TY - JOUR
T1 - Characterization, in Vivo Evaluation, and Molecular Modeling of Different Propofol-Cyclodextrin Complexes to Assess Their Drug Delivery Potential at the Blood-Brain Barrier Level
AU - Shityakov, Sergey
AU - Salmas, Ramin Ekhteiari
AU - Durdagi, Serdar
AU - Salvador, Ellaine
AU - Pápai, Katalin
AU - Yáñez-gascón, Maria Josefa
AU - Pérez-sánchez, Horacio
AU - Puskás, István
AU - Roewer, Norbert
AU - Förster, Carola
AU - Broscheit, Jens-albert
PY - 2016/10/24
Y1 - 2016/10/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84992751108&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.6b00215
DO - 10.1021/acs.jcim.6b00215
M3 - Article
C2 - 27589557
AN - SCOPUS:84992751108
SN - 1549-9596
VL - 56
SP - 1914
EP - 1922
JO - JOURNAL OF CHEMICAL INFORMATION AND MODELING
JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING
IS - 10
ER -