Lipid domain

Theoretical models of the film viscosity lead to values about 10 times smaller than those often observed [113, 114]. It may be that the experimental phenomenology is not that supposed in derivations such as those of Eqs. rV-20 and IV-22. Alternatively, it may be that virtually all of the measured surface viscosity is developed in the substrate through its interactions with the film (note Fig. IV-3). Recent hydrodynamic calculations of shape transitions in lipid domains by Stone and McConnell indicate that the transition rate depends only on the subphase viscosity [115]. Brownian motion of lipid monolayer domains also follow a fluid mechanical model wherein the mobility is independent of film viscosity but depends on the viscosity of the subphase [116]. This contrasts with the supposition that there is little coupling between the monolayer and the subphase [117] complete explanation of the film viscosity remains unresolved. 

Several groups have studied the structure of chiral phases illustrated in Fig. IV-15 [167,168]. These shapes can be understood in terms of an anisotropic line tension arising from the molecular symmetry. The addition of small amounts of cholesterol reduces X and produces thinner domains. Several studies have sought an understanding of the influence of cholesterol on lipid domain shapes [168,196]. 

While recent attention has been largely on proteins, it should be borne in mind that membrane fusion ultimately involves the merger of phospholipid bilayers. However, little is known about the specific membrane lipid requirements. When membranes fuse, energetically unfavorable transition states are generated that may require specific lipids and lipid domains for stabilization. Although there is some evidence for a specific influence of lipids on exocytosis, it is still unclear whether specific lipid metabolites are needed or even generated at the site of membrane merger. 

Jessup W, Gelissen IC, Gaus K, Kritharides L (2006) Roles of ATP binding cassette transporters Al and Gl, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages. Curr Opin Lipidol 17(3) 247-57... 

As discussed above, lipid membranes are dynamic structures with heterogeneous structure involving different lipid domains. The coexistence of different kinds of domains implies that boundaries must exist. The appearance of leaky interfacial regions, or defects, has been suggested to play a role in abrupt changes in solute permeabilities in the two-phase coexistence regions [91,92]. 

The intercellular route is considered to be the predominantly used pathway in most cases, especially when steady-state conditions in the stratum corneum are reached. In case of intercellular absorption, substance transport occurs in the bilayer-structured, continuous, intercellular lipid domain within the stratum corneum. Although this pathway is very tortuous and therefore much longer in distance than the overall thickness of the stratum corneum, the intercellular route is considered to yield much faster absorption due to the high diffusion coefficient of most drugs within the lipid bilayer. Resulting from the bilayer structure, the intercellular pathway provides hydrophilic and lipophilic regions, allowing more hydrophilic substances to use the hydrophilic and more lipophilic substances to use the lipophilic route. In addition, it is possible to influence this pathway by certain excipients in the formulation. 

Glycerophospholipids and cholesterol join together with specialized glycosyl ph osphatidylinositol—linked proteins to form lipid domains or rafts, which move together as a unit laterally through the membrane. 

This review emphasizes an intriguing and potentially useful aspect of the polymerization of lipid assemblies, i.e. polymerization and domain formation within an ensemble of molecules that is usually composed of more than one amphiphile. General aspects of domain formation in binary lipid mixtures and the polymerization of lipid bilayers are discussed in Sects. 1.1 and 1.2, respectively. More detailed reviews of these topics are available as noted. The mutual interactions of lipid domains and lipid polymerization are described in the subsequent sections. Given the proper circumstances the polymerization of lipid monolayers or bilayers can lock in the phase separation of lipids, i.e. pre-existing lipid domains within the ensemble as described in Sect. 2. Section 3 reviews the evidence for the polymerization-initiated phase separation of polymeric domains from the unpolymerized lipids. 

Epifluorescence microscopy has been fruitfully employed to characterize lipid domains in phospholipid monolayers. The sizes and shapes are dependent... 

A similar study by O Brien and coworkers utilized bilayers composed of a shorter chain diacetylenicPC (9) and DSPC or DOPC [37]. Phase separation was demonstrated in bilayers by calorimetry and photopolymerization behavior. DSC of the 9/DSPC (1 1) bilayers exhibited transitions at 40 °C and 55 °C, which were attributed to domains of the individual lipids. Polymerization at 20 °C proceeded at similar rates in the mixed bilayers and pure 9 bilayers. A dramatic hysteresis effect was observed for this system, if the bilayers were first incubated at T > 55 °C then cooled back to 20 °C, the DSC peak for the diacetylenicPC at 40 °C disappeared and the bilayers could no longer be photopolymerized. The phase transition and polymerizability of the vesicles could be restored simply by cooling to ca. 10 °C. A similar hysteretic behavior was also observed for pure diacetylenicPC bilayers. Mixtures of 9 and DOPC exhibited phase transitions for both lipids (T = — 18 °C and 39 °C) plus a small peak at intermediate temperatures. Photopolymerization at 20 °C initially proceeded at a similar rate as observed for pure 9 but slowed after 10% conversion. These results were attributed to the presence of mixed lipid domains... 

Fig. 9. Schematic representation of a polymerized phase-separated vesicle, i.e. a molecular whiffle ball. The holes are formed by removal of the nonpolymerized lipid domains by the procedures described in the text.

The authors surmised that the crosslinking polymerization of 14 resulted in the formation of only small polymers. They estimated an aggregation number, N < 10, for the domains of crosslinked 14 [43]. The careful analysis of the phase behavior of these lipids and the effect of polymerization at selected conditions coincided with the realization that polymerization of a lipid that is miscible with a second nonreactive lipid could cause phase separation of the lipids into enriched domains. This polymerization-induced lipid domain formation is considered more completely in the following section of this review. 

Klausner RD, Kleinfeld AM, Hoover RL, Kamovsky MJ Lipid domains in membranes evidence derived from structural perturbations induced by free fatty acids and lifetime heterogeneity analysis. J Biol Chem 1980 255 1286-1295. 

Miscibility of a natural lipid (DMPC) and the monomeric and polymeric lecithin analogue (26) was studied in large unilamellar vesicles using freeze-fracture electron microscopy and photobleaching by H. Gaub 100>. Before polymerization the two lipids appear miscible at all compositions in the fluid state and at DMPC concentrations at or below 50 mol/o in the solid state. After polymerization a two-dimensional solution of the polymer in DMPC is obtained at T > T (T phase transition temperature of polymeric 26) while lateral phase segregation into DMPC-rich domains and patches of the polymer is observed T < T. The diameter of the polymerized lipid domains was found to average 400 A. 

Turunen, T.M., et al. 1994. Effect of some penetration enhancers on epithelial membrane lipid domains Evidence from fluorescence spectroscopy studies. Pharm Res 11 288. 

Azone (laurocapram) is used extensively as a transdermal permeation enhancer, and has also found use in buccal drug delivery. It is a lipophilic surfactant in nature (Figure 10.4). Permeation of salicylic acid was enhanced by the pre-application of an Azone emulsion in vivo in a keratinized hamster cheek pouch model [35]. Octreotide and some hydrophobic compounds absorption have also been improved by the use of Azone [36], Azone was shown to interact with the lipid domains and alter the molecular moment on the surface of the bilayers [37], In skin it has been proposed that Azone was able to form ion pairs with anionic drugs to promote their permeation [38],... 

White, S.H., D. Mirejovsky, and G.I. King. 1988. Structure of lamellar lipid domains and corneo-cyte envelopes in murine stratum corneum An X-ray diffraction study. Biochemistry 27 3725. 

McIntosh, T.J., M.E. Stewart, and D.T. Downing. 1996. X-ray diffraction analysis of isolated skin lipids Reconstitution of intercellular lipid domains. Biochemistry 35 3649. 

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