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Thermodynamics of Selective Serotonin Reuptake Inhibitors Partitioning Into 1,2-Dioleoyl-Sn-Glycero- Cite This: RSC Adv., 2020, 10,39338 3-Phosphocholine Bilayers†

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Thermodynamics of Selective Serotonin Reuptake Inhibitors Partitioning Into 1,2-Dioleoyl-Sn-Glycero- Cite This: RSC Adv., 2020, 10,39338 3-Phosphocholine Bilayers† RSC Advances View Article Online PAPER View Journal | View Issue Thermodynamics of selective serotonin reuptake inhibitors partitioning into 1,2-dioleoyl-sn-glycero- Cite this: RSC Adv., 2020, 10,39338 3-phosphocholine bilayers† Dat T. N. Ngo, ad Trinh Q. Nguyen, ‡ad Hieu K. Huynh b and Trang T. Nguyen *cd Knowledge of thermodynamics of lipid membrane partitioning of amphiphilic drugs as well as their binding site within the membrane are of great relevance not only for understanding the drugs' pharmacology but also for the development and optimization of more potent drugs. In this study, the interaction between two representatives of selective serotonin reuptake inhibitors, including paroxetine and sertraline, and large unilamellar vesicles (LUVs) composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) was investigated by second derivative spectrophotometry and Fourier transform infrared spectroscopy (FTIR) to determine the driving force of the drug partitioning across lipid membranes. It was found that Creative Commons Attribution-NonCommercial 3.0 Unported Licence. temperature increase from 25 to 42 C greatly enhanced the partitioning of paroxetine and sertraline into DOPC LUVs, and sertraline intercalated into the lipid vesicles to a greater extent than paroxetine in the temperature range examined. The partitioning of both drugs into DOPC LUVs was a spontaneous, endothermic and entropy-driven process. FTIR measurements suggested that sertraline could penetrate deeply into the acyl tails of DOPC LUVs as shown by the considerable shifts in the lipid's CH2 and C]O stretching modes induced by the drug. Paroxetine, however, could reside closer to the head groups of À the lipid since its presence caused a larger shift in the PO2 bands of DOPC LUVs. The findings reported Received 27th August 2020 here provide valuable insights into the influence of small molecules' chemical structure on their Accepted 14th October 2020 molecular interaction with the lipid bilayer namely their possible binding sites within the lipid bilayer and This article is licensed under a DOI: 10.1039/d0ra07367a their thermodynamics profiles of partitioning, which could benefit rational drug design and drug delivery rsc.li/rsc-advances systems. Open Access Article. Published on 27 October 2020. Downloaded 9/29/2021 4:44:41 PM. 1. Introduction Selective serotonin reuptake inhibitors (SSRIs) have been considered as the rst-line medicines for the treatment of Most of the drugs available on the market target trans- depression and other mental disorders11 since they alleviate the membrane proteins.1 As a result, the ability of a drug molecule symptoms of depression by raising serotonin level. When SSRIs to cross the cell membrane and interact with lipid bilayers is are administered, they inhibit the neuronal uptake pump for a critical benchmark in drug design, development and optimi- serotonin by binding to the serotonin transporter, and thus zation.2 Additionally, the thermodynamics of drug–lipid prevent the re-uptake of serotonin.12,13 To reach their targets, membrane interaction not only offers essential information SSRIs must partition into cell membranes, as a result, any regarding the force that drives a drug across lipid membranes interactions between SSRIs and lipid membranes are crucial in but also reveals its pharmacological behavior, thus it has been understanding the mechanism of action of the drugs. SSRIs of great research interest.3–10 have been found to not only accumulate in the cell membranes14,15 but also alter the physical structure and prop- 16–19 a erties of lipid bilayers upon their partitioning. It was previ- Department of Biotechnology, International University, Block 6, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Vietnam ously reported that uoxetine, a common SSRI, partitioned to bUniversity of Medicine and Pharmacy at Ho Chi Minh City, 217 Hong Bang, Ward 11, a greater extent into liquid-crystalline 1,2-dioleoyl-sn-glycero-3- District 5, Ho Chi Minh City, Vietnam phosphocholine (DOPC) bilayers than into solid-gel 1,2-dipal- cDepartment of Chemical Engineering, International University, Block 6, Linh Trung mitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers and the Ward, Thu Duc District, Ho Chi Minh City, Vietnam. E-mail: [email protected] membrane partitioning of uoxetine increased with tempera- d Vietnam National University, Ho Chi Minh City, Vietnam ture in which the lipid phase changed from solid-gel to liquid- † Electronic supplementary information (ESI) available: Figures show the crystalline.16 Furthermore, uoxetine structurally disordered mathematical addition of the pure DOPC spectrum to the spectrum of either 16 PAX or SER. See DOI: 10.1039/d0ra07367a both DOPC and DPPC bilayers upon its partitioning. The ff ‡ Deceased. disordering e ect of uoxetine upon its partitioning into 1,2- 39338 | RSC Adv.,2020,10,39338–39347 This journal is © The Royal Society of Chemistry 2020 View Article Online Paper RSC Advances dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and DPPC (À16.5 C 27), mimicking well the uid cell membranes, and bilayers was also observed.19 thus has been commonly used as a model lipid for probing Although SSRIs–lipid membrane interactions have been drug–lipid membrane interactions.18,28–31 subjected to several studies, the thermodynamics of SSRIs Thermodynamics of membrane partitioning of PAX and SER partitioning into lipid membranes, especially the Gibbs free was determined by measuring DOPC liposome/water partition energy, enthalpy and entropy change of partitioning, has not coefficients (Kp) of the drugs at varying temperatures using been described. Moreover, the force that drives the partitioning second derivative spectrophotometry, an effective method in of SSRIs into lipid bilayer has not yet been elucidated. Addi- measurement of drug partitioning owing to its ability to elimi- tionally, previous studies on SSRIs–lipid membrane interaction nate the light scattering from lipid vesicles.16,17,32,33 Gibbs energy were only carried out with uoxetine as the representative (DG), enthalpy (DG) and entropy (DS) change of the drug par- drug16,17,19 while little attention has been paid to paroxetine titioning were then extracted from Van't Hoff gure in which (PAX) and sertraline (SER) in spite of their wide usage in the logarithms of Kp values were plotted against inversed temper- treatment of depression.11,20,21 ature. Along with partition coefficient determination, the As cationic amphiphilic drugs, PAX and SER are dened by conformational changes in DOPC bilayer were investigated by two main physicochemical attributes: a hydrophobic ring FTIR to provide complementary information regarding the system and a basic, nitrogen-containing group.22 In PAX, the thermodynamics proles of SSRIs-DOPC LUVs interaction. hydrophobic ring system is composed of a piperidine bearing Particularly, the ordering degree of the lipid acyl chains before 1,3-benzodioxol-5-yloxymethyl and 4-uorophenyl substituents and aer the drug partitioning can be revealed by changes in 34 at positions 3 and 4, respectively, while the nonpolar moiety of the location of the CH2 stretching bands and the hydration SER is tetralin which has methylamino and 3,4-dichlorophenyl state of the interfacial regions can be obtained by frequency À 35 substituents at positions 1 and 4, respectively. The nitrogen- shis in the C]O and PO2 bands of the lipid head groups. containing group of PAX is the piperidine group, while that of Creative Commons Attribution-NonCommercial 3.0 Unported Licence. SER is the methylamino group, both of which are secondary amine. Additionally, the halogen moiety on the hydrophobic 2. Methods ring system of the two drugs also differs, in which PAX has one uorine atom while SER possesses two chlorine atoms. Due to Paroxetine (PAX) and sertraline (SER) were obtained from Sigma the heterogeneity in their chemical structures, the physico- Aldrich (USA). 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) chemical properties of PAX and SER, such as log P and total in chloroform was purchased from Avanti Polar Lipids (USA) polar surface area (TPSA), are also different, which lead to the and used without further puri cation. The stock solution of À1 dissimilarity in pharmacokinetic and pharmacologic action lipid was made at a concentration of 20 mg mL . HEPES (4-(2- ff between PAX and SER.21,23–26 The chemical structures of PAX and hydroxyethyl)-1-piperazine-ethanesulfonic acid) bu er was ob- This article is licensed under a SER were depicted in Fig. 1. tained from Sigma Aldrich (USA). All liquid suspensions were ff In this study, thermodynamics of the two SSRIs, PAX and prepared with 10 mM HEPES bu er containing 50 mM NaCl, at SER, partitioning into lipid membranes, were characterized in pH 7.4. an attempt to provide a more comprehensive understanding of Open Access Article. Published on 27 October 2020. Downloaded 9/29/2021 4:44:41 PM. SSRIs–lipid membrane interactions. Large unilamellar vesicles 2.1 Preparation of large unilamellar vesicles (LUVs) composed of DOPC were chosen in the present work as a model of lipid membranes. With a cis double bond between Chloroform in the lipid solution was removed by evaporation the C9 and C10 in each chain (see Fig. 1), DOPC exists in the using a stream of nitrogen. The residual amount of chloroform liquid-crystalline state at a temperature above its Tm was further removed under vacuum for at least 8 h at room temperature. The dried lipid lm was then suspended with HEPES buffer at pH 7.4 and sonicated at room temperature. The lipid suspensions were subjected to 5 cycles of a cooling–heat- ing process. Large unilamellar vesicles (LUVs) were produced by extruding the lipid suspensions through a polycarbonate membrane of 0.1 mm pore size (Whatman Inc., USA) using a mini-extruder (Avanti Polar Lipids, USA). 2.2 Preparation of drug–liposome mixtures Sample solutions were prepared by adding the drug solution at a xed concentration (0.50 mM for PAX and 0.045 mM for SER) to different concentrations of the lipid suspensions.
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