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Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

In vivo sustained release of the retrograde transport inhibitor retro-2.1 formulated in a thermosensitive hydrogel

Résumé

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)-block-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.

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Chimie
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Dates et versions

cea-04352592 , version 1 (02-02-2024)

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Paternité

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Robin Vinck, Laetitia Anvi Nguyen, Mathilde Munier, Lucie Caramelle, Diana Karpman, et al.. In vivo sustained release of the retrograde transport inhibitor retro-2.1 formulated in a thermosensitive hydrogel. International Journal of Molecular Sciences, 2022, 23, pp.14611. ⟨10.3390/ijms232314611⟩. ⟨cea-04352592⟩
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