ci6b00215_si_001.pdf (443.96 kB)
Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol–Cyclodextrin Complexes To Assess Their Drug Delivery Potential at the Blood–Brain Barrier Level
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 BroscheitIn 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.