barbier5Alain Pruvost6Jean-Christophe Cintrat7Daniel Gillet8SIMoS, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceSPI, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceSCBM, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceSIMoS, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceDepartment of Pediatrics, Clinical Sciences Lund, Lund University, 22242 Lund, SwedenSIMoS, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceSPI, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceSCBM, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceSIMoS, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, FranceA recently developed inhibitor of retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens, such as toxins, parasites, intracellular bacteria and viruses. To circumvent its low aqueous solubility, a formulation in poly(ethylene glycol)-<i>block</i>-poly(D,L)lactide micelle nanoparticles was developed. This formulation enabled the study of the pharmacokinetic parameters of Retro-2.1 in mice following intravenous and intraperitoneal injections, revealing a short blood circulation time, with an elimination half-life of 5 and 6.7 h, respectively. To explain the poor pharmacokinetic parameters, the metabolic stability of Retro-2.1 was studied in vitro and in vivo, revealing fast cytochrome-P-450-mediated metabolism into a less potent hydroxylated analogue. Subcutaneous injection of Retro-2.1 formulated in a biocompatible and bioresorbable polymer-based thermosensitive hydrogel allowed for sustained release of the drug, with an elimination half-life of 19 h, and better control of its metabolism. This study provides a guideline on how to administer this promising lead in vivo in order to study its efficacy.https://www.mdpi.com/1422-0067/23/23/14611retrograde transport inhibitorbroad spectrumRetro-2.1formulationthermosensitive hydrogelpharmacokinetic |
| spellingShingle | Robin Vinck Laetitia Anvi Nguyen Mathilde Munier Lucie Caramelle Diana Karpman Julien Barbier Alain Pruvost Jean-Christophe Cintrat Daniel Gillet In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel International Journal of Molecular Sciences retrograde transport inhibitor broad spectrum Retro-2.1 formulation thermosensitive hydrogel pharmacokinetic |
| title | In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel |
| title_full | In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel |
| title_fullStr | In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel |
| title_full_unstemmed | In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel |
| title_short | In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel |
| title_sort | in vivo sustained release of the retrograde transport inhibitor retro 2 1 formulated in a thermosensitive hydrogel |
| topic | retrograde transport inhibitor broad spectrum Retro-2.1 formulation thermosensitive hydrogel pharmacokinetic |
| url | https://www.mdpi.com/1422-0067/23/23/14611 |
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