Modern Studies on Drug-Membrane Interactions

A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Functions".

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 25167

Special Issue Editors


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Guest Editor
Institute of Chemical Kinetics and Combustion, Institutskaya St., 3, 630090 Novosibirsk, Russia
Interests: drug delivery systems; drug-membrane interaction; antiviral drugs; metal chelators; antitumor drugs; anthracycline antibiotics; glycyrrhizic acid; thiosemicarbazones; lipid peroxidation; nuclear magnetic resonance; molecular dynamics simulations
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Institute of Chemical Kinetics and Combustion, Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: carotenoids; drug delivery systems; spin chemistry; free radicals; antioxidant activity; electron transfer; membrane biophysics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the target of many drugs is inside the cell, the study of drug interactions with cell membranes is at the heart of understanding the mechanism of drug action in organisms. Such studies open up new perspectives for rational drug design, based not only on the interaction of a drug molecule with the active site of an enzyme, but also on the interaction with a biological membrane (membrane permeability for a drug, the effect of a drug molecule on the structure and dynamics of biological membranes). The results of such studies make it possible to evaluate and analyze the bioavailability and efficacy of a medicinal product.

This Special Issue, titled “Modern Studies on Drug–Membrane Interactions” and published by the journal Membranes, seeks contributions to assess state-of-the-art research as well as future developments in the field of drug–membrane interaction studies. Topics include, but are not limited to, the interactions of drugs and natural compounds with biomimetic membranes, including liposomes, monolayers, and micelles; in-cell studies of drug–membrane interaction; new techniques and methods in the study of drug–membrane interactions. Authors are invited to submit their latest results; both original papers and reviews are welcome.

Kind regards,

Dr. Olga Yurevna Selyutina
Dr. Nikolay Polyakov
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Membranes is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • lipid membrane
  • drug–membrane interaction
  • membrane permeability
  • drug delivery

Published Papers (8 papers)

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Research

22 pages, 3118 KiB  
Article
Buccal Thin Films as Potent Permeation Enhancers for Cytisine Transbuccal Delivery
by Viviana De Caro, Giuseppe Angellotti, Fabio D’Agostino and Giulia Di Prima
Membranes 2022, 12(11), 1169; https://doi.org/10.3390/membranes12111169 - 21 Nov 2022
Cited by 2 | Viewed by 2005
Abstract
Cytisine (CYT) is a powerful anti-smoking compound which could greatly benefit from transbuccal delivery because of both its unfavorable pharmacokinetics after oral administration and its intrinsic ability to permeate the buccal mucosa. This work aims to design CYT-loaded buccal thin films suitable for [...] Read more.
Cytisine (CYT) is a powerful anti-smoking compound which could greatly benefit from transbuccal delivery because of both its unfavorable pharmacokinetics after oral administration and its intrinsic ability to permeate the buccal mucosa. This work aims to design CYT-loaded buccal thin films suitable for transbuccal drug delivery due to its capability of promoting the interaction between CYT and the buccal membrane. The solvent casting method was employed to prepare several thin films combining various excipients such as matrixing polymers, mucoadhesion agents, plasticizers and other compounds as humectants and sweeteners, component ratios and solvents. A total of 36 compositions was prepared and four of them emerged as the most promising in terms of aspect and flexibility. They all demonstrated homogeneity, thinness, low swelling degree, and controlled drug release according to the Power Law and Peppas-Sahlin mathematical models. Mainly, they proved able to interact with the ex vivo porcine buccal mucosa producing mucoadhesive effects, and act as potent permeation enhancers. In particular, Film B emerged as suitable as it produced a 10.6-fold Kp enhancement and a great Js value (52.33 μg/cm2·h−1), even when compared to highly concentrated CYT solutions. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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16 pages, 2248 KiB  
Article
Novel O-Methylglucoside Derivatives of Flavanone in Interaction with Model Membrane and Transferrin
by Sylwia Cyboran-Mikołajczyk, Dorota Bonarska-Kujawa, Katarzyna Męczarska, Agnieszka Krawczyk-Łebek and Edyta Kostrzewa-Susłow
Membranes 2022, 12(10), 978; https://doi.org/10.3390/membranes12100978 - 8 Oct 2022
Cited by 2 | Viewed by 1314
Abstract
Flavonoids were biotransformed using various microorganisms, in order to obtain new compounds with potentially high biological activity. The aim of this work was to determine and compare the biological activity of four novel 6-methylflavanone O-methylglucosides. The tested compounds have the same flavonoid [...] Read more.
Flavonoids were biotransformed using various microorganisms, in order to obtain new compounds with potentially high biological activity. The aim of this work was to determine and compare the biological activity of four novel 6-methylflavanone O-methylglucosides. The tested compounds have the same flavonoid core structure and an attached O-methylglucose and hydroxyl group at different positions of ring A or B. The studies on their biological activity were conducted in relation to phosphatidylcholine membrane, erythrocytes and their membrane, and with human transferrin. These studies determined the compounds’ toxicity and their impact on the physical properties of the membranes. Furthermore, the binding ability of the compounds to holo-transferrin was investigated. The obtained results indicate that used compounds bind to erythrocytes, change their shape and decrease osmotic fragility but do not disrupt the membrane structure. Furthermore, the used compounds ordered the area of the polar heads of lipids and increased membrane fluidity. However, the results indicate the binding of these compounds in the hydrophilic region of the membranes, like other flavonoid glycosides. The used flavanones formed complexes with transferrin without inducing conformational changes in the protein’s structure. The relationship between their molecular structure and biological activity was discussed. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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15 pages, 4507 KiB  
Article
Stereoselectivity of Interaction of Nonsteroidal Anti-Inflammatory Drug S-Ketoprofen with L/D-Tryptophan in Phospholipid Membranes
by Anna V. Mastova, Olga Yu. Selyutina and Nikolay E. Polyakov
Membranes 2022, 12(5), 460; https://doi.org/10.3390/membranes12050460 - 24 Apr 2022
Cited by 7 | Viewed by 2151
Abstract
The mechanisms of stereoselectivity of the interaction of chiral drugs with active sites of enzymes and cell receptors attract significant attention. The first reason is the difference in therapeutic activity of the enantiomers of the common drugs. Another reason is the interest in [...] Read more.
The mechanisms of stereoselectivity of the interaction of chiral drugs with active sites of enzymes and cell receptors attract significant attention. The first reason is the difference in therapeutic activity of the enantiomers of the common drugs. Another reason is the interest in the role of chiral inversion of amino acids involved in various peptides in the development of many diseases including Alzheimer’s, Parkinson’s, type II diabetes, and a number of other pathological conditions. In our study we use elementary chemical process—electron transfer (ET) to simulate individual stages of ligand–receptor and enzyme–substrate interactions. In particular, previous studies of photoinduced ET in chiral donor-acceptor dyads consisting of the nonsteroidal anti-inflammatory drug (R/S)-ketoprofen and (L)-tryptophan show the stereo and spin selectivity of ET in diastereomers. The present study is devoted to the interaction of (S)-ketoprofen with L- and D-enantiomers of tryptophan in homogeneous aqueous solution and in phospholipid membranes. The study was done using the NMR technique and molecular modeling. These approaches confirm efficient penetration of ketoprofen into the lipid bilayer and binding with tryptophan molecule. The short-lived paramagnetic intermediates formed during the photoinduced ET from electron donor tryptophan to ketoprofen have been detected using the chemically induced dynamic nuclear polarization (CIDNP) technique. It was found that S-ketoprofen interacts stereoselectively with tryptophan enantiomers in the lipid membrane. The formation of the ketyl radical of ketoprofen under irradiation leads to the oxidation of membrane lipids and may be the cause of ketoprofen phototoxicity. However, in contrast to a homogeneous solution in phosphate buffer saline, where the amino acid tryptophan accelerates the photodecomposition of KP due to intramolecular hydrogen transfer, tryptophan in a lipid membrane significantly reduces the rate of photodegradation due to a reversible electron (or hydrogen) transfer reaction. The stereoselectivity in the rate of KP and lipids decomposition under UV irradiation of S-ketoprofen in the presence of tryptophan enantiomers in lipid bilayer has been detected. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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10 pages, 2256 KiB  
Article
RCCS Bioreactor-Based Modeled Microgravity Affects Gastric Cancer Cells and Improves the Chemotherapeutic Effect
by Nina Rembiałkowska, Dagmara Baczyńska, Magda Dubińska-Magiera, Anna Choromańska, Katarzyna Bieżuńska-Kusiak, Agnieszka Gajewska-Naryniecka, Vitalij Novickij, Jolanta Saczko, Dawid Przystupski and Julita Kulbacka
Membranes 2022, 12(5), 448; https://doi.org/10.3390/membranes12050448 - 21 Apr 2022
Cited by 7 | Viewed by 2446
Abstract
(1) Background: The main purpose of the study was to determine whether altered gravity might alter cell viability, improve drug delivery and modulate the expression of drug resistance-related genes. (2) Methods: This study investigated the intracellular mechanisms activated by microgravity in human resistant [...] Read more.
(1) Background: The main purpose of the study was to determine whether altered gravity might alter cell viability, improve drug delivery and modulate the expression of drug resistance-related genes. (2) Methods: This study investigated the intracellular mechanisms activated by microgravity in human resistant and sensitive gastric cancer cells (EPG85-257 RDB) and (EPG85-257 P). We used a rotary cell culture system (RCCS) developed by NASA to expose cells to altered gravity. The antitumor potential of microgravity was simulated by the RCCS bioreactor, and its effectiveness was evaluated in sensitive cell lines compared to chemotherapy-resistant cells concerning drug-sensitive cancer cells. Microgravity with chemotherapy was estimated by the viability assay, cytoskeleton imaging, MDR (multidrug resistance) gene expression analysis, MTCO-1 (mitochondrially encoded cytochrome C oxidase I), and 8-OHdG immunocytochemical analysis. (3) Results: We found that altered gravity combined with doxorubicin was cytotoxic to cancer cells. Cells following simulated microgravity revealed decreased expression of genes related to drug resistance and increased DNA/RNA damage marker expression. Cytoskeleton evaluation demonstrated significant reorganization of F-actin fibers after exposure to changed gravity conditions. (4) Conclusions: Intracellular alterations caused by simulated microgravity can increase gastric cancer cells’ sensitivity to chemotherapy. We have obtained satisfactory results showing the correlation between altered gravity and MDR phenomena which seems promising in future therapeutic applications. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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17 pages, 2223 KiB  
Article
Versatile Encapsulation and Synthesis of Potent Liposomes by Thermal Equilibration
by Steven A. Roberts, Chaebin Lee, Shrishti Singh and Nitin Agrawal
Membranes 2022, 12(3), 319; https://doi.org/10.3390/membranes12030319 - 11 Mar 2022
Cited by 6 | Viewed by 3051
Abstract
The wide-scale use of liposomal delivery systems is challenged by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes but are limited by low efficiencies (passive) or high drug specificities (active). Here, we [...] Read more.
The wide-scale use of liposomal delivery systems is challenged by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes but are limited by low efficiencies (passive) or high drug specificities (active). Here, we present an efficient and universal loading strategy for synthesizing therapeutic liposomes. Integrating a thermal equilibration technique with our unique liposome synthesis approach, co-loaded targeting nanovesicles can be engineered in a scalable manner with potencies 200-fold higher than typical passive encapsulation techniques. We demonstrate this capability through simultaneous co-loading of hydrophilic and hydrophobic small molecules and targeted delivery of liposomal Doxorubicin to metastatic breast cancer cell line MDA-MB-231. Molecular dynamic simulations are used to explain interactions between Doxorubicin and liposome membrane during thermal equilibration. By addressing the existing challenges, we have developed an unparalleled approach that will facilitate the formulation of novel theranostic and pharmaceutical strategies. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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26 pages, 1905 KiB  
Article
Calculation of Permeability Coefficients from Solute Equilibration Dynamics: An Assessment of Various Methods
by Margarida M. Cordeiro, Armindo Salvador and Maria João Moreno
Membranes 2022, 12(3), 254; https://doi.org/10.3390/membranes12030254 - 23 Feb 2022
Viewed by 8755
Abstract
Predicting the rate at which substances permeate membrane barriers in vivo is crucial for drug development. Permeability coefficients obtained from in vitro studies are valuable for this goal. These are normally determined by following the dynamics of solute equilibration between two membrane-separated compartments. [...] Read more.
Predicting the rate at which substances permeate membrane barriers in vivo is crucial for drug development. Permeability coefficients obtained from in vitro studies are valuable for this goal. These are normally determined by following the dynamics of solute equilibration between two membrane-separated compartments. However, the correct calculation of permeability coefficients from such data is not always straightforward. To address these problems, here we develop a kinetic model for solute permeation through lipid membrane barriers that includes the two membrane leaflets as compartments in a four-compartment model. Accounting for solute association with the membrane allows assessing various methods in a wide variety of conditions. The results showed that the often-used expression Papp = β × r/3 is inapplicable to very large or very small vesicles, to moderately or highly lipophilic solutes, or when the development of a significant pH gradient opposes the solute’s flux. We establish useful relationships that overcome these limitations and allow predicting permeability in compartmentalised in vitro or in vivo systems with specific properties. Finally, from the parameters for the interaction of the solute with the membrane barrier, we defined an intrinsic permeability coefficient that facilitates quantitative comparisons between solutes. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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15 pages, 12142 KiB  
Article
Photoinduced Oxidation of Lipid Membranes in the Presence of the Nonsteroidal Anti-Inflammatory Drug Ketoprofen
by Anna V. Mastova, Olga Yu. Selyutina, Veronika I. Evseenko and Nikolay E. Polyakov
Membranes 2022, 12(3), 251; https://doi.org/10.3390/membranes12030251 - 22 Feb 2022
Cited by 7 | Viewed by 1678
Abstract
The damage of cell membranes induced by photosensitive drugs has attracted the significant attention of researchers in various fields of medicine. Ketoprofen (KP) is known to be the most photosensitive among the nonsteroidal anti-inflammatory drugs. The phototoxic side effects of KP and other [...] Read more.
The damage of cell membranes induced by photosensitive drugs has attracted the significant attention of researchers in various fields of medicine. Ketoprofen (KP) is known to be the most photosensitive among the nonsteroidal anti-inflammatory drugs. The phototoxic side effects of KP and other non-steroidal anti-inflammatory drugs are associated with the action of free radicals, but there is insufficient information about the nature of these radicals. In the present study, free radicals formed upon KP irradiation within lipid membranes were studied using nuclear magnetic resonance (NMR) and chemically induced dynamic nuclear polarization (CIDNP) methods, as well as a molecular dynamics simulation. Our study confirmed the effective penetration of KP into the lipid bilayer and showed a significant effect of the nature of the medium on the photolysis mechanism. While, in a homogeneous solution, the main channel of KP photolysis is free radical-mediated monomolecular decomposition with formation of radical pairs of benzyl and CO2H radicals, then, in the lipid membrane, the reaction route shifts towards the bimolecular reaction of KP photoreduction. In addition, the effect of the presence an electron donor (the amino acid tryptophan) on lipid oxidation has been studied. It was found that photoreaction of KP with tryptophan proceeds more efficiently than with lipid molecules. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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14 pages, 2489 KiB  
Article
Lipid Specific Membrane Interaction of Aptamers and Cytotoxicity
by Md. Ashrafuzzaman, Hanouf A. M. AlMansour, Maha A. S. AlOtaibi, Zahid Khan and Gouse M. Shaik
Membranes 2022, 12(1), 37; https://doi.org/10.3390/membranes12010037 - 27 Dec 2021
Cited by 3 | Viewed by 2815
Abstract
We aim to discover diagnostic tools to detect phosphatidylserine (PS) externalization on apoptotic cell surface using PS binding aptamers, AAAGAC and TAAAGA, and hence to understand chemotherapy drug efficacy when inducing apoptosis into cancer cells. The entropic fragment-based approach designed aptamers have been [...] Read more.
We aim to discover diagnostic tools to detect phosphatidylserine (PS) externalization on apoptotic cell surface using PS binding aptamers, AAAGAC and TAAAGA, and hence to understand chemotherapy drug efficacy when inducing apoptosis into cancer cells. The entropic fragment-based approach designed aptamers have been investigated to inspect three aspects: lipid specificity in aptamers’ membrane binding and bilayer physical properties-induced regulation of binding mechanisms, the apoptosis-induced cancer cell surface binding of aptamers, and the aptamer-induced cytotoxicity. The liposome binding assays show preferred membrane binding of aptamers due to presence of PS in predominantly phosphatidylcholine-contained liposomes. Two membrane stiffness reducing amphiphiles triton X-100 and capsaicin were found to enhance membrane’s aptamer adsorption suggesting that bilayer physical properties influence membrane’s adsorption of drugs. Microscopic images of fluorescence-tagged aptamer treated LoVo cells show strong fluorescence intensity only if apoptosis is induced. Aptamers find enhanced PS molecules to bind with on the surface of apoptotic over nonapoptotic cells. In cytotoxicity experiments, TAAAGA (over poor PS binding aptamer CAGAAAAAAAC) was found cytotoxic towards RBL cells due to perhaps binding with nonapoptotic externalized PS randomly and thus slowly breaching plasma membrane integrity. In these three experimental investigations, we found aptamers to act on membranes at comparable concentrations and specifically with PS binding manner. Earlier, we reported the origins of actions through molecular mechanism studies—aptamers interact with lipids using mainly charge-based interactions. Lipids and aptamers hold distinguishable charge properties, and hence, lipid–aptamer association follows distinguishable energetics due to electrostatic and van der Waals interactions. We discover that our PS binding aptamers, due to lipid-specific interactions, appear as diagnostic tools capable of detecting drug-induced apoptosis in cancer cells. Full article
(This article belongs to the Special Issue Modern Studies on Drug-Membrane Interactions)
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