The Interaction of Heptakis (2,6-di-O-Methyl)-β-cyclodextrin with Mianserin Hydrochloride and Its Influence on the Drug Toxicity

Abstract

One tetracyclic antidepressant, mianserin hydrochloride (MIA), has quite significant side effects on a patients’ health. Cyclodextrins, which are most commonly used to reduce the undesirable features of contained drugs within their hydrophobic interior, also have the potential to alter the toxic behavior of the drug. The present paper contains investigations and the characteristics of interaction mechanisms for MIA and the heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) system, and evaluated the effects of the complexation on MIA cytotoxicity. In order to assess whether there was an interaction between MIA and DM-β-CD molecules, isothermal titration calorimetry (ITC) have been chosen. Electrospray ionization mass spectrometry (ESI-MS) helped to establish the complex stoichiometry, and circular dichroism spectroscopy was used to describe the process of complex formation. In order to make a wider interpretative perspective, the molecular docking results have been performed. The viability of Chinese hamster cells were investigated in the presence of DM-β-CD and its complexes with MIA in order to estimate the cytotoxicity of the drug and the conjugate with the chosen cyclodextrin. The viability of B14 cells treated with MIA+DM-β-CD is lower (the toxicity is higher) than with MIA alone, and no protective effects have been observed for complexes of MIA with DM-β-CD in any ratio.

Thermodynamic Studies of Interactions between Sertraline Hydrochloride and Randomly Methylated β-Cyclodextrin Molecules Supported by Circular Dichroism Spectroscopy and Molecular Docking Results

“…This selection was justified inter alia in the least errors of the fitted parameters [53] in comparison to results obtained from the other models like e.g., "Two-sets of sites" [53,54]. Moreover, the first point (Figure 2) from first injection during the fitting sessions was discarded considering the circumstances described previously [26]. The "One-set of independent sites model" [49,50] was selected among available in the ORIGIN 7 program options [51,52] to get the thermodynamical parameters (Table 1).…”

“…This selection was justified inter alia in the least errors of the fitted parameters [53] in comparison to results obtained from the other models like e.g., "Two-sets of sites" [53,54]. Moreover, the first point (Figure 2) from first injection during the fitting sessions was discarded considering the circumstances described previously [26].…”

“…Unfortunately, it was not possible to check the energy of RMβCD with SRT complexes with a stoichiometry greater than 1:1, because the available crystal structure of this cyclodextrin has only one molecule in its independent cell [48]. To obtain results comparable to those for SRT docking in RMβCD, the remaining 1:1 type complex was obtained by stepwise removal of successive βCD (or TMβCD) molecules from the structure and re-optimization of the resulting complex was performed [26] and the results of all molecular docking studies are presented in Table 3 and Figures 7-12 The geometry of the SRT-βCD complex with stoichiometry 1:3 (I-II-III or "head-to-headto-tail" as in [69,70]) obtained by the Molecular Docking (MD) simulations with the use of βCD crystal structure with refcode 648855 [67] from The Cambridge Structural Database (CSD) [47].…”

“…Such a low maximum possible concentration of SRT forces the drug solution to become a titrand placed in a measuring cell and RMβCD to get a titrant position in an injecting syringe [36,73]. Although cyclodextrin is a macromolecule it is used as a ligand and the drug plays a role of a macromolecule in the measuring cell, it is a very common situation and a more detailed justification for this is provided in the previous article [26]. Into a measuring cell (volume of 1.4275 mL) filled with an aqueous solution of SRT with concentration of 0.45 mM, a solution of RMβCD (15 mM) [74] was added by injection 55 portions of 5 µL titrant solution.…”

“…The basis for advanced tests of the cyclodextrins application are still information about inclusion complexation by natural and modified cyclodextrins, as well as the factors involved in controlling the supramolecular interactions [21]. Lately, the interactions between antidepressant drugs and cyclodextrins were examined [22][23][24][25][26], mostly in order to gain the better water solubility of the drug [27][28][29], or to decrease its toxicity [30,31] or even for taste-masking [32]. One of the antidepressants, sertraline hydrochloride, belonging to the class of selective serotonin reuptake inhibitors (SSRIs) [33,34] and also tested as potential anti-Helicobacter pylori compound [35] has already been tested in the presence of β-cyclodextrin and the derivatives [36][37][38][39][40] inter alia in our laboratory [31,41,42].…”