Fatty acid vesicles

doi:10.1016/j.cocis.2007.05.005

Current Opinion in Colloid & Interface Science

Volume 12, Issue 2, April 2007, Pages 75-80

https://doi.org/10.1016/j.cocis.2007.05.005 Get rights and content

Abstract

Results obtained from recent studies on the preparation and application of fatty acid vesicles are reviewed, focusing on some of the particular properties of fatty acid vesicles in comparison with conventional phospholipid vesicles (liposomes): (i) pH dependency which allows reversible transformations from non-vesicular to vesicular aggregates, and (ii) dynamic features that place fatty acid vesicles in between conventional vesicles formed from double-chain amphiphiles and micelles formed from single-chain surfactants. There are two main research areas in which fatty acid vesicles have been studied actively during the last years: (i) basic physico-chemical properties, and (ii) applications as protocell models. Applications of fatty acid vesicles in the fields of food additives and drug delivery are largely unexplored, which is at least partially due to concerns regarding the colloidal stability of fatty acid vesicles (pH- and divalent cation-sensitivity). Recently, fatty acid vesicles were prepared from highly unsaturated fatty acids (docosahexaenoic acid) and the pH range of vesicle formation could be extended to high or low pH values by preparing mixed vesicles through addition of a second type of single-chain amphiphile that stabilizes the vesicle bilayer but itself is not a fatty acid.

Introduction

Fatty acid vesicles are colloidal suspensions of closed lipid bilayers that are composed of fatty acids and their ionized species (soap). They are observed in a small region within the fatty acid–soap–water ternary phase diagram above the chain-melting temperature (T_m) of the corresponding fatty acid–soap mixture [1]. The formation of fatty acid vesicles was first reported by Gebicki and Hicks in 1973 and the following years for oleic acid (cis-9-octadecenoic acid) and linoleic acid (cis,cis-9,12-octadecadienoic acid), and the vesicles formed were initially named “ufasomes”: “unsaturated fatty acid liposomes” [2]. Later investigations have shown that fatty acid vesicles form not only from unsaturated fatty acids but also from saturated such as octanoic acid and decanoic acid [3], [4].

Compared with diacylglycerophospholipid vesicles (conventional liposomes), fatty acid vesicles have some unique properties. One important feature is the dynamic nature of fatty acid vesicles owing to the fact that they are composed of single-chain amphiphiles. The concentration of non-associated monomers in equilibrium with vesicles is considerably higher than in the case of double-chain phospholipids. For example, while the monomer concentration in equilibrium with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers is around 10^− 10 M [5], the monomer concentration of oleic acid in equilibrium with oleic acid vesicles is between 0.4 mM and 0.7 mM [6] (depending on the conditions, it could also be below 0.1 mM [7^••]). Therefore, the flip-flop of molecules between two monolayer leaflets of fatty acid bilayers and the exchange between fatty acid vesicles via monomers are expected to occur more rapidly than in the case of liposomes formed from double-chain phospholipids. The second important feature is the formation of a range of fatty acid/soap aggregates just by changing the total concentration and the protonation/ionization ratio of the terminal carboxylic acid [4], [8]. A titration curve of the oleic acid/oleate system determined at a total concentration of 80 mM is given in Fig. 1(A). Fatty acid vesicles always contain two types of amphiphiles, the non-ionized, neutral form and the ionized form (the negatively charged soap), and their ratio is critical for the vesicle stability. Fatty acid vesicles are actually mixed “fatty acid/soap vesicles”, but for the sake of simplicity, we just call them here “fatty acid vesicles”. The formation of fatty acid vesicles is restricted to a rather narrow pH range (ca.7–9), where approximately half of the carboxylic groups are ionized [4]. The pH range for vesicle formation varies depending on the chemical structure of fatty acids. Fatty acids with a longer aliphatic chain tend to form vesicles at a higher pH, because the molecules can be packed more tightly in the membrane. It should be noted that the local pH value at the membrane surface can be substantially lower than the pH of the bulk solution (the measured pH) [9]. Fig. 1(B) and (C) show electron micrographs of unilamellar vesicles formed from rac-2-methyldodecanoic acid and decanoic acid, respectively [10], [11•]. These vesicles formed at lower pH regions compared with oleic acid vesicles. Micelles are the dominant aggregation species at higher pH (higher ratio of ionized to protonated molecules), whereas oil droplets form in the low pH region. In dilute systems (> 95 wt.% water), transitions from one type of fatty acid/soap structure to another can be induced easily by changing the pH.

This review compiles recent research and developments on fatty acid vesicles and fatty acid-based vesicles, focusing on (i) consequences of the dynamic features of this particular type of single-chain surfactant and consequences of pH induced aggregate transformations; (ii) current considerations as models for protocells, the hypothetical compartment structures that may have preceded the first cells during the processes that led to a transformation of non-living matter into the first living systems; and (iii) reports on fatty acid-based mixed vesicles that extend the conditions for vesicle formation and may find applications in scientific and technological areas.

Section snippets

Dynamic formation and transformation of fatty acid vesicles

One of the most prominent features of fatty acid vesicles is the dynamic formation and transformation induced by changes of the environmental conditions. The fact that a range of fatty acid aggregates are formed just by changing the protonation/ionization ratio of the terminal carboxylic acid and by changing the overall concentration provides an excellent opportunity to study physico-chemical properties of different aggregate structures. For example, the organization of the hydrophobic interior

Fatty acid vesicles as protocell model

The simplicity of the chemical structure of fatty acids and the dynamic formation of fatty acid vesicles has stimulated many “origin-of-life-investigators” interested in understanding the formation of the first cell-like compartments (hypothetical protocells). Fatty acids — more likely than double-chain, glycerol-based phospholipids — may have been present in the prebiotic environment on Earth [22], [23]. Although the narrow pH range of vesicle formation and their instability in the presence of

Expansion to mixed fatty acid-based vesicle systems

Possible applications of fatty acid vesicles in cosmetics, medicine and food technology remain largely unexplored. This may be at least partially due to concerns regarding the colloidal stability of the vesicles. However, there are some recent studies, using either new types of fatty acids or mixed systems with other surfactants, which may change the situation in future. For example, cis-4,7,10,13,16,19-docosahexaenoic acid (DHA), which is closely related to various cellular functions and human

More detailed studies needed on fatty acid vesicles

For realizing applications based on fatty acid vesicles, one still needs a deeper understanding of their self-assembly process. In the case of oleic acid vesicles, a detailed physico-chemical investigation by using a nitroxide-labeled fatty acid and electron spin resonance spectroscopy indicated, for example, that the vesicles may coexist with micelles (or non-vesicular aggregates) also in regions of the titration curve in which originally only vesicles (bilayers) were thought to exist in

Conclusions

Fatty acid vesicles provide a useful experimental system to study thermodynamic and kinetic aspects of surfactant self-assembly, owing to the characteristic dynamic features and the pH-induced aggregate transformations. Although the physicochemical properties of fatty acid vesicles have been studied to some extent in the last three decades, there are still many aspects that require more detailed studies, e.g. regarding a model explaining the matrix effect [47], [48], [49] and fatty acid vesicle

Acknowledgements

The authors thank Marjeta Šentjurc (Jozef Stefan Institute, Ljubljana, Slovenia) and Vesna Nöthig-Laslo (Rudjer Boškoviæ Institute, Zagreb, Croatia) for the stimulating discussions.

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Citation Excerpt :
The association of oleic acid and ethanol was also responsible for the narrow size distribution as evidenced by the polydispersity index values (lower than 0.2 for all formulations), so as to predict suitable stability over time [44]. Finally, the negative surface charges ranging from −33 ± 0.6 to −41 ± 1.4 mV were elicited by the presence of ionized species of oleic acid and the amphiphilic nature of phospholipon® 90G [45]. In order to confirm the assumed stability, the oleoethosomes were analyzed at 25 °C (room temperature) and 35 °C (physiological skin temperature) by using a Turbiscan Lab Expert® (Fig. 1).
The topical administration of a drug compound remains the first choice for the treatment of many local skin ailments. Many skin diseases can be treated by applying the active formulation directly to the skin, but unfortunately some drugs are unable to overcome the stratum corneum and exert their pharmacological action. An example is thymoquinone, a naturally derived drug obtained from Nigella sativa L. and potentially effective in the treatment of inflammatory and oxidative skin conditions. Since its physico-chemical properties are not suitable for overcoming the stratum corneum, we wanted to circumvent the problem by proposing new lipid-based nanovesicles called “oleoethosomes”, made up of naturally derived ingredients, for its delivery. Among several formulations of oleoethosomes, the sample made up of 2% (w/w) oleic acid:PL90G 1:1 (molar ratio), and ethanol 15% showed the best physico-chemical characteristics and above all it showed the capacity to contain a suitable amount of thymoquinone (2 mg/ml). The formulation was tested in vitro on stratum corneum and viable epidermis membranes confirming its ability to induce the passage of thymoquinone through the human stratum corneum and to act as a permeation enhancer. In fact, it showed thymoquinone permeation values of 22.63 ± 1.49% regarding the applied drug amount. Oleoethosomes were compared with oleosomes, another kind of naturally derived nanosystems but free of ethanol. The experimental data confirmed that ethanol was an important component that enhanced the activity of the oleoethosomes when tested on the skin of healthy volunteers. The thymoquinone-loaded oleoethosome treatment demonstrated a significantly greater extent of anti-inflammatory activity than the treatment with thymoquinone-loaded oleosomes or the conventional dosage form of the drug. These in vivo results confirmed the synergic effect between oleic acid and ethanol on the lipid and protein compartments of the outermost skin layer, thus promoting a greater penetration capacity.
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Experiments: This study demonstrates the combination of an optical micromanipulation platform, polarized optical video microscopy and microfluidics in a comprehensive approach for the analysis of pH-driven structural transformations in emulsions. The new platform, together with synchrotron small angle X-ray scattering, was then applied to research the food-relevant, pH-responsive, oleic acid in water system.
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¹: Of special interest.

²: Of outstanding interest.

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Fatty acid vesicles

Abstract

Introduction

Section snippets

Dynamic formation and transformation of fatty acid vesicles

Fatty acid vesicles as protocell model

Expansion to mixed fatty acid-based vesicle systems

More detailed studies needed on fatty acid vesicles

Conclusions

Acknowledgements

J Mol Biol

Biophys J

J Am Chem Soc

J Phys Chem B

J Colloid Interface Sci

Colloid Polym Sci

Langmuir

Formation and properties of fatty acid vesicles (liposomes)

Ufasomes are stable particles surrounded by unsaturated fatty acid membranes

Nature

Liposomes from ionic, single-chain amphiphiles

Biochemistry

Ionization and phase behavior of fatty acids in water: application of the Gibbs phase rule

Biochemistry

Autopoietic self-reproduction of fatty acid vesicles

J Am Chem Soc

Membrane growth can generate a transmembrane pH gradient in fatty acid vesicles

Proc Natl Acad Sci U S A

Phase equilibria and phase structure in the ternary systems sodium or potassium octanoate–octanoic acid–water

Colloid Polym Sci

Anionic lipid headgroups as a proton-conducting pathway along the surface of membranes: a hypothesis

Proc Natl Acad Sci U S A

Autopoietic self-reproduction of chiral fatty acid vesicles

J Am Chem Soc

From decanoate micelles to decanoic acid/dodecylbenzenesulfonate vesicles

Langmuir

Investigating internal structural differences between micelles and unilamellar vesicles of decanoic acid/sodium decanoate

J Phys Chem B

Equilibrium vesicles: fact or fiction?

Colloids Surf A

Thermodynamic and kinetic stability. Properties of micelles and vesicles formed by the decanoic acid/decanoate system

Colloids Surf A

Matrix effect in the size distribution of fatty acid vesicles

J Phys Chem B

Cooperative micelle binding and matrix effect in oleate vesicle formation

J Phys Chem B

A matrix effect in mixed phospholipid/fatty acid vesicle formation

J Phys Chem B

Giant vesicle formation from oleic acid/sodium oleate on glass surfaces induced by adsorbed hydrocarbon molecules

Langmuir

Chemistry and physics of primitive membranes

Top Curr Chem

Surfactant assemblies and their various possible roles for the origin(s) of life

Orig Life Evol Biosph

Self-assembly processes in the prebiotic environment

Philos Trans R Soc Lond B Biol Sci