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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.<\/jats:p>","DOI":"10.3390\/ijms232314611","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T09:50:52Z","timestamp":1669197052000},"page":"14611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2730-0121","authenticated-orcid":false,"given":"Robin","family":"Vinck","sequence":"first","affiliation":[{"name":"SIMoS, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"},{"name":"SCBM, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laetitia Anvi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"SPI, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Munier","sequence":"additional","affiliation":[{"name":"SCBM, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Caramelle","sequence":"additional","affiliation":[{"name":"SIMoS, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7220-7658","authenticated-orcid":false,"given":"Diana","family":"Karpman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Clinical Sciences Lund, Lund University, 22242 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-4973","authenticated-orcid":false,"given":"Julien","family":"Barbier","sequence":"additional","affiliation":[{"name":"SIMoS, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-7735","authenticated-orcid":false,"given":"Alain","family":"Pruvost","sequence":"additional","affiliation":[{"name":"SPI, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5758-8077","authenticated-orcid":false,"given":"Jean-Christophe","family":"Cintrat","sequence":"additional","affiliation":[{"name":"SCBM, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-3599","authenticated-orcid":false,"given":"Daniel","family":"Gillet","sequence":"additional","affiliation":[{"name":"SIMoS, D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.cell.2010.01.043","article-title":"Inhibition of Retrograde Transport Protects Mice from Lethal Ricin Challenge","volume":"141","author":"Stechmann","year":"2010","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1021\/jm4002346","article-title":"N-Methyldihydroquinazolinone Derivatives of Retro-2 with Enhanced Efficacy against Shiga Toxin","volume":"56","author":"Noel","year":"2013","journal-title":"J. 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