American Chemical Society
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Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol–Cyclodextrin Complexes To Assess Their Drug Delivery Potential at the Blood–Brain Barrier Level

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journal contribution
posted on 2016-09-02, 00:00 authored by Sergey Shityakov, Ramin Ekhteiari Salmas, Serdar Durdagi, Ellaine Salvador, Katalin Pápai, Maria Josefa Yáñez-Gascón, Horacio Pérez-Sánchez, István Puskás, Norbert Roewer, Carola Förster, Jens-Albert Broscheit
In this study, we investigated the ability of the general anesthetic propofol (PR) to form inclusion complexes with modified β-cyclodextrins, including sulfobutylether-β-cyclodextrin (SBEβCD) and hydroxypropyl-β-cyclodextrin (HPβCD). The PR/SBEβCD and PR/HPβCD complexes were prepared and characterized, and the blood–brain barrier (BBB) permeation potential of the formulated PR was examined in vivo for the purpose of controlled drug delivery. The PR/SBEβCD complex was found to be more stable in solution with a minimal degradation constant of 0.25 h–1, a t1/2 of 2.82 h, and a Kc of 5.19 × 103 M–1 and revealed higher BBB permeability rates compared with the reference substance (PR-LIPURO) considering the calculated brain-to-blood concentration ratio (logBB) values. Additionally, the diminished PR binding affinity to SBEβCD was confirmed in molecular dynamics simulations by a maximal Gibbs free energy of binding (ΔGbind = −18.44 kcal·mol–1), indicating the more rapid PR/SBEβCD dissociation. Overall, the results demonstrated that SBEβCD has the potential to be used as a prospective candidate for drug delivery vector development to improve the pharmacokinetic and pharmacodynamic properties of general anesthetic agents at the BBB level.