Drug Permeation through Biological Barriers

Drug Delivery ◽  
2001 ◽  
Author(s):  
W. Mark Saltzman
Keyword(s):  
Plasma Membrane ◽  
Lipid Composition ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Average Molecular Weight ◽  
Transport Proteins ◽  
Cross Sectional ◽  
Tissue Properties ◽  
Experimental Systems ◽  
Outer Leaflet

In multicellular organisms, thin lipid membranes serve as semipermeable barriers between aqueous compartments. The plasma membrane of the cell separates the cytoplasm from the extracellular space; endothelial cell membranes separate the blood within the vascular space from the rest of the tissue. Properties of the lipid membrane are critically important in regulating the movement of molecules between these aqueous spaces. While certain barrier properties of membranes can be attributed to the lipid components, accessory molecules within the cell membrane—particularly transport proteins and ion channels—control the rate of permeation of many solutes. Transport proteins permit the cell to regulate the composition of its intracellular environment in response to extracellular conditions. The relationship between membrane structure, membrane function, and cell physiology is an area of active, ongoing study. Our interest here is practical: what are the basic mechanisms of drug movement through membranes and how can one best predict the rate of permeation of an agent through a membrane barrier? To answer that question, this section presents rates of permeation measured in some common experimental systems and models of membrane permeation that can be used for prediction. The external surface of the plasma membrane carries a carbohydrate-rich coat called the glycocalyx; charged groups in the glycocalyx, which are provided principally by carbohydrates containing sialic acid, cause the surface to be negatively charged. On average, the plasma membrane of human cells contains, by mass, 50% protein, 45% lipid, and 5% carbohydrate. Given the mass ratio of protein to lipid is ~ 1 : 1, and assuming reasonable values for the average molecular weight and cross-sectional area for each type of molecule (50 × Mw,lipid = Mw,protein; Alipid = 50 Å2 and Aprotein = 1,000 Å2), the area fraction of protein on a typical membrane is ~ 33%. The lipid composition varies in membranes from different cells depending on the type of cell and its function. In addition, the outermost monolayer of lipids, called the outer leaflet, has a different lipid composition from the inner leaflet.

scholarly journals Efficient replacement of plasma membrane outer leaflet phospholipids and sphingolipids in cells with exogenous lipids

2016 ◽  
Vol 113 (49) ◽  
pp. 14025-14030 ◽  
Author(s):  
Guangtao Li ◽  
JiHyun Kim ◽  
Zhen Huang ◽  
Johnna R. St. Clair ◽  
Deborah A. Brown ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Composition ◽  
Mammalian Cells ◽  
Cellular Membrane ◽  
Membrane Lipid ◽  
Exchange Method ◽  
Cellular Behavior ◽  
Outer Leaflet ◽  
Lipid Exchange ◽  
Cellular Lipids

Our understanding of membranes and membrane lipid function has lagged far behind that of nucleic acids and proteins, largely because it is difficult to manipulate cellular membrane lipid composition. To help solve this problem, we show that methyl-α-cyclodextrin (MαCD)-catalyzed lipid exchange can be used to maximally replace the sphingolipids and phospholipids in the outer leaflet of the plasma membrane of living mammalian cells with exogenous lipids, including unnatural lipids. In addition, lipid exchange experiments revealed that 70–80% of cell sphingomyelin resided in the plasma membrane outer leaflet; the asymmetry of metabolically active cells was similar to that previously defined for erythrocytes, as judged by outer leaflet lipid composition; and plasma membrane outer leaflet phosphatidylcholine had a significantly lower level of unsaturation than phosphatidylcholine in the remainder of the cell. The data also provided a rough estimate for the total cellular lipids residing in the plasma membrane (about half). In addition to such lipidomics applications, the exchange method should have wide potential for investigations of lipid function and modification of cellular behavior by modification of lipids.

scholarly journals Mimicking the Mammalian Plasma Membrane: An Overview of Lipid Membrane Models for Biophysical Studies

Biomimetics ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 3
Author(s):  
Alessandra Luchini ◽  
Giuseppe Vitiello
Keyword(s):  
Plasma Membrane ◽  
Lipid Bilayers ◽  
Lipid Membranes ◽  
Cell Membranes ◽  
Lipid Membrane ◽  
Lipid Phase ◽  
Chemical Information ◽  
Lipid Species ◽  
Membrane Models ◽  
The Impact

Cell membranes are very complex biological systems including a large variety of lipids and proteins. Therefore, they are difficult to extract and directly investigate with biophysical methods. For many decades, the characterization of simpler biomimetic lipid membranes, which contain only a few lipid species, provided important physico-chemical information on the most abundant lipid species in cell membranes. These studies described physical and chemical properties that are most likely similar to those of real cell membranes. Indeed, biomimetic lipid membranes can be easily prepared in the lab and are compatible with multiple biophysical techniques. Lipid phase transitions, the bilayer structure, the impact of cholesterol on the structure and dynamics of lipid bilayers, and the selective recognition of target lipids by proteins, peptides, and drugs are all examples of the detailed information about cell membranes obtained by the investigation of biomimetic lipid membranes. This review focuses specifically on the advances that were achieved during the last decade in the field of biomimetic lipid membranes mimicking the mammalian plasma membrane. In particular, we provide a description of the most common types of lipid membrane models used for biophysical characterization, i.e., lipid membranes in solution and on surfaces, as well as recent examples of their applications for the investigation of protein-lipid and drug-lipid interactions. Altogether, promising directions for future developments of biomimetic lipid membranes are the further implementation of natural lipid mixtures for the development of more biologically relevant lipid membranes, as well as the development of sample preparation protocols that enable the incorporation of membrane proteins in the biomimetic lipid membranes.

scholarly journals Lipid Composition but not Curvature Is the Determinant Factor for the Low Molecular Mobility Observed on the Membrane of Virus-Like Vesicles

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 415 ◽  
Author(s):  
Iztok Urbančič ◽  
Juliane Brun ◽  
Dilip Shrestha ◽  
Dominic Waithe ◽  
Christian Eggeling ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Composition ◽  
Molecular Mobility ◽  
Lipid Membrane ◽  
Dynamic Properties ◽  
Super Resolution ◽  
Correlation Spectroscopy ◽  
Stimulated Emission ◽  
Membrane Composition ◽  
Hiv 1

Human Immunodeficiency Virus type-1 (HIV-1) acquires its lipid membrane from the plasma membrane of the infected cell from which it buds out. Previous studies have shown that the HIV-1 envelope is an environment of very low mobility, with the diffusion of incorporated proteins two orders of magnitude slower than in the plasma membrane. One of the reasons for this difference is thought to be the HIV-1 membrane composition that is characterised by a high degree of rigidity and lipid packing, which has, until now, been difficult to assess experimentally. To further refine the model of the molecular mobility on the HIV-1 surface, we herein investigated the relative importance of membrane composition and curvature in simplified model membrane systems, large unilamellar vesicles (LUVs) of different lipid compositions and sizes (0.1–1 µm), using super-resolution stimulated emission depletion (STED) microscopy-based fluorescence correlation spectroscopy (STED-FCS). Establishing an approach that is also applicable to measurements of molecule dynamics in virus-sized particles, we found, at least for the 0.1–1 µm sized vesicles, that the lipid composition and thus membrane rigidity, but not the curvature, play an important role in the decreased molecular mobility on the vesicles’ surface. This observation suggests that the composition of the envelope rather than the particle geometry contributes to the previously described low mobility of proteins on the HIV-1 surface. Our vesicle-based study thus provides further insight into the dynamic properties of the surface of individual HIV-1 particles, as well as paves the methodological way towards better characterisation of the properties and function of viral lipid envelopes in general.

The roles of the diversity of amphipathic lipids in shaping membranes by membrane-shaping proteins

2020 ◽  
Vol 48 (3) ◽  
pp. 837-851
Author(s):  
Manabu Kitamata ◽  
Takehiko Inaba ◽  
Shiro Suetsugu
Keyword(s):  
Fatty Acid ◽  
Lipid Composition ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Membrane Lipids ◽  
Cell Types ◽  
Cellular Lipid ◽  
Head Groups ◽  
Packing Defects ◽  
Membrane Bending

Lipid compositions of cells differ according to cell types and intracellular organelles. Phospholipids are major cell membrane lipids and have hydrophilic head groups and hydrophobic fatty acid tails. The cellular lipid membrane without any protein adapts to spherical shapes, and protein binding to the membrane is thought to be required for shaping the membrane for various cellular events. Until recently, modulation of cellular lipid membranes was initially shown to be mediated by proteins recognizing lipid head groups, including the negatively charged ones of phosphatidylserine and phosphoinositides. Recent studies have shown that the abilities of membrane-deforming proteins are also regulated by the composition of fatty acid tails, which cause different degrees of packing defects. The binding of proteins to cellular lipid membranes is affected by the packing defects, presumably through modulation of their interactions with hydrophobic amino acid residues. Therefore, lipid composition can be characterized by both packing defects and charge density. The lipid composition regarding fatty acid tails affects membrane bending via the proteins with amphipathic helices, including those with the ArfGAP1 lipid packing sensor (ALPS) motif and via membrane-deforming proteins with structural folding, including those with the Bin–Amphiphysin–Rvs167 (BAR) domains. This review focuses on how the fatty acid tails, in combination with the head groups of phospholipids, affect protein-mediated membrane deformation.

scholarly journals Lipid composition but not curvature is a determinant of a low molecular mobility within HIV-1 lipid envelope

2018 ◽  
Author(s):  
Iztok Urbančič ◽  
Juliane Brun ◽  
Dilip Shrestha ◽  
Dominic Waithe ◽  
Christian Eggeling ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Composition ◽  
Molecular Mobility ◽  
Lipid Membrane ◽  
Dynamic Properties ◽  
Super Resolution ◽  
Membrane Curvature ◽  
Correlation Spectroscopy ◽  
Membrane Composition ◽  
Hiv 1

AbstractHuman Immunodeficiency Virus type-1 (HIV-1) acquires its lipid membrane from the plasma membrane of the infected cell from where it buds out. Previous studies have shown that the HIV-1 envelope is a very low mobility environment with the diffusion of incorporated proteins two orders of magnitude slower than in plasma membrane. One of the reasons for this difference is thought to be due to HIV-1 membrane composition that is characterised by a high degree of rigidity and lipid packing. To further refine the model of the molecular mobility on HIV-1 surface, we here investigated the relative importance of membrane composition and curvature in Large Unilamellar Vesicles of different composition and size (0.2–1 μm) by super-resolution STED microscopy-based fluorescence correlation spectroscopy (STED-FCS) analysis. We find that lipid composition and its rigidity but not membrane curvature play an important role in the decreased molecular mobility on vesicle surface thus confirming that this factor is an essential determinant of HIV-1 low surface mobility. Our results provide further insight into the dynamic properties of the surface of individual HIV-1 particles.

Tissue Barriers to Molecular and Cellular Transport

2004 ◽  
Author(s):  
W. Mark Saltzman
Keyword(s):  
Growth Factors ◽  
Cell Surface ◽  
Lipid Membranes ◽  
Extracellular Space ◽  
Quantitative Methods ◽  
Molecular Diffusion ◽  
Lipid Membrane ◽  
Underlying Mechanism ◽  
Tissue Properties ◽  
Molecular Movement

Previous chapters have revealed the importance of molecular diffusion in tissue engineering. Molecules—and gradients of molecules—may represent the underlying mechanism of tissue induction and pattern formation (Chapter 3); growth factors—and the rate of delivery of growth factors to a cell surface—can influence the rate of cell proliferation (Chapter 4); chemoattractants can influence the rate and pattern of cell migration within a tissue space (Chapter 7). To think quantitatively about these processes, it is often helpful to think about molecular concentrations and the spatial variations in concentration that produce diffusion fluxes. This idea has been illustrated earlier in the book for specific examples such as bicoid gradient formation in the insect embryo (Section 3.3.4) and ligand diffusion to the cell surface (Section 4.3.2). Some of the basic concepts of molecular transport are also reviewed in Appendix B. But tissues are often heterogeneous structures, formed by the assembly of cells and the accumulation of matrix materials in the extracellular space. The heterogeneous composition of tissues can have a dramatic influence on local rates of molecular movement through the tissue; capillary endothelial cells prevent the diffusion of intravascular proteins into the tissue interstitial space, for example. This chapter discusses this concept and provides quantitative methods for evaluating rates of molecular movement between tissue spaces that are separated by diffusive barriers. In addition, the last section of the chapter shows how this same analysis may be useful when thinking about rates of cellular movement between tissue compartments. In multicellular organisms, thin lipid membranes serve as semipermeable barriers between aqueous compartments. The plasma membrane of the cell separates the cytoplasm from the extracellular space; endothelial cell membranes separate the blood within the vascular space from the rest of the tissue. Properties of the lipid membrane are critically important in regulating the movement of molecules between aqueous spaces. While certain barrier properties of membranes can be attributed to the lipid components, accessory molecules within the cell membrane—particularly transport proteins and ion channels—control the rate of permeation of many solutes.

Gangliosides as modulators of cell function

1992 ◽  
Vol 262 (6) ◽  
pp. C1341-C1355 ◽  
Author(s):  
C. B. Zeller ◽  
R. B. Marchase
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
Cell Adhesion ◽  
Sialic Acid ◽  
Membrane Proteins ◽  
Cell Function ◽  
Physiological Significance ◽  
Present Evidence ◽  
Experimental Systems ◽  
Outer Leaflet

Gangliosides, sialic acid-containing glycosphingolipids, are found in the outer leaflet of the plasma membrane of all vertebrate tissues and species. This report presents a brief introduction to the gangliosides and reviews thechemistry and topography of their biosynthesis. It also presents an overview of the present evidence supporting a physiological significance for the gangliosides in a variety of experimental systems. This includes consideration of their potential roles in development and cell adhesion. In addition, experimental examples in which gangliosides appear to influence signal transduction processes through their interactions with plasma membrane proteins are discussed.

scholarly journals Electrochemical Properties of Lipid Membranes Self-Assembled from Bicelles

Membranes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 11
Author(s):  
Damian Dziubak ◽  
Kamil Strzelak ◽  
Slawomir Sek
Keyword(s):  
Electrochemical Properties ◽  
Self Assembly ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Membrane Resistance ◽  
Electrochemical Characteristics ◽  
Freeze Thaw ◽  
Lipid Films ◽  
Supported Lipid Membranes

Supported lipid membranes are widely used platforms which serve as simplified models of cell membranes. Among numerous methods used for preparation of planar lipid films, self-assembly of bicelles appears to be promising strategy. Therefore, in this paper we have examined the mechanism of formation and the electrochemical properties of lipid films deposited onto thioglucose-modified gold electrodes from bicellar mixtures. It was found that adsorption of the bicelles occurs by replacement of interfacial water and it leads to formation of a double bilayer structure on the electrode surface. The resulting lipid assembly contains numerous defects and pinholes which affect the permeability of the membrane for ions and water. Significant improvement in morphology and electrochemical characteristics is achieved upon freeze–thaw treatment of the deposited membrane. The lipid assembly is rearranged to single bilayer configuration with locally occurring patches of the second bilayer, and the number of pinholes is substantially decreased. Electrochemical characterization of the lipid membrane after freeze–thaw treatment demonstrated that its permeability for ions and water is significantly reduced, which was manifested by the relatively high value of the membrane resistance.

scholarly journals Interactions of Linear Analogues of Battacin with Negatively Charged Lipid Membranes

Membranes ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 192
Author(s):  
Kinga Burdach ◽  
Dagmara Tymecka ◽  
Aneta Urban ◽  
Robert Lasek ◽  
Dariusz Bartosik ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Liquid Crystalline ◽  
Lipid Membrane ◽  
Attenuated Total Reflection ◽  
Gram Positive ◽  
Insertion Depth ◽  
Force Microscopy ◽  
Acyl Chains ◽  
Hydrophobic Portion ◽  
Membrane Fluidization

The increasing resistance of bacteria to available antibiotics has stimulated the search for new antimicrobial compounds with less specific mechanisms of action. These include the ability to disrupt the structure of the cell membrane, which in turn leads to its damage. In this context, amphiphilic lipopeptides belong to the class of the compounds which may fulfill this requirement. In this paper, we describe two linear analogues of battacin with modified acyl chains to tune the balance between the hydrophilic and hydrophobic portion of lipopeptides. We demonstrate that both compounds display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive pathogens. Therefore, their mechanism of action was evaluated on a molecular level using model lipid films mimicking the membrane of Gram-positive bacteria. The surface pressure measurements revealed that both lipopeptides show ability to bind and incorporate into the lipid monolayers, resulting in decreased ordering of lipids and membrane fluidization. Atomic force microscopy (AFM) imaging demonstrated that the exposure of the model bilayers to lipopeptides leads to a transition from the ordered gel phase to disordered liquid crystalline phase. This observation was confirmed by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) results, which revealed that lipopeptide action causes a substantial increase in the average tilt angle of lipid acyl chains with respect to the surface normal to compensate for lipopeptide insertion into the membrane. Moreover, the peptide moieties in both molecules do not adopt any well-defined secondary structure upon binding with the lipid membrane. It was also observed that a small difference in the structure of a lipophilic chain, altering the balance between hydrophobic and hydrophilic portion of the molecules, results in different insertion depth of the active compounds.

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