Chapter Four - Interactions of Flavonoids With Lipidic Mesophases

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Abstract

Along having various health benefits, flavonoids are increasingly being recognized as potent antioxidants and anticancer compounds. However, despite significant efforts over the last few decades to develop novel delivery systems providing higher drug bioavailability, many biofunctional aspects are still unsolved. In this chapter, we review the current knowledge on flavonoid–lipid interactions and elucidate in particular their influence on lipidic self-assembled mesophases. The interactions of flavonoids with phospholipid-based planar membranes and monoglycerides-based curved membranes are presented in detail; the main structural changes in these self-assemblies are summarized, and the correlation between membranes’ structure and function is discussed. Based on those considerations, especially the importance of membrane curvature and possible biological implications are highlighted.

Introduction

Mesophasic materials suitably describe matter that exhibits both solid and fluid-like properties. They may be fluid-like, but at the same time exhibit quasi long-range order as observed by X-ray scattering, or display anisotropic physical properties-like birefringence at a local scale. As such, liquid crystalline structures display an intermediate molecular order between that of a solid and a liquid. These thermodynamically stable structures exhibit various macroscopic properties, e.g., some mesophases spontaneously disperse into vesicles and micelles; others, instead, present a highly viscous bulk phase coexisting with excess of water. Their water/lipid interfacial surface topography can be either isotropic as in planar or spherical structures (identical principle curvatures are given) or anisotropic as in elongated tubular or bicontinuous cubic structures (differing principle curvatures are given) [1], [2].

The physical properties of liquid crystalline mesophases are mainly affected by the properties of their building blocks. Their molecular shape and charge as well as their specific interactions with each other and solvent molecules are the important factors which govern the self-assembly of various types of lipidic lyotropic mesophases [3]. Additionally, thermodynamic conditions, such as temperature and pressure, play important roles in regulating the self-assembled superstructure of molecules [4].

Self-assembly arises due to the amphiphilic nature of aggregating molecules and is driven by the hydrophobic effect [5]. In this review, we restrict ourselves to lyotropic liquid crystalline systems as given in lipid/water systems, which are well known for their extraordinarily rich polymorphism forming mesophasic structures with 1D, 2D, or 3D periodicities [6], [7], [8], [9]. Although the biological impact of this polymorphism has been widely discussed [3], [10], the implications for drug delivery are far from being exploited. The most apparent mesophases in excess water conditions concern (i) the fluid lamellar Lα phase (planar bilayers), (ii) the bicontinuous double-diamond and primitive cubic phase (V2 phases; saddle-like shaped bilayers) as well as (iii) the inverse hexagonal (H2 phase; curved monolayers), and (iv) two inverse micellar phases have been reported to resist high water concentrations, that is, one with cubic symmetry (Fd3m space group) [11], [12] and one with hexagonal closed packing (space group P63/mmc) [13]. We note that similar self-assembled structures in pure crystalline states are widely found in nature. Owing to their large lattice cell dimensions, constructive interference of scattered electromagnetic waves with a few hundred nanometres wavelength occurs. Accordingly, these photonic crystals are identified as source of color in many living species, known as structural coloration [14]. Examples of such natural appearance include a shiny green color on the wing scales of the butterfly species, Papilio palinurus [15], and a brilliant green iridescence of a weevil, Lamprocyphus augustus [16]. The lattice parameter of the natural diamond cubic phase in the latter example was found to be 450 nm.

Over the last few decades, the importance of these mesophases has been increasingly acknowledged [10], [17], [18], [19], and their utilization in the design effective delivery systems has been widely recognized [20], [21], [22], [23], [24], [25], [26], [27]. Particularly, due to their identified therapeutic potentials, the encapsulation of flavonoids is of great interest for the development of smart food and novel pharmaceutical products [21], [27], [28], [29]. Therefore, probing the interactions between flavonoids and lipid self-assemblies will help in elucidating their stability, release behavior, and bioactivity. In this chapter, we will provide perspectives toward the establishment of new strategies in formulation of novel food and drinks for the smart delivery of nutraceuticals. There have been many studies in the literature reporting the interactions of flavonoids with planar lipid membranes [30], [31], [32], [33], [34], but often the reports are not conclusive yet, and sometimes even contradicting. This review, in its first part, provides a summative view about the current knowledge available on flavonoids interactions with planar membranes. In the second part, we discuss the very few works existing on flavonoids’ interactions with curved membrane systems and highlight our most recent advances in understanding the interactions of bicontinuous cubic phases with flavonoid quercetin.

Section snippets

Flavonoids Interacting With Planar Membranes

The planar lipid bilayers are formed mainly through self-assembly of phospholipids and cholesterol, which are the most abundant constituents of the cell membrane matrix. Phospholipids, due to their special molecular structure and similar cross-sectional area in hydrophilic head group and hydrophobic tails, reveal cylindrical molecular shapes. Simple lamellar biointerface models containing phospholipids and sterols are widely applied in biophysical studies in order to mimic different

Different Curved Membranes as Mesophases in Bulk

Bicontinuous cubic phases are liquid crystalline materials, which form commonly upon self-assembly of monoglycerides in excess water. Monoglycerides are products of esterification of glycerol and fatty acids or lipolysis of vegetable oils, and thus are abundant in our daily diet. Therefore, the formation of bicontinuous cubic phases is relevant to gastrointestinal digestion [91], [92], [93]. Depending on the fat composition, temperature and pH, bicontinuous cubic (V2) and other mesophasic

Conclusions

The physicochemical properties of planar phospholipid-based membranes are explained, and the importance of interacting bioactive molecules such as flavonoids and cholesterol with fluid lamellar bilayers is elucidated. We demonstrate that flavonoids, similarly to cholesterol, have a significant influence on membrane structure and fluidity. Low flavonoids contents can be considered as impurities in the membrane and hence, increase the membrane fluidity, which is followed by an increase in

Acknowledgment

We thank Prof Brent S. Murray (School of Food Science & Nutrition, University of Leeds) and Prof Andrew Nelson (School of Chemistry, University of Leeds) for their useful discussions regarding membrane fluidity alterations with flavonoids.

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