Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Parenteral Nanoemulsion for Optimized Delivery of GL-II-73 to the Brain-Comparative In Vitro Blood-Brain Barrier and In Vivo Neuropharmacokinetic Evaluation
Δημιουργός/Συγγραφέας:	Jezdić, Kristina Đoković, Jelena Jančić, Ivan Ilić, Tanja Bufan, Biljana Marković, Bojan Ivanović, Jana Stanković, Tijana Cekić, Nebojša D [EL] Παπαδημητρίου, Βασιλική[EN] Papadimitriou, Vassiliki Sharmin, Dishary Mondal, Prithu Cook, James M Savić, Snežana D Savić, Miroslav M
Ημερομηνία:	2025-03-10
Γλώσσα:	Αγγλικά
ISSN:	1999-4923
DOI:	10.3390/pharmaceutics17030354
Άλλο:	40143018
Περίληψη:	Background/Objectives: GL-II-73 is a positive allosteric modulator that is selective for α5GABAA receptors and has physicochemical properties that favor nanocarrier formulations when parenteral delivery to the central nervous system is desired. Our aim was to develop an optimized nanoemulsion containing GL-II-73 and subsequently test whether this would improve permeation across the blood-brain 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-brain 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 ± 1.5, PDI of 0.123 ± 0.009 and zeta potential of -40.7 ± 1.5, pH of 5.16 ± 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 α5GABAA 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 α5GABAA receptors in the brain.
Τίτλος πηγής δημοσίευσης:	Pharmaceutics
Τόμος/Κεφάλαιο:	17
Τεύχος:	3
Θεματική Κατηγορία:	[EL] Θεραπευτική. Φαρμακολογία[EN] Therapeutics.Pharmacology [EL] Φαρμακευτική τεχνολογία[EN] Pharmaceutical technology [EL] Νανοτεχνολογία[EN] Nanotechnology [EL] Βιοτεχνολογία[EN] Biotechnology
Λέξεις-Κλειδιά:	GL-II-73 blood–brain barrier brain targeting neuropharmacokinetics α5GABAA receptors
Χρηματοδότης:	Science Fund of the Republic of Serbia National Institutes of Health, USA
EU Grant identifier:	7749108 451-03-47/2023-01/200161 2R01 DA043204-06A1 (NIDA) R01 AA029023 (NIAAA) R01 DA054177 (NIDA)
Κάτοχος πνευματικών δικαιωμάτων:	© 2025 by the authors. Licensee MDPI, Basel, Switzerland.
Όροι και προϋποθέσεις δικαιωμάτων:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/).
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.3390/pharmaceutics17030354
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο