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Cited by 26Drug Solubulity and Delivery SystemsBarrier Structure and Function StudiesAdvanced Drug Delivery Systems

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Sevoflurane-Sulfobutylether-β-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies

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Shityakov, Sergey, Puskás, István, Pápai, Katalin, Salvador, Ellaine, Roewer, Norbert, Förster, Carola, Broscheit, Jens-Albert·2015·Molecules
DOI 10.3390/molecules200610264PMC PMC6272776
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Abstract

The objective of the present investigation was to study the ability of sulfobutylether-β-cyclodextrin (SBEβCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEβCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of -1.727 ± 0.042 kcal·mol-1 and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.

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Crossref · 10.3390/molecules200610264

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Figures

Figure 1 Reconstructed 3D structure of the solid-state lyophilized SEV-SBEβCD before grinding taken by a normal digital camera (A); The top (B); default (C); and front (D) view of the SEV-SBEβCD surface 3D plot was generated to evaluate and visualize the porosity using the array of height values (HV) measured in arbitrary units (au) with hue color function. The substance was in a round bottom flask, and the material in the photo represents an approximately 50 × 40 mm area.
Figure 1 Reconstructed 3D structure of the solid-state lyophilized SEV-SBEβCD before grinding taken by a normal digital camera (A); The top (B); default (C); and front (D) view of the SEV-SBEβCD surface 3D plot was generated to evaluate and visualize the porosity using the array of height values (HV) measured in arbitrary units (au) with hue color function. The substance was in a round bottom flask, and the material in the photo represents an approximately 50 × 40 mm area.CC BY · PubMed Central
Figure 2 X-ray powder diffraction patterns (A) as red (SBEβCD) and green curves (SEV-SBEβCD) and polarized light microscopy (B) of the SEV-SBEβCD complex at 100× magnification. The beam intensity is measured in counts per second, abbreviated as cps.
Figure 2 X-ray powder diffraction patterns (A) as red (SBEβCD) and green curves (SEV-SBEβCD) and polarized light microscopy (B) of the SEV-SBEβCD complex at 100× magnification. The beam intensity is measured in counts per second, abbreviated as cps.CC BY · PubMed Central
Figure 3 Capillary elecropherograms of the SBEβCD compound (A) and SEV-SBEβCD complex (B) on a 50 cm, 50 μm uncoated fused-silica capillary. The signal intensity is measured in milli absorbance units, abbreviated as mAU.
Figure 3 Capillary elecropherograms of the SBEβCD compound (A) and SEV-SBEβCD complex (B) on a 50 cm, 50 μm uncoated fused-silica capillary. The signal intensity is measured in milli absorbance units, abbreviated as mAU.CC BY · PubMed Central
Figure 4 pEND cell viability assay to measure SEV-SBEβCD toxic effect over time (24 h). The luminescence is measured in percentage to a control group (untreated cells). 10% solution of DMSO was used as positive control. The median toxic dose level is abbreviated as TD50. The thresholds are depicted as dashed lines. Data represent means ± standard deviation of three independent experiments
Figure 4 pEND cell viability assay to measure SEV-SBEβCD toxic effect over time (24 h). The luminescence is measured in percentage to a control group (untreated cells). 10% solution of DMSO was used as positive control. The median toxic dose level is abbreviated as TD50. The thresholds are depicted as dashed lines. Data represent means ± standard deviation of three independent experimentsCC BY · PubMed Central
Figure 5 TER measurements (A) and FITC-dextran (4 kDa) permeation assay (B) of propranolol as system validation substance and SEV-SBEβCD complex. Collagen 4-coated empty inserts were used as a control. The fluorescence is measured in relative fluorescence units, abbreviated as RFU. Data represent means ± standard deviation of three independent experiments.
Figure 5 TER measurements (A) and FITC-dextran (4 kDa) permeation assay (B) of propranolol as system validation substance and SEV-SBEβCD complex. Collagen 4-coated empty inserts were used as a control. The fluorescence is measured in relative fluorescence units, abbreviated as RFU. Data represent means ± standard deviation of three independent experiments.CC BY · PubMed Central
Figure 6 Transwell® BBB transport studies of propranolol as a system validation substance (A) and SEV-SBEβCD (B). Collagen 4-coated empty inserts were used as a control. Second-order polynomial (quadratic) curves are implemented to connect and fit the data points. Data represent means ± standard deviation of three independent experiments.
Figure 6 Transwell® BBB transport studies of propranolol as a system validation substance (A) and SEV-SBEβCD (B). Collagen 4-coated empty inserts were used as a control. Second-order polynomial (quadratic) curves are implemented to connect and fit the data points. Data represent means ± standard deviation of three independent experiments.CC BY · PubMed Central
Figure 7 Three-dimensional models of the SBE7βCD (A) structure and SEV-SBE7βCD (B) complex (obtained by molecular docking) with MLP-surfaces around the cyclodextrin molecule and best conformational pose (cluster with RMSD values of 2 Å) of the ligand. logPMLP (C) and MLP-Pocket (D) display the distribution of lipophilicity for the SBE7βCD binding site and pose conformations of sevoflurane. The thresholds are depicted as dashed lines. MLP calculated as hydrophobic fitting points depicted in smaller colored spheres according to the MLP range from red (the most polar points) to blue (the most hydrophobic points). MLP-pocket in the center of the center of SBE7βCD molecule is depicted in bigger colored spheres. Molecular surface was calculated to visualize the cyclodextrin cavity. The ball-and-stick SEV model is colored according to its atomic composition. Hydrogen atoms are omitted to enhance clarity.
Figure 7 Three-dimensional models of the SBE7βCD (A) structure and SEV-SBE7βCD (B) complex (obtained by molecular docking) with MLP-surfaces around the cyclodextrin molecule and best conformational pose (cluster with RMSD values of 2 Å) of the ligand. logPMLP (C) and MLP-Pocket (D) display the distribution of lipophilicity for the SBE7βCD binding site and pose conformations of sevoflurane. The thresholds are depicted as dashed lines. MLP calculated as hydrophobic fitting points depicted in smaller colored spheres according to the MLP range from red (the most polar points) to blue (the most hydrophobic points). MLP-pocket in the center of the center of SBE7βCD molecule is depicted in bigger colored spheres. Molecular surface was calculated to visualize the cyclodextrin cavity. The ball-and-stick SEV model is colored according to its atomic composition. Hydrogen atoms are omitted to enhance clarity.CC BY · PubMed Central
Figure 8 Schematic representations of sevoflurane, compound A, and sulfobutyl-ether7-β-cyclodextrin (SBE7βCD) molecules.
Figure 8 Schematic representations of sevoflurane, compound A, and sulfobutyl-ether7-β-cyclodextrin (SBE7βCD) molecules.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Barash, P.G., Cullen, B.F., and Stoelting, R.K. (2001). Clinical Anesthesia, Lippincott Williams& Wilkins. [4th ed.].

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Metadata

Authors
Shityakov, S., Puskás, I., Pápai, K., Salvador, E., Roewer, N., Förster, C., & Broscheit, J.-A.
Affiliations
  • University of Würzburg (DE)
  • CycloLab (Hungary) (HU)
  • Sapiotec Ltd., 97078 Würzburg, Germany
Corresponding author
Shityakov, Sergey
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2015-06-03
Volume
20
Issue
6
Pages
10264-10279
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules200610264
PMC
PMC6272776
OpenAlex
W1584701817
Cited by
26
References
42
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2022: 4 · 2020: 1 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 2
FWCI
2.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Bundesministerium für Bildung und Forschung (EO1004, BMBF01)
  • Julius-Maximilians-Universität Würzburg
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
sevoflurane, sulfobutylether-β-cyclodextrin, inclusion complexes, blood-brain barrier permeability, cytotoxicity, apparent permeability, binding affinity, drug solubility enhancement, volatile anesthetics, controlled drug delivery
MeSH terms
Sevoflurane, Animals, Blood-Brain Barrier, Brain, Capillary Permeability, Cell Survival, Delayed-Action Preparations, Drug Compounding, Methyl Ethers, Propranolol, Anesthetics, Inhalation, Endothelial Cells, beta-Cyclodextrins, Mice, Primary Cell Culture, Molecular Docking Simulation

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