Vesicle carriers

Transferosomes represent another system of encapsulation using ultradeformable vesicle carriers for bioactive molecules, applied until now for direct transdermal drug delivery. They are built from polar lipids and have high flexibility, and are rich in unsaturated fatty acids and carotenoid pigments." ... 

Phospholipids e.g. form spontaneously multilamellar concentric bilayer vesicles73 > if they are suspended e.g. by a mixer in an excess of aqueous solution. In the multilamellar vesicles lipid bilayers are separated by layers of the aqueous medium 74-78) which are involved in stabilizing the liposomes. By sonification they are dispersed to unilamellar liposomes with an outer diameter of 250-300 A and an internal one of 150-200 A. Therefore the aqueous phase within the liposome is separated by a bimolecular lipid layer with a thickness of 50 A. Liposomes are used as models for biological membranes and as drug carriers. 

In eukaryotes there is also evidence that Met(O) is actively transported. It has been reported that Met(O) is transported into purified rabbit intestinal and renal brush border membrane vesicles by a Met-dependent mechanism and accumulates inside the vesicles against a concentration gradient102. In both types of vesicles the rate of transport is increased with increasing concentrations of Na+ in the incubation medium. The effect of the Na+ is to increase the affinity of Met(O) for the carrier. Similar to that found in the bacterial system, the presence of Met and other amino acids in the incubation medium decreased the transport of Met(O). These results suggest that Met(O) is not transported by a unique carrier. 

A variety of other clinically important infections, such as brucellosis, listeriosis, salmonellosis, and various Mycobacterium infections, are of interest as these are often localized in organs rich in MPS cells. Liposome encapsulation has been demonstrated to improve therapeutic indices of several drugs in a number of infectious models. The natural avidity of macrophages for liposomes can also be exploited in the application of the vesicles as carriers of immunomodulators to activate these cells to an microbicidal, antiviral, or tumoricidal state. These studies were recently reviewed by Emmen and Storm (1987), Popescu et al. (1987), and Alving (1988). In addition to the treatment of "old" infectious diseases, the concept of MPS-directed drug delivery is of considerable interest for the therapy AIDS, possibly enabling control of human immunodeficiency virus replication in human macrophages. 

Gregoriadis, G. (1988a). Fate of injected liposomes Observations on entrapped solute retention, vesicle clearance and tissue distribution in vivo, in Liposomes as Drug Carriers Recent Trends and Progress (G. Gregoriadis, ed.), John Wiley and Sons, Chichester, pp. 3-18. 

As described above, because MAO is bound to mitochondrial outer membranes, MAOIs first increase the concentration of monoamines in the neuronal cytosol, followed by a secondary increase in the vesicle-bound transmitter. The enlarged vesicular pool will increase exocytotic release of transmitter, while an increase in cytoplasmic monoamines will both reduce carrier-mediated removal of transmitter from the synapse (because the favourable concentration gradient is reduced) and could even lead to net export of transmitter by the membrane transporter. That MAOIs increase the concentration of extracellular monoamines has been confirmed using intracranial microdialysis (Ferrer and Artigas 1994). 

Specific carotenoid-protein complexes have been reported in plants and invertebrates (cyanobacteria, crustaceans, silkworms, etc.), while data on the existence of carotenoproteins in vertebrates are more limited. As alternatives for their water solubilization, carotenoids could use small cytosolic carrier vesicles." Carotenoids can also be present in very fine physical dispersions (or crystalline aggregates) in aqueous media of oranges, tomatoes, and carrots. Thus these physicochemical characteristics of carotenoids as well as those of other pigments are important issues for the understanding of their bioavailability. 

As an example, let us consider a system, which contains a photocatalyst Ru(bipy) 3, in the inner volume of the vesicle, an electron carrier, e.g. cetylviologen (Cj V in the membrane, and... 

It proves possible to anchor catalysts of H2 evolution to the outer and inner surface of the vesicle membrane. These catalysts are finely dispersed (10-20 A in diameter) metal Pt or Pd particles formed via reduction of appropriate salts in vesicle suspension (see [15, 16] and refs, therein). Among the viologen-type electron carriers a promising one is p-bis (1,2,5-triphenyl-4-pyridil)benzene which possesses reduction potential low enough for water reduction at neutral pH. Recently, using this mediator we succeeded in H2 evolution conjugated with PET... 

The most important application recently developed for synthetic liposomes is as potential drug carriers for controlled release, especially for cancer chemotherapy (7). In general, the success of liposomes as vehicles for the transport of specific drugs will largely depend on their stability under physiological conditions. Unlike the naturally occurring membranes, the synthetic vesicles have very limited stability, and this is a... 

Solute uptake can also be evaluated in isolated cell suspensions, cell mono-layers, and enterocyte membrane vesicles. In these preparations, uptake is normalized by enzyme activity and/or protein concentration. While the isolation of cells in suspension preparations is an experimentally easy procedure, disruption of cell monolayers causes dedifferentiation and mucosal-to-serosal polarity is lost. While cell monolayers from culture have become a popular drug absorption screening tool, differences in drug metabolism and carrier-mediated absorption [70], export, and paracellular transport may be cell-type- and condition-depen-dent. 

H Yuasa, D Fleisher, GL Amidon. Noncompetitive inhibition of cephradine uptake by enalapril in rabbit intestinal brush-border membrane vesicles An enalapril specific inhibitory binding site on the peptide carrier. J Pharmacol Exp Ther 269 1107-1111, 1994. 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

Other systems like electroporation have no lipids that might help in membrane sealing or fusion for direct transfer of the nucleic acid across membranes they have to generate transient pores, a process where efficiency is usually directly correlated with membrane destruction and cytotoxicity. Alternatively, like for the majority of polymer-based polyplexes, cellular uptake proceeds by clathrin- or caveolin-dependent and related endocytic pathways [152-156]. The polyplexes end up inside endosomes, and the membrane disruption happens in intracellular vesicles. It is noteworthy that several observed uptake processes may not be functional in delivery of bioactive material. Subsequent intracellular obstacles may render a specific pathway into a dead end [151, 154, 156]. With time, endosomal vesicles become slightly acidic (pH 5-6) and finally fuse with and mature into lysosomes. Therefore, polyplexes have to escape into the cytosol to avoid the nucleic acid-degrading lysosomal environment, and to deliver the therapeutic nucleic acid to the active site. Either the carrier polymer or a conjugated endosomolytic domain has to mediate this process [157], which involves local lipid membrane perturbation. Such a lipid membrane interaction could be a toxic event if occurring at the cell surface or mitochondrial membrane. Thus, polymers that show an endosome-specific membrane activity are favorable. 

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