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Our aim was to develop an optimized nanoemulsion containing GL-II-73 and subsequently test whether this would improve permeation across the blood\u2013brain barrier (BBB) and availability in the brain. Methods: The nanoemulsions were formulated and subjected to detailed physiochemical characterization. The optimized formulation was tested in comparison to a solution of GL-II-73 in the appropriate solvent in an in vitro model of the blood\u2013brain barrier based on human induced pluripotent stem cell-derived microvascular endothelial cells, astrocytes, and pericytes. Plasma and brain exposure to GL-II-73 and its metabolite MP-III-022 was investigated in an in vivo neuropharmacokinetic study in rats exposed to the selected nanoemulsion and the conventional solution formulation. Results: The selected biocompatible nanoemulsion exhibited satisfactory physicochemical properties for parenteral administration, with a Z-ave of 122.0 \u00b1 1.5, PDI of 0.123 \u00b1 0.009 and zeta potential of \u221240.7 \u00b1 1.5, pH of 5.16 \u00b1 0.04, and adequate stability after one year of storage, and allowed the localization of GL-II-73 in the stabilization layer. The permeability of GL-II-73 through the BBB was twice as high with the selected nanoemulsion as with the solution. The availability of GL-II-73 and MP-III-022 (also a positive allosteric modulator selective for \u03b15GABAA receptors) in the brain was 24% and 61% higher, respectively, after intraperitoneal administration of the nanoemulsion compared to the solution; the former increase was statistically significant. Conclusions: The increased permeability in vitro proved to be a good predictor for the improved availability of GL-II-73 in brain tissue in vivo from the formulation obtained by encapsulation in a nanoemulsion. The putative additive effect of the parent molecule and its metabolite MP-III-022 could lead to enhanced and\/or prolonged modulation of \u03b15GABAA receptors in the brain.<\/jats:p>","DOI":"10.3390\/pharmaceutics17030354","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T08:46:41Z","timestamp":1741596401000},"page":"354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Parenteral Nanoemulsion for Optimized Delivery of GL-II-73 to the Brain\u2014Comparative In Vitro Blood\u2013Brain Barrier and In Vivo Neuropharmacokinetic Evaluation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2208-2252","authenticated-orcid":false,"given":"Kristina","family":"Jezdi\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0936-4276","authenticated-orcid":false,"given":"Jelena","family":"\u0110okovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Jan\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1937-1704","authenticated-orcid":false,"given":"Tanja","family":"Ili\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1861-5700","authenticated-orcid":false,"given":"Biljana","family":"Bufan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-4394","authenticated-orcid":false,"given":"Bojan","family":"Markovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Ivanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tijana","family":"Stankovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neboj\u0161a D.","family":"Ceki\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Technology, University of Ni\u0161, 16000 Leskovac, Serbia"},{"name":"DCP Hemigal, 16000 Leskovac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-3115","authenticated-orcid":false,"given":"Vassiliki","family":"Papadimitriou","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dishary","family":"Sharmin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prithu","family":"Mondal","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-3022","authenticated-orcid":false,"given":"James M.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, 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