Liposomes, lipids, and micelles

Using N-terminus modified polylysine, we developed a synthesis for an amphiphilic polychelator, A,a-(DTPA-polylysyl)glutaryl phosphatidyl ethanolamine (DTPA-PL-NGPE). This polychelator was incorporated into the liposomal membrane and micelle core during liposome or micelle preparation. This system sharply increased the number of chelated Gd atoms attached to a single lipid anchor. This increased the number of bound reporter metal atoms per vesicle and decreased the dosage of an administered... 

For decades, colloid and surface scientists have known that amphiphilic molecules such as phospholipids can self-assemble or self-organize themselves into supramolecular structures of bilayer lipid membranes (planar BLMs and spherical liposomes), emulsions, and micelles [2-4]. As a matter of fact, our current understanding of the structure and function of biomembranes can be traced to the studies of these experimental systems such as soap films and Langmuir monolayers, which have evolved as a direct consequence of applications of classical principles of colloid and interfacial chemistry. As already mentioned in Section I, the seminal work on the self-assembly of planar lipid bilayers and bilayer or black lipid membranes was carried out in 1959-1963. The idea started while one of the authors was reading a paperback edition of Soap Bubbles by C. 

A large variety of drug delivery systems are described in the literature, such as liposomes (Torchilin, 2006), micro and nanoparticles (Kumar, 2000), polymeric micelles (Torchilin, 2006), nanocrystals (Muller et al., 2011), among others. Microparticles are usually classified as microcapsules or microspheres (Figure 8). Microspheres are matrix spherical microparticles where the drug may be located on the surface or dissolved into the matrix. Microcapsules are characterized as spherical particles more than Ipm containing a core substance (aqueous or lipid), normally lipid, and are used to deliver poor soluble molecules... 

Figure 14-22. Formation of lipid membranes, micelles, emulsions, and liposomes from am-phipathic lipids, eg, phospholipids.

The relative concentration of gadolinium can be significantly increased as compared to that achievable with liposomes because the physical stability of the mixed micelles is reached for relatively low amounts of additional lipids and surfactants. It is also worth mentioning that the gadolinium-heads of the complexes embedded in micelles are all exposed to the aqueous phase and can interact directly with the water molecules of the bulk, a situation which is usually not met with liposome systems. 

Liposomes and micelles are lipid vesicles composed of self-assembled amphiphilic molecules. Amphiphiles with nonpolar tails (i.e., hydrophobic chains) self-assemble into lipid bilayers, and when appropriate conditions are present, a spherical bilayer is formed. The nonpolar interior of the bilayer is shielded by the surface polar heads and an aqueous environment is contained in the interior of the sphere (Figure 10.3A). Micelles are small vesicles composed of a shell of lipid the interior of the micelle is the hydrophobic tails of the lipid molecules (Figure 10.3B). Liposomes have been the primary form of lipid-based delivery system because they contain an aqueous interior phase that can be loaded with biomacromolecules. The ability to prepare liposomes and micelles from compounds analogous to pulmonary surfactant is frequently quoted as a major advantage of liposomes over other colloidal carrier systems. 

CL-DNA complexes form spontaneously when solutions of cationic liposomes (typically containing both a cationic lipid and a neutral helper lipid) are combined. We have discovered several distinct nanoscale structures of CL-DNA complexes by synchrotron X-ray diffraction, three of which are schematically shown in Fig. 1. These are the prevalent lamellar phase with DNA sandwiched between cationic membranes (Lo,c) [22], the inverted hexagonal phase with DNA encapsulated within inverse lipid tubes (Hnc) [23], and the more recently discovered Hj0 phase with hexagonally arranged rod-like micelles surrounded by DNA chains forming a continuous substructure with honeycomb symmetry [24]. Both the neutral lipid and the cationic lipid can drive the formation of specific structures of CL-DNA complexes. The inverse cone shape of DOPE favors formation of the... 

Lipid. Lipids or surfactants had been used widely in the delivery of pharmacologically active materials in the form of liposomes, emulsions, or micelles. Since the first description of their potential for exogenous gene transfer, much progress has been made in the development of improved cationic lipid structures and formulations with enhanced gene transfection activity. 

The existence of the hydrophobic effect [14] in the formation of micelles, liposomes and other aggregates in water has been recognized and elaborately studied for several decades. Detergents, lipids and many derivatives made from them have been extensively studied and there are numerous reviews which document these in greater detail [15]. Synthetic bilayer membranes (BLMs) have been studied for the past three decades by using a variety of physical techniques [16]. Hydrophobic interaction has also been utilized for the design of hosts that bind guest molecules in water [17]. 

Another type of self-assembly mode is based on looser molecular interactions, where one of the main binding forces comes from hydrophobic interactions in aqueous media. Amphiphihc molecules (amphiphiles) that have a hydrophihc part and a hydrophobic part form various assembhes in water and on water. The simplest example of this kind of assembly is a micelle, where amphiphiles seh-assemble in order to expose their hydrophilic part to water and shield the other part from water due to hydrophobic interactions. A similar mechanism also leads to the formation of other assembhes, such as hpid bilayers. These molecules form spherical assembhes and/or two-dimensional membranes that are composed of countless numbers of molecules. These assembhes are usually very flexible. When external signals are applied to them, they respond flexibly while maintaining their fundamental organization and shape. This research held was initiated by the work of Bangham in 1964. It was found that dispersions of hpid molecules extracted from cells in water spontaneously form cell-like assembhes (liposomes). In 1977, Kunitake and Okahata demonstrated the formation of similar assembhes from various arti-flcial amphiphiles. The latter finding showed that natural lipids and artificial amphiphiles are not fundamentally different. 

Then, perfluoropropane was entrapped within lipids like micelles. In addition, the lipid nanobubbles were encapsulated within liposomes. To confirm the structure of BLs, we observed BLs with transmission electron microscope. Interestingly, BLs had nanobubbles into lipid bilayer. Therefore, we called this Bubble liposome because of this structure. This structure of BLs was different from that of conventional microbubbles and nanobubbles which had lipid monolayer. 

Recent studies show that intracellular stability of the lipid/DNA complex and the necessary dissociation of the DNA molecule from its vector depend both on the pfCs of the chosen lipids and on the pH of the product [48]. Safinya etal. describe how not only the main cationic lipid but also the helper lipids influence the physical characteristics of the resulting Kpid phase [49]. For instance, when formulating DOTAP liposomes with Di-oleoylphosphatidylcholine (DOPC), lamellar structures are achieved. However, when exchanging DOPC for DOPE as helper lipid, inverse hexagonal micelles are produced. One may speculate whether different lipid phase characteristics lead to defined biopharmaceutical variations [50]. 

IV) PEG-lipids are used to improve pharmacokinetic properties and (V) cholesterol is used to stabilize liposomes, (b) Possible lipid aggregates for n vivo use. (I) Micelles can be prepared from micelle-forming lipids and from PEG-lipids. (II) A conventional liposome consists of a phospholipid bilayer. 

Ill) Improved stabilization of liposomes can be achieved by incorporating a small amount of PEG-lipids and cholesterol. (IV) Microemulsions consist of a surfactant (amphiphile) monolayer covering oil. (V) Micelles can contain a hydrophobic nanoparticle. (VI) Bilayer on nanoparticles of silica, mica, glass, or iron oxide. Reproduced from Mulder, W. J. M. Strijkers, G. J. van Tilborg, G. A. F. etal. NMR Biomed. 2006, 19,142. ... 

Phospholipids II micelles, liposomes, lipoproteins and membranes Lipids and iipid metaboiism 83... 

In summary, the relative activities of various antioxidants vary widely according to the site of action in different systems, the charge and solubility of components in micelle compared to emulsions, liposome systems and solutions (Table 10.16). The interfacial behavior of antioxidants varies between bulk oil and different colloidal lipid systems. For example, polar antioxidants such as Trolox are more active in mixed micelle systems consisting of emulsifiers and free fatty acids than in corn oil-in-water emulsions, where they partition mainly in the water phase (see next Section). Although linoleic acid is commonly used... 

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